proinflammatory cytokine IL-1β in the spleen and in the frontal cortex of juvenile rats[177]. Therefore, even if PS convincingly alters cellular and humoral immunity in laboratory animals, thus providing a focus for investigating stress-induced immune compromise, whether these effects are anti- or proinflammatory is currently a matter of debate.

Moreover, it has to be noted that most studies in the field mainly focused on short-term immune consequences of PS, either analyzing the immune system of the offspring immediately after birth, when it is not yet totally mature[207,309], or early in the postnatal life, during lactation[12,13,309], at weaning[13,309], or in the adolescence up to early adulthood[13,156,192,309,325]. To our knowledge, none of these reports described long-term effects of PS on the immune function later in adult life. In this view, we explored long-lasting consequences of PS on the immune competence of adult male rats and reported the development of a PS-evoked proinflammatory condition as rats reach full maturity[342]. In particular, PS increased the activity of the cellular immune system in rats at 6 months of age, evidenced by an increase in percentages of blood CD8+ and NK cells, and a higher proliferation in response to phytohemagglutinin-A *in vitro* paralleled by an increased secretion of gamma interferon (IFN-γ). Interestingly, these alterations were undetectable in younger PS rats (7 weeks old), except for a slight increase in the mRNA expression of several proinflammatory cytokines in peripheral blood mononuclear cells. Moreover, *in vivo* neutralization of IFN-γ in young rats induced a marginal increase in IgG1, but no effects on the percentage of all circulating lymphocyte subpopulations. Finally, our work indicates that such proinflammatory alterations of the basal immune surveillance develop over time as animals grow old. The functional significance of these findings (beneficial vs. detrimental) for adult and aging PS individuals towards further insults occurring later in life is still questionable; however, it appears from this report and others that the immune system of control and PS rats would not equally face infections. Considering that IFN-γ is one of the major cytokines released in the course of T helper (Th) 1-mediated immune responses that are especially recruited for facing intracellular infections[319,328], one can speculate that PS animals could be more efficient in fighting such infections; however, if confronted with conditions requiring them to mount a Th2-orientated immune response, such as a parasitic threat or allergies[57,372], these PS organisms would need more time as compared to controls to reorientate their immune system and thus such a proinflammatory profile would be damaging for the immediate survival of these individuals. In this view, neonatal maternal deprivation in rats has indeed been shown to facilitate primary infection by nematodes and to enhance gastrointestinal inflammatory responses in the adult offspring[18]. Furthermore, considering Th1-mediated immune responses, one could even fear that the proinflammatory immune profile observed at adulthood in PS rats could later favor the development of autoimmune conditions in aging PS rats. In this view, it has been shown for example that IFN-γ-deficient mice are protected against autoimmune disease of hair follicles[98]. Thus, whatever the species considered and the PS paradigm used, data from the literature clearly indicate that perturbations of the fetal development programs are both short- and long-term modifications of the immune function. In particular, PS might grant an immediate protection towards specific environmental threats, but at the expense of an increased sensitivity to autoimmunity in the long term.

## Putative Mechanisms Underlying Prenatal Stress-Evoked Immune Alterations

While examining the mechanisms underlying these reported PS-evoked alterations of immune functions in the offspring, one has to consider two hypotheses. First, as already demonstrated for other parameters of the developing organism, like for the glucose transport (see, “Role of Nutrients in Growth” above), one could suspect a defect in the feto-placental barrier and, more especially, a deficit in the passive transfer of the maternal immunity to the unborn child and/or to the neonate. However, in mice, the transplacental transfer of total and herpes simplex virus-specific IgG antibodies, and the subsequent protection of neonates towards herpes simplex virus infections, has been shown to persist despite acute maternal stress and the resulting increase in GC both in maternal and fetal organisms[375]. Similarly, the prenatal transfer of IgG in rhesus monkeys has been documented to resist both a DEX treatment and a prolonged
period of stress during pregnancy[51]. Both studies thus suggest that transplacental immunity is resilient to maternal stress, at least in rodents and primates. Moreover, if such a mechanism would trigger alterations of the immune system in PS descendants, these dysfunctions would then last until weaning, while the neonate primarily relies on the passive maternal immunity for its own immune protection. In this case, one would expect a partial (at least, if not full) recovery of the immune function in adolescent and adult individuals. In this view, such a deficit in the passive transfer of maternal immunity would not provide an explanation for the long-lasting consequences of PS on the immune function and appears not to be the main cause of the documented PS-induced alterations of immunity, thus suggesting that PS-evoked alterations in the *in utero* development of immune organs might rather be involved.

Indeed, most studies focused on GC for explaining the mechanisms by which gestational stress can have lasting consequences on the developing organism. As far as the immune system is concerned, stress at adulthood is known to influence the thymic output of CD4⁺ and CD8⁺ cells[379] on which depends the peripheral CD4⁺/CD8⁺ ratio[68]. In this view, since (1) altered circulating GC levels have been reported in PS fetuses in several PS models[32, 85, 185, 234, 322], (2) GG modulate the surface expression of CD4 and CD8 markers[369], and (3) the thymic selection of T cells is directly influenced by the level of CD4 or CD8 expression[97, 275], thus altered levels of GC occurring in PS fetuses might likely affect T cell selection and thereby the peripheral CD4⁺/CD8⁺ ratio as reported in many studies[12, 177, 192, 342]. However, besides the highly probable role of GC in programming dysfunctions of the immune system in PS progenies, one cannot exclude the involvement of other stress-related molecules, such as catecholamines. Indeed, in rodents, for example, it is well known that the sympatho-adrenal system of PS animals exhibits a greater sensitivity to stress at adulthood[364]. Since the thymus is innervated by noradrenergic fibers[83], PS might also alter the noradrenergic innervation of the developing thymus, thus affecting thymocyte selection and leading to an altered CD4⁺/CD8⁺ ratio as documented in several studies[12, 177, 192, 342]. Considering that immune cells express receptors for both hormones and neurotransmitters[280], we suggest that the altered peripheral CD4⁺/CD8⁺ ratio in young and adult PS progenies probably results from the combination of both increased circulating GC and impaired noradrenergic innervation in the fetal and neonatal developing organism. Moreover, we and others have shown that maternal perturbations do not stop at birth with the cessation of the stress protocol, but continue throughout lactation[69, 72, 307]. In most experimental paradigms, PS animals are raised by their biological mothers, which emphasizes a further potential impact of GC and other stress-related factors on thymocyte selection during the neonatal period[341], and further underlines the potential consequences of a disturbed maternal care on the setup of the immune system during the first months/years of life. In this view, one could expect a reversion of such PS-induced alterations of immune parameters by cross-fostering experiments as already demonstrated for other systems such as the HPA axis reactivity at adulthood[14, 19, 20, 202]. Finally, one has to keep in mind that PS-evoked alterations of the immune function might further enhance the dysfunctions of other physiological systems, such as the HPA axis. In this view, mice exposed to corticosterone during the last week of gestation and until weaning display an increased expression of the mRNA coding for the leukemia inhibitory factor (LIF) in the hypothalamus as well as altered emotional behaviors[243]. Since the proinflammatory cytokine LIF is known to stimulate ACTH secretion in response to emotional and inflammatory stresses[8, 48], and has been recently linked to depressive-like behaviors[244], one can thus expect that the up-regulation of the central LIF mRNA expression might further alter the reactivity of the HPA axis in PS progenies as well as their behavioral responses in the face of stressful situations. These results further underline the permanent cross-talk between nervous, immune, and endocrine systems that is highly susceptible to homeostasis perturbations.

In conclusion, taken together, these observations indicate that events of the fetal life can persistently influence the function of the immune system of individuals long after birth and tilt the balance away from health toward illness. In mammalian species that are quite totally dependent on the mother for survival, it can also make the neonate particularly vulnerable to subsequent disturbances of the maternal care, which is particularly critical in the setting up of immune functions. One has to remember, however, that the primary impact of gestational stress on the progeny aims at favoring their immediate survival as well as that of the maternal organism. In this view, sometimes the prenatal disturbance is just salient enough to
period of stress during pregnancy[51]. Both studies thus suggest that transplacental immunity is resilient to maternal stress, at least in rodents and primates. Moreover, if such a mechanism would trigger alterations of the immune system in PS descendants, these dysfunctions would then last until weaning, while the neonate primarily relies on the passive maternal immunity for its own immune protection. In this case, one would expect a partial (at least, if not full) recovery of the immune function in adolescent and adult individuals. In this view, such a deficit in the passive transfer of maternal immunity would not provide an explanation for the long-lasting consequences of PS on the immune function and appears not to be the main cause of the documented PS-induced alterations of immunity, thus suggesting that PS-evoked alterations in the *in utero* development of immune organs might rather be involved.

Indeed, most studies focused on GC for explaining the mechanisms by which gestational stress can have lasting consequences on the developing organism. As far as the immune system is concerned, stress at adulthood is known to influence the thymic output of CD4⁺ and CD8⁺ cells[379] on which depends the peripheral CD4⁺/CD8⁺ ratio[68]. In this view, since (1) altered circulating GC levels have been reported in PS fetuses in several PS models[32,85,185,234,322], (2) GG modulate the surface expression of CD4 and CD8 markers[369], and (3) the thymic selection of T cells is directly influenced by the level of CD4 or CD8 expression[97,275], thus altered levels of GC occurring in PS fetuses might likely affect T cell selection and thereby the peripheral CD4⁺/CD8⁺ ratio as reported in many studies[12,177,192,342]. However, besides the highly probable role of GC in programming dysfunctions of the immune system in PS progenies, one cannot exclude the involvement of other stress-related molecules, such as catecholamines. Indeed, in rodents, for example, it is well known that the sympatho-adrenal system of PS animals exhibits a greater sensitivity to stress at adulthood[364]. Since the thymus is innervated by noradrenergic fibers[83], PS might also alter the noradrenergic innervation of the developing thymus, thus affecting thymocyte selection and leading to an altered CD4⁺/CD8⁺ ratio as documented in several studies[12,177,192,342]. Considering that immune cells express receptors for both hormones and neurotransmitters[280], we suggest that the altered peripheral CD4⁺/CD8⁺ ratio in young and adult PS progenies probably results from the combination of both increased circulating GC and impaired noradrenergic innervation in the fetal and neonatal developing organism. Moreover, we and others have shown that maternal perturbations do not stop at birth with the cessation of the stress protocol, but continue throughout lactation[69,72,307]. In most experimental paradigms, PS animals are raised by their biological mothers, which emphasizes a further potential impact of GC and other stress-related factors on thymocyte selection during the neonatal period[341], and further underlines the potential consequences of a disturbed maternal care on the setup of the immune system during the first months/years of life. In this view, one could expect a reversion of such PS-induced alterations of immune parameters by cross-fostering experiments as already demonstrated for other systems such as the HPA axis reactivity at adulthood[14,19,20,202]. Finally, one has to keep in mind that PS-evoked alterations of the immune function might further enhance the dysfunctions of other physiological systems, such as the HPA axis. In this view, mice exposed to corticosterone during the last week of gestation and until weaning display an increased expression of the mRNA coding for the leukemia inhibitory factor (LIF) in the hypothalamus as well as altered emotional behaviors[243]. Since the proinflammatory cytokine LIF is known to stimulate ACTH secretion in response to emotional and inflammatory stresses[8,48], and has been recently linked to depressive-like behaviors[244], one can thus expect that the up-regulation of the central LIF mRNA expression might further alter the reactivity of the HPA axis in PS progenies as well as their behavioral responses in the face of stressful situations. These results further underline the permanent cross-talk between nervous, immune, and endocrine systems that is highly susceptible to homeostasis perturbations.

In conclusion, taken together, these observations indicate that events of the fetal life can persistently influence the function of the immune system of individuals long after birth and tilt the balance away from health toward illness. In mammalian species that are quite totally dependent on the mother for survival, it can also make the neonate particularly vulnerable to subsequent disturbances of the maternal care, which is particularly critical in the setting up of immune functions. One has to remember, however, that the primary impact of gestational stress on the progeny aims at favoring their immediate survival as well as that of the maternal organism. In this view, sometimes the prenatal disturbance is just salient enough to
shift the regulatory set points of the physiological systems that will mature later after birth, such as the adaptive immune response. But in other cases of more severe gestational perturbations, the impact is so potent that the trajectory of fetal development is derailed towards pathology. Our research in rodents indicates that chronic maternal stress during gestation has this type of saliency, capable of leaving a lasting mark on behavior and physiology that can persist into adulthood, and eventually program lasting immune dysfunctions that might render individuals more susceptible to autoimmunity. Thus, such studies further support the hypothesis that pathologies of the adulthood, including those of the immune system, can be programmed during prenatal/perinatal life as previously suggested by Barker[17] and others.

## PRENATAL STRESS AND THE PROGRAMMING OF DISEASES OF THE ADULT

The role of PS in the programming of adult diseases has gained importance over the past decades since the initial work of Barker[17]. Indeed, a limited supply of nutrients during the course of fetal development has been associated with the occurrence of coronary heart diseases and related disorders in adults. For obvious ethical and methodological concerns, animal models of gestational stress have been widely used for deciphering the mechanisms of PS-programmed diseases of the adult[223]. Notwithstanding the role of PS in the development of mood-related and metabolic diseases, the evolutionary role of all modifications observed in the fetuses of stressed mothers must be underlined. Up to now, PS has mostly been considered as deleterious for the survival of individuals. The question needs to be discussed in terms of adaptation in a truly unfavorable environment from an ecological perspective. In fact, most studies conducted on PS animal models have been performed within strict and controlled laboratory conditions that are usually distant from natural living conditions of the species considered. Moreover, data obtained from human cohorts are often inconsistent, as previously mentioned. As a consequence, one has to keep in mind these restrictions during the present discussion.

## Prenatal Stress and the Occurrence of Mood-Related Disorders

Among PS-induced disturbances, modifications of emotional behavior are often described in various species, including humans[365,366]. In fact, in most animal models, numerous alterations reported in PS offspring are highly similar to human symptoms of anxiety and depression. As an example, adult PS rats exhibit alterations of circadian rhythms and a higher vulnerability to drugs that are classically associated with increased anxiety or depression-like behaviors[75,203,216,366] (see also "PS and the Programming of the HPA Axis" above). Similarly, behaviors classically disrupted in schizophrenic patients, like the sensorimotor gating reflected by the prepulse inhibition and the sensory gating reflected in measures of the N40 auditory evoked potential, have been described in rodent progenies whose mothers were exposed to infection or to a variable stress paradigm[164,212]. In humans, a tight connection between early stress exposure and the occurrence of anxiety disorders during adolescence has been evidenced[251]. The Avon Longitudinal Study of Parents and Children revealed that mood disturbances in pregnancy, anxiety and/or depression, are associated with altered salivary cortisol levels in 10-year-old children[230] and result in lasting disturbances of sleep in toddlers, like nighttime waking, nightmares, or difficulties in falling asleep[231]. In another cohort, the Dutch Hunger Winter Study, the sharply defined period of famine has been associated with an increased risk of hospital treatment for major affective disorders[30]. Moreover, this study provides accurate data on the impact of middle-to-late gestational nutritional deficiency in the etiology of major affective disorders, like unipolar or bipolar depression, which affects both men and women, although the effects appear to be somewhat weaker in the latter. These data further underline the high prevalence of the risk of schizophrenia and of schizoid/schizotypal personality disorder in the birth cohort exposed to a severe famine during early gestation as initially showed by Susser and coworkers[317,318]. Such a disorder has been associated with increased brain abnormalities, predominantly white matter hyperintensities[145]. Altogether, these results highlight the possible existence of a continuum of psychiatric diseases, from affective disorders to schizophrenia, whose type
shift the regulatory set points of the physiological systems that will mature later after birth, such as the adaptive immune response. But in other cases of more severe gestational perturbations, the impact is so potent that the trajectory of fetal development is derailed towards pathology. Our research in rodents indicates that chronic maternal stress during gestation has this type of saliency, capable of leaving a lasting mark on behavior and physiology that can persist into adulthood, and eventually program lasting immune dysfunctions that might render individuals more susceptible to autoimmunity. Thus, such studies further support the hypothesis that pathologies of the adulthood, including those of the immune system, can be programmed during prenatal/perinatal life as previously suggested by Barker[17] and others.

## PRENATAL STRESS AND THE PROGRAMMING OF DISEASES OF THE ADULT

The role of PS in the programming of adult diseases has gained importance over the past decades since the initial work of Barker[17]. Indeed, a limited supply of nutrients during the course of fetal development has been associated with the occurrence of coronary heart diseases and related disorders in adults. For obvious ethical and methodological concerns, animal models of gestational stress have been widely used for deciphering the mechanisms of PS-programmed diseases of the adult[223]. Notwithstanding the role of PS in the development of mood-related and metabolic diseases, the evolutionary role of all modifications observed in the fetuses of stressed mothers must be underlined. Up to now, PS has mostly been considered as deleterious for the survival of individuals. The question needs to be discussed in terms of adaptation in a truly unfavorable environment from an ecological perspective. In fact, most studies conducted on PS animal models have been performed within strict and controlled laboratory conditions that are usually distant from natural living conditions of the species considered. Moreover, data obtained from human cohorts are often inconsistent, as previously mentioned. As a consequence, one has to keep in mind these restrictions during the present discussion.

## Prenatal Stress and the Occurrence of Mood-Related Disorders

Among PS-induced disturbances, modifications of emotional behavior are often described in various species, including humans[365,366]. In fact, in most animal models, numerous alterations reported in PS offspring are highly similar to human symptoms of anxiety and depression. As an example, adult PS rats exhibit alterations of circadian rhythms and a higher vulnerability to drugs that are classically associated with increased anxiety or depression-like behaviors[75,203,216,366] (see also "PS and the Programming of the HPA Axis" above). Similarly, behaviors classically disrupted in schizophrenic patients, like the sensorimotor gating reflected by the prepulse inhibition and the sensory gating reflected in measures of the N40 auditory evoked potential, have been described in rodent progenies whose mothers were exposed to infection or to a variable stress paradigm[164,212]. In humans, a tight connection between early stress exposure and the occurrence of anxiety disorders during adolescence has been evidenced[251]. The Avon Longitudinal Study of Parents and Children revealed that mood disturbances in pregnancy, anxiety and/or depression, are associated with altered salivary cortisol levels in 10-year-old children[230] and result in lasting disturbances of sleep in toddlers, like nighttime waking, nightmares, or difficulties in falling asleep[231]. In another cohort, the Dutch Hunger Winter Study, the sharply defined period of famine has been associated with an increased risk of hospital treatment for major affective disorders[30]. Moreover, this study provides accurate data on the impact of middle-to-late gestational nutritional deficiency in the etiology of major affective disorders, like unipolar or bipolar depression, which affects both men and women, although the effects appear to be somewhat weaker in the latter. These data further underline the high prevalence of the risk of schizophrenia and of schizoid/schizotypal personality disorder in the birth cohort exposed to a severe famine during early gestation as initially showed by Susser and coworkers[317,318]. Such a disorder has been associated with increased brain abnormalities, predominantly white matter hyperintensities[145]. Altogether, these results highlight the possible existence of a continuum of psychiatric diseases, from affective disorders to schizophrenia, whose type
and severity may be related to the gestational timing when famine occurs. In addition, a rising incidence in autism has been noticed since the early 1980s that cannot be explained only by the change in diagnostic criteria[262]. Although this neurodevelopmental disorder is considered to be one of the most genetically determined, industrialization of our modern societies has triggered dramatic modifications in the prenatal environment that have been hypothesized to account also for the increased occurrence of this psychiatric disease[262]. Among factors implicated in the etiology of autism, the hyperdopaminergic state is commonly pointed out[1,273]. In this view, chronically elevated maternal dopamine through diet, exposure to toxins like mercury (vaccines, dental amalgams, etc.), medications, illness/fever, or psychosocial stress can significantly heighten the risk for autism[262]. Beyond the associated impact of pollution and toxins, one may underline the role of diet since, as mentioned earlier, it has been crucial in the hominid evolution. We currently eat more meat and more proteins that provide larger amounts of amino acids like tyrosine. This increased supply in tyrosine and/or phenylalanine to the brain can thus augment the synthesis of dopamine. Hence, the increased rate of autism in our industrialized societies might be not only due to genetic deficits or a better DMS IV diagnosis, but to combined factors chronically affecting the mother during pregnancy.

In conclusion, both animal models and studies conducted on human cohorts clearly suggest that PS may be at the origin of neurodevelopmental modifications that later lead to amended emotional behavior, such adverse effects being mediated by alterations of the early neuroendocrine programming. These behavioral responses were probably adapted to a formely hostile environment where a higher vigilance, an augmented response to stress, and/or an increased anxiety would have favored the immediate survival of individuals. However, nowadays, such behaviors appear to be inadequate in our urbanized societies where, in the absence of predators, the “*struggle for life*” does not exist anymore with the same physical intensity. The resulting deficiencies may alter social integration of such PS individuals and eventually lead to the development of affective disorders that can give rise to more severe psychopathologies.

## Prenatal Stress and the Occurrence of Metabolic Disorders

Substantial evidences emphasize the association between a too-small birth weight, an index of poor fetal growth, and/or preterm delivery, with elevated risks of developing metabolic disorders at adulthood[16,17,304]. In this view, the metabolic syndrome, characterized by the occurrence of glucose intolerance associated with impaired insulin action or insulin resistance, hypertriglyceridemia, and hypertension has been related to a small birth weight[250]. These diseases have also been associated with chronically elevated levels of plasma GC[288].

### Type II Diabetes

In rodents, an association between a low birth weight and the subsequent development of type II diabetes has been shown in the adult offspring generated from mothers exposed to food restriction or emotional stress, like restraint during gestation[107, 126, 128, 185]. In particular, Lesage and coworkers[185] demonstrated that PS rats aged 24 months exhibit hyperglycemia under basal conditions and after a glucose load, but no variation in insulinemia. These changes reflect the occurrence of type II diabetes. Further evidences of a determining role of the fetal environment in the susceptibility towards type II diabetes arose from an epidemiological study among men in their 60s[125]. Men who displayed both lower birth weights and lower weights at 1 year of age were more likely to develop poor glucose tolerance and type II diabetes at adulthood. In support of these data, twin studies have demonstrated discordances for type II diabetes with the diabetic twin having a significantly lower birth weight than his nondiabetic sibling regardless of zygosity[259]. The causes of this metabolic disease remain incompletely elucidated, however. Besides the data highlighting the influence of the fetal environment on the occurrence of diabetes in old age, Hattersley and Tooke[130] proposed the “*Fetal Insulin Hypothesis*”, which associates both impaired fetal growth and susceptibility to type II diabetes at adulthood with genetically determined
and severity may be related to the gestational timing when famine occurs. In addition, a rising incidence in autism has been noticed since the early 1980s that cannot be explained only by the change in diagnostic criteria[262]. Although this neurodevelopmental disorder is considered to be one of the most genetically determined, industrialization of our modern societies has triggered dramatic modifications in the prenatal environment that have been hypothesized to account also for the increased occurrence of this psychiatric disease[262]. Among factors implicated in the etiology of autism, the hyperdopaminergic state is commonly pointed out[1,273]. In this view, chronically elevated maternal dopamine through diet, exposure to toxins like mercury (vaccines, dental amalgams, etc.), medications, illness/fever, or psychosocial stress can significantly heighten the risk for autism[262]. Beyond the associated impact of pollution and toxins, one may underline the role of diet since, as mentioned earlier, it has been crucial in the hominid evolution. We currently eat more meat and more proteins that provide larger amounts of amino acids like tyrosine. This increased supply in tyrosine and/or phenylalanine to the brain can thus augment the synthesis of dopamine. Hence, the increased rate of autism in our industrialized societies might be not only due to genetic deficits or a better DMS IV diagnosis, but to combined factors chronically affecting the mother during pregnancy.

In conclusion, both animal models and studies conducted on human cohorts clearly suggest that PS may be at the origin of neurodevelopmental modifications that later lead to amended emotional behavior, such adverse effects being mediated by alterations of the early neuroendocrine programming. These behavioral responses were probably adapted to a formely hostile environment where a higher vigilance, an augmented response to stress, and/or an increased anxiety would have favored the immediate survival of individuals. However, nowadays, such behaviors appear to be inadequate in our urbanized societies where, in the absence of predators, the “*struggle for life*” does not exist anymore with the same physical intensity. The resulting deficiencies may alter social integration of such PS individuals and eventually lead to the development of affective disorders that can give rise to more severe psychopathologies.

## Prenatal Stress and the Occurrence of Metabolic Disorders

Substantial evidences emphasize the association between a too-small birth weight, an index of poor fetal growth, and/or preterm delivery, with elevated risks of developing metabolic disorders at adulthood[16,17,304]. In this view, the metabolic syndrome, characterized by the occurrence of glucose intolerance associated with impaired insulin action or insulin resistance, hypertriglyceridemia, and hypertension has been related to a small birth weight[250]. These diseases have also been associated with chronically elevated levels of plasma GC[288].

### Type II Diabetes

In rodents, an association between a low birth weight and the subsequent development of type II diabetes has been shown in the adult offspring generated from mothers exposed to food restriction or emotional stress, like restraint during gestation[107, 126, 128, 185]. In particular, Lesage and coworkers[185] demonstrated that PS rats aged 24 months exhibit hyperglycemia under basal conditions and after a glucose load, but no variation in insulinemia. These changes reflect the occurrence of type II diabetes. Further evidences of a determining role of the fetal environment in the susceptibility towards type II diabetes arose from an epidemiological study among men in their 60s[125]. Men who displayed both lower birth weights and lower weights at 1 year of age were more likely to develop poor glucose tolerance and type II diabetes at adulthood. In support of these data, twin studies have demonstrated discordances for type II diabetes with the diabetic twin having a significantly lower birth weight than his nondiabetic sibling regardless of zygosity[259]. The causes of this metabolic disease remain incompletely elucidated, however. Besides the data highlighting the influence of the fetal environment on the occurrence of diabetes in old age, Hattersley and Tooke[130] proposed the “*Fetal Insulin Hypothesis*”, which associates both impaired fetal growth and susceptibility to type II diabetes at adulthood with genetically determined
insulin resistance. However, this alternative hypothesis has been criticized, for no association with birth weight has been documented in cases of polymorphisms known to be associated with insulin resistance [84]. Consequently, even if genetic polymorphisms may have an impact in the development of diabetes, the impaired fetal growth caused by an altered gestational environment has stronger influences on the apparition of the disease. In this view, future research should assess the relative contributions of genetic factors and the fetal environment in the occurrence of low-birth-weight offspring.

## Obesity

Like for type II diabetes, a small birth weight has also been associated with another component of the metabolic syndrome, namely the central obesity [250]. However, the occurrence of this disease certainly hinges on the intrauterine development as well as on postnatal influences. In fact, biological features of obesity like hyperphagia, increased plasma leptin, hyperglycemia, or adipocyte hypertrophy are associated with a rapid neonatal catch-up growth after maternal nutrient restriction during gestation [24,76]. On the contrary, maternal food restriction during lactation triggers a delayed catch-up growth, restoring biological features to control levels with normal body fat and plasma leptin. Thus, the programming of obesity and related disorders in the offspring may depend on the maternal environment as well as on the timing of nutrient reduction and/or nutrient availability throughout the perinatal development. Moreover, as stressed out by Prentice [261], the early programming of the “fat-brain axis” is not comparable between humans and rodents. Indeed, the appetite regulatory system and the feedback loops from adipose tissues seem to be set up prenatally in humans, but not in rodents. Therefore, except for a study showing a higher obesity among young men whose mothers endured the Dutch winter famine during the first and second trimester of pregnancy [268], the link between prenatal undernutrition and the further development of obesity at adulthood is tenuous and inconsistent. Conversely, more consistent data gathered in humans suggest a predisposition to hyperphagia and obesity in relation to a higher maternal weight gain during pregnancy and/or an early postnatal overfeeding [261]. Finally, one can also mention an anecdotic link between maternal diet and PS consequences on infant temperament [267]. Indeed, mothers who reported consuming chocolate daily rated their infants at 6 months of age as more positively reactive and active. Moreover, while PS predicted more negatively tuned maternal ratings of the infant temperament, this effect was not observed in stressed mothers who reported weekly or daily chocolate consumption. These data are among the first to suggest a positive impact of a particular kind of food to reverse some PS negative effects on the progeny.

## Cardiovascular Diseases

Another component of metabolic diseases also linked to a small birth weight is arterial hypertension. In humans, increases in both diastolic and systolic blood pressure and heart rate have been described following a mild psychological stressor in women who were smaller at birth, but not in men, suggesting an *in utero* programming of cardiovascular reactivity [351]. Moreover, a rapid postnatal growth has been described to diminish the longevity. In rats, the life span is adversely affected when animals exhibit a rapid catch-up growth following *in utero* growth restriction; in humans, similar effects of the catch-up growth are observed with adverse long-term outcomes in terms of blood pressure or death from cardiovascular diseases [127]. In fact, maternal hypoxia, malnutrition, or restraint stress lead to offspring with similar cardiovascular responses to acute stress at adulthood and no basal differences in hemodynamics [147,249,327]. In particular, adult PS animals exposed to acute mild stress present with an increased systolic blood pressure with an extended recovery delay. In general, PS female offspring display a greater and more prolonged cardiovascular response than males [147]. This impaired responsiveness to an adverse environment could be deleterious in the long term, especially in the case of chronic stress leading to arterial hypertension. High levels of maternal GC are thought to later program cardiovascular diseases. Indeed, GC are known to increase blood pressure in adult animals [337].
insulin resistance. However, this alternative hypothesis has been criticized, for no association with birth weight has been documented in cases of polymorphisms known to be associated with insulin resistance [84]. Consequently, even if genetic polymorphisms may have an impact in the development of diabetes, the impaired fetal growth caused by an altered gestational environment has stronger influences on the apparition of the disease. In this view, future research should assess the relative contributions of genetic factors and the fetal environment in the occurrence of low-birth-weight offspring.

## Obesity

Like for type II diabetes, a small birth weight has also been associated with another component of the metabolic syndrome, namely the central obesity [250]. However, the occurrence of this disease certainly hinges on the intrauterine development as well as on postnatal influences. In fact, biological features of obesity like hyperphagia, increased plasma leptin, hyperglycemia, or adipocyte hypertrophy are associated with a rapid neonatal catch-up growth after maternal nutrient restriction during gestation [24,76]. On the contrary, maternal food restriction during lactation triggers a delayed catch-up growth, restoring biological features to control levels with normal body fat and plasma leptin. Thus, the programming of obesity and related disorders in the offspring may depend on the maternal environment as well as on the timing of nutrient reduction and/or nutrient availability throughout the perinatal development. Moreover, as stressed out by Prentice [261], the early programming of the “fat-brain axis” is not comparable between humans and rodents. Indeed, the appetite regulatory system and the feedback loops from adipose tissues seem to be set up prenatally in humans, but not in rodents. Therefore, except for a study showing a higher obesity among young men whose mothers endured the Dutch winter famine during the first and second trimester of pregnancy [268], the link between prenatal undernutrition and the further development of obesity at adulthood is tenuous and inconsistent. Conversely, more consistent data gathered in humans suggest a predisposition to hyperphagia and obesity in relation to a higher maternal weight gain during pregnancy and/or an early postnatal overfeeding [261]. Finally, one can also mention an anecdotic link between maternal diet and PS consequences on infant temperament [267]. Indeed, mothers who reported consuming chocolate daily rated their infants at 6 months of age as more positively reactive and active. Moreover, while PS predicted more negatively tuned maternal ratings of the infant temperament, this effect was not observed in stressed mothers who reported weekly or daily chocolate consumption. These data are among the first to suggest a positive impact of a particular kind of food to reverse some PS negative effects on the progeny.

## Cardiovascular Diseases

Another component of metabolic diseases also linked to a small birth weight is arterial hypertension. In humans, increases in both diastolic and systolic blood pressure and heart rate have been described following a mild psychological stressor in women who were smaller at birth, but not in men, suggesting an *in utero* programming of cardiovascular reactivity [351]. Moreover, a rapid postnatal growth has been described to diminish the longevity. In rats, the life span is adversely affected when animals exhibit a rapid catch-up growth following *in utero* growth restriction; in humans, similar effects of the catch-up growth are observed with adverse long-term outcomes in terms of blood pressure or death from cardiovascular diseases [127]. In fact, maternal hypoxia, malnutrition, or restraint stress lead to offspring with similar cardiovascular responses to acute stress at adulthood and no basal differences in hemodynamics [147,249,327]. In particular, adult PS animals exposed to acute mild stress present with an increased systolic blood pressure with an extended recovery delay. In general, PS female offspring display a greater and more prolonged cardiovascular response than males [147]. This impaired responsiveness to an adverse environment could be deleterious in the long term, especially in the case of chronic stress leading to arterial hypertension. High levels of maternal GC are thought to later program cardiovascular diseases. Indeed, GC are known to increase blood pressure in adult animals [337].
Similarly, patients with Cushings syndrome (chronic overproduction of cortisol) are frequently hypertensive[368]. Different experiments were carried out to demonstrate the role of elevated maternal GC on the development of hypertension in the offspring. In particular, the treatment of undernourished (low protein diets) gestating rats with metapyrone (an inhibitor of 11β-hydroxylase) inhibits the corticosterone synthesis in both the dam and fetuses, thus preventing the development of hypertension in the adult PS offspring[172]. The effects of an excess maternal GC might be direct or indirect, acting, for example, at the hypothalamic level (AVP neurons of the PVN) or at the level of vascular smooth muscle cells, like thoracic aorta, where binding of GC on type II receptor augments artery resistance, thus eliciting increased blood pressure[171,292]. Moreover, GC can also modify the development and maturation of specific organs involved in the control and maintenance of blood pressure[295]. In this view, a low maternal weight at the end of pregnancy and a low birth weight have been associated with a decreased arterial compliance capacity associated with a reduced vessel size in individuals born as term singletons around the period of the Dutch famine whereas no change on the carotid size or stiffness has been observed in the descendants[240].

Since neuroendocrine and physiological modifications induced by the deleterious maternal environment may give PS offspring the ability to survive in a poor milieu, i.e., where a catch-up growth is impossible, the above-reported data account for an indirect support of the evolutionary significance of PS alterations. In this view, one may speculate that an immediate prevention of the rapid neonatal catch-up growth in PS infants may reduce the risk of adult-onset obesity and its related disorders, like hypertension and type II diabetes.

## Is Prenatal Stress Programming of Adult Diseases Mandatory?

As mentioned in the previous sections, the severity of the disorders displayed by the PS offspring is a function of the developmental window at which the maternal stress occurs. Nevertheless, several data obtained in both rodents and humans point out the importance of the postnatal environment on the offspring development. In rats, the role of early environmental events, like infantile stimulation (or handling), has been clearly established in the optimal development of the progeny[186,310,326,363]. Indeed, repeated short-duration handlings of pups appear to exert a positive long-term effect on their HPA axis reactivity when faced with stressors in comparison with nonhandled animals[187,335]. It has been suggested that the effects of handling are mediated by changes in maternal care, like increases in the licking/grooming of handled pups by the mother[191]. In fact, newborn rodents, virtually immobile and incapable of body temperature maintenance, are strongly dependent on the initiation of a specific set of maternal behaviors for their survival that include, for example, sniffing and exploration of pups, mouthing, pup retrieval, and nursing[264]. Moreover, a direct relationship between maternal care and postnatal individual differences in behavioral and HPA axis responses to stress has been established[93,96,104]. In a restraint PS rat model, early adoption of the offspring, irrespective of the stress experience of the foster mother, reverses the effects of PS; adoption *per se* increases maternal behavior and decreases the HPA axis activity in the adult offspring following acute stress[14,70,202]. In mammals, the maternal behavior, whose initiation and maintenance involve specific neural circuits controlled by various genetic factors, is a highly conserved set of behavioral capacities that are crucial for the reproductive success[181]. Variations in maternal, and more generally parental, care early in the life of the offspring might durably influence their development and vulnerability to illness throughout life[37,151]. In a rat model of high maternal care (high vs. low licking/arched-back nursing dams, LG-ABN), the offspring exhibit differences in the behavior (low emotionality), neurobiology (high levels of GABAa receptor in amygdala and locus coeruleus), and neuroendocrine responses to stress (reduced plasma ACTH and corticosterone, enhanced GC feedback) in comparison with offspring from low maternal care dams[35,36,44,45,92,93,94,95]. These data support the hypothesis of a programming of the offspring’s neuroendocrine and behavioral responses to stress mediated by the behavior of the mother. Furthermore, such a maternal influence on the programming of the progeny has been reinforced by recent
Similarly, patients with Cushings syndrome (chronic overproduction of cortisol) are frequently hypertensive[368]. Different experiments were carried out to demonstrate the role of elevated maternal GC on the development of hypertension in the offspring. In particular, the treatment of undernourished (low protein diets) gestating rats with metapyrone (an inhibitor of 11β-hydroxylase) inhibits the corticosterone synthesis in both the dam and fetuses, thus preventing the development of hypertension in the adult PS offspring[172]. The effects of an excess maternal GC might be direct or indirect, acting, for example, at the hypothalamic level (AVP neurons of the PVN) or at the level of vascular smooth muscle cells, like thoracic aorta, where binding of GC on type II receptor augments artery resistance, thus eliciting increased blood pressure[171,292]. Moreover, GC can also modify the development and maturation of specific organs involved in the control and maintenance of blood pressure[295]. In this view, a low maternal weight at the end of pregnancy and a low birth weight have been associated with a decreased arterial compliance capacity associated with a reduced vessel size in individuals born as term singletons around the period of the Dutch famine whereas no change on the carotid size or stiffness has been observed in the descendants[240].

Since neuroendocrine and physiological modifications induced by the deleterious maternal environment may give PS offspring the ability to survive in a poor milieu, i.e., where a catch-up growth is impossible, the above-reported data account for an indirect support of the evolutionary significance of PS alterations. In this view, one may speculate that an immediate prevention of the rapid neonatal catch-up growth in PS infants may reduce the risk of adult-onset obesity and its related disorders, like hypertension and type II diabetes.

Is Prenatal Stress Programming of Adult Diseases Mandatory?

As mentioned in the previous sections, the severity of the disorders displayed by the PS offspring is a function of the developmental window at which the maternal stress occurs. Nevertheless, several data obtained in both rodents and humans point out the importance of the postnatal environment on the offspring development. In rats, the role of early environmental events, like infantile stimulation (or handling), has been clearly established in the optimal development of the progeny[186,310,326,363]. Indeed, repeated short-duration handlings of pups appear to exert a positive long-term effect on their HPA axis reactivity when faced with stressors in comparison with nonhandled animals[187,335]. It has been suggested that the effects of handling are mediated by changes in maternal care, like increases in the licking/grooming of handled pups by the mother[191]. In fact, newborn rodents, virtually immobile and incapable of body temperature maintenance, are strongly dependent on the initiation of a specific set of maternal behaviors for their survival that include, for example, sniffing and exploration of pups, mouthing, pup retrieval, and nursing[264]. Moreover, a direct relationship between maternal care and postnatal individual differences in behavioral and HPA axis responses to stress has been established[93,96,104]. In a restraint PS rat model, early adoption of the offspring, irrespective of the stress experience of the foster mother, reverses the effects of PS; adoption *per se* increases maternal behavior and decreases the HPA axis activity in the adult offspring following acute stress[14,70,202]. In mammals, the maternal behavior, whose initiation and maintenance involve specific neural circuits controlled by various genetic factors, is a highly conserved set of behavioral capacities that are crucial for the reproductive success[181]. Variations in maternal, and more generally parental, care early in the life of the offspring might durably influence their development and vulnerability to illness throughout life[37,151]. In a rat model of high maternal care (high vs. low licking/arched-back nursing dams, LG-ABN), the offspring exhibit differences in the behavior (low emotionality), neurobiology (high levels of GABAa receptor in amygdala and locus coeruleus), and neuroendocrine responses to stress (reduced plasma ACTH and corticosterone, enhanced GC feedback) in comparison with offspring from low maternal care dams[35,36,44,45,92,93,94,95]. These data support the hypothesis of a programming of the offspring’s neuroendocrine and behavioral responses to stress mediated by the behavior of the mother. Furthermore, such a maternal influence on the programming of the progeny has been reinforced by recent
data showing that offspring from high-LG-ABN mothers exhibited differences in DNA methylation, as compared to offspring from low-LG-ABN mothers[359]. These effects emerge over the first week of life, persist into adulthood, are reversed with cross-fostering, and are associated with altered histone acetylation and transcription factor binding to the GC receptor promoter. DNA methylation thus alters GC receptor expression through modifications of the chromatin structure[211,359,360,361,362]. In line with these arguments, Cameron and coworkers[37] suggested the existence of a phenotypic plasticity associated, for example, with parental investment that may be greater in more complex species like mammals. However, the influence of the maternal exposure to adverse environments on the mother-offspring interaction appears to be a common feature across all species caring for their young. In such a situation of adversity, the development of defensive responses to threats and/or of reproductive strategies might be altered in the progeny. Furthermore, epidemiological studies suggest that environmental adversity can alter parental care and thus influence child development. Similarly, in rodents, restraint stress during gestation exerts lasting effects on emotional reactivity of the dams, characterized by a higher anxiety and less care to the offspring[69]. In another model of PS in rodents, gestational stress can directly alter maternal care *via* the neuroendocrine systems that normally regulate this behavior[45]. These data also stress a nongenomic transmission mechanism of the effects of environmental adversity on maternal care across generations. Taken together, these studies emphasize the critical influence of parental care, especially after birth when children or pups develop or achieve their development. Deficits in parental attention combined to PS may have deeper effects on the offspring’s development, resulting in emotional and/or cognitive anomalies. As suggested by Hinde[137], natural selection has shaped the offspring to subtle changes in parental behaviors as a forecast of the environmental conditions they will face following separation from the parents. Besides the importance of parental care, an enriched environment at birth and until weaning can also reverse PS deleterious consequences by restoring abnormal behaviors like emotional reactivity or motor skills[46]. In fact, rat offspring reared in an enriched environment display increased social and play behaviors, a reduced emotionality, a reversion of several immunological alterations, and a decrease in the enhanced morphine-induced place preference[177,214,374]. Moreover, a longitudinal cross-housing study reveals that the postnatal environment could attenuate the effects of the prenatal condition on cognitive functions and more especially on synaptic structural changes in the hippocampus, with a higher immunoreactivity of neural cell adhesion molecule (NCAM), BDNF, and synaptic-vesicle protein (SYP), markers of neuronal and/or synapses development[166]. Indeed, a small hippocampal volume has been associated with both low birth weight and low maternal care in human females[34]. Thus, the detrimental effects of PS can be counteracted by an enriched stimulating environment after birth. The beneficial effect of enriched environment on brain development and behavior is corroborated by data from an animal model of autism induced by prenatal exposure to valproic acid. Specific environmental experiences, such as behavioral-cognitive therapy, might then attenuate autistic features and favor damage rehabilitation[188,290].

In conclusion, the gestational and early postnatal maternal programming appears to have contributed to the adaptation and survival of species in ever-changing environments. Such developmental responses have been conserved and have likely contributed to the epidemic occurrence of the metabolic syndrome, and the development of various mood disorders or psychiatric diseases. Several questions remain in abeyance, however, for a clear understanding of the mechanisms that can regulate and/or modify this maternal programming. In the developmental environmental context, such a fetal and/or neonatal plasticity might be used as windows of opportunity to prevent potential detrimental effects of maternal programming and/or enhance its beneficial impacts.
data showing that offspring from high-LG-ABN mothers exhibited differences in DNA methylation, as compared to offspring from low-LG-ABN mothers[359]. These effects emerge over the first week of life, persist into adulthood, are reversed with cross-fostering, and are associated with altered histone acetylation and transcription factor binding to the GC receptor promoter. DNA methylation thus alters GC receptor expression through modifications of the chromatin structure[211,359,360,361,362]. In line with these arguments, Cameron and coworkers[37] suggested the existence of a phenotypic plasticity associated, for example, with parental investment that may be greater in more complex species like mammals. However, the influence of the maternal exposure to adverse environments on the mother-offspring interaction appears to be a common feature across all species caring for their young. In such a situation of adversity, the development of defensive responses to threats and/or of reproductive strategies might be altered in the progeny. Furthermore, epidemiological studies suggest that environmental adversity can alter parental care and thus influence child development. Similarly, in rodents, restraint stress during gestation exerts lasting effects on emotional reactivity of the dams, characterized by a higher anxiety and less care to the offspring[69]. In another model of PS in rodents, gestational stress can directly alter maternal care *via* the neuroendocrine systems that normally regulate this behavior[45]. These data also stress a nongenomic transmission mechanism of the effects of environmental adversity on maternal care across generations. Taken together, these studies emphasize the critical influence of parental care, especially after birth when children or pups develop or achieve their development. Deficits in parental attention combined to PS may have deeper effects on the offspring’s development, resulting in emotional and/or cognitive anomalies. As suggested by Hinde[137], natural selection has shaped the offspring to subtle changes in parental behaviors as a forecast of the environmental conditions they will face following separation from the parents. Besides the importance of parental care, an enriched environment at birth and until weaning can also reverse PS deleterious consequences by restoring abnormal behaviors like emotional reactivity or motor skills[46]. In fact, rat offspring reared in an enriched environment display increased social and play behaviors, a reduced emotionality, a reversion of several immunological alterations, and a decrease in the enhanced morphine-induced place preference[177,214,374]. Moreover, a longitudinal cross-housing study reveals that the postnatal environment could attenuate the effects of the prenatal condition on cognitive functions and more especially on synaptic structural changes in the hippocampus, with a higher immunoreactivity of neural cell adhesion molecule (NCAM), BDNF, and synaptic-vesicle protein (SYP), markers of neuronal and/or synapses development[166]. Indeed, a small hippocampal volume has been associated with both low birth weight and low maternal care in human females[34]. Thus, the detrimental effects of PS can be counteracted by an enriched stimulating environment after birth. The beneficial effect of enriched environment on brain development and behavior is corroborated by data from an animal model of autism induced by prenatal exposure to valproic acid. Specific environmental experiences, such as behavioral-cognitive therapy, might then attenuate autistic features and favor damage rehabilitation[188,290].

In conclusion, the gestational and early postnatal maternal programming appears to have contributed to the adaptation and survival of species in ever-changing environments. Such developmental responses have been conserved and have likely contributed to the epidemic occurrence of the metabolic syndrome, and the development of various mood disorders or psychiatric diseases. Several questions remain in abeyance, however, for a clear understanding of the mechanisms that can regulate and/or modify this maternal programming. In the developmental environmental context, such a fetal and/or neonatal plasticity might be used as windows of opportunity to prevent potential detrimental effects of maternal programming and/or enhance its beneficial impacts.
GENERAL CONCLUSION AND IMPLICATIONS FOR HUMAN BEINGS

In the present review, we have stressed the idea according to which an immature organism relies quite heavily on its environment, namely the maternal womb, from which it gathers information that will guide its harmonious growth and development. In the gestational context, this would imply an early programming of several physiological/biological systems to ensure the fetal-maternal interaction (Fig. 4). In particular, the nervous system, together with its two other counterparts, the endocrine and the immune systems, appears to be intrinsically programmed from very early on to react in a responsive manner and to learn from environmental stimuli in order to adjust internal parameters of the developing embryo/fetus to its environment, i.e., to the maternal one. In this view, such an early programming aims at maintaining the fetal homeostasis. This permanent responsiveness to the context allows for a greater flexibility in the developmental trajectory and thus seems to have been selected through evolution for ensuring the survival both at the level of the individual and at the level of the species. However, there is a potential cost to this apparently endless flexibility: an increased risk for an adverse outcome if the stimulation exceeds the

<figure><img src="image_5.png" /><figcaption>FIGURE 4. Developmental environment and early programming. Environmental influences are often considered to begin after birth, however, the prenatal *in utero* environment plays also a fundamental role in the early programming of the physiological integrity of the fetus. Ever-changing environmental conditions can indeed produce different outcomes on the development of the organism by impacting the fetal brain. In particular, early stressful events during gestation might shape the developing brain, notably the HPA and HPG axis, as well as their common interface, namely the limbic system. Thus, any event occurring during the perinatal period may affect various aspects of the neuroendocrine programming. Such early environmental changes can be either advantageous and promote an optimal development, or deleterious and alter the development, subsequently programming modifications of cardiovascular system, immune function, GC regulation, behavior, cognition, memory, learning, emotion, sexual behavior, or levels of sexual hormones, etc. and ultimately leading to the development of adult diseases as initially suggested by Barker[17]. GC: glucocorticoids; HPA : hypothalamo-pituitary-adrenal axis; HPG : hypothalamo-pituitary-gonadotropic axis</figcaption></figure>

tolerable limits of the developing organisms. Nevertheless, this perspective should not mean that all
environmental changes are to be considered as deleterious for the fetus. Indeed, sometimes the
disturbance will be just salient enough to shift the regulatory set points of the physiological systems that
GENERAL CONCLUSION AND IMPLICATIONS FOR HUMAN BEINGS

In the present review, we have stressed the idea according to which an immature organism relies quite heavily on its environment, namely the maternal womb, from which it gathers information that will guide its harmonious growth and development. In the gestational context, this would imply an early programming of several physiological/biological systems to ensure the fetal-maternal interaction (Fig. 4). In particular, the nervous system, together with its two other counterparts, the endocrine and the immune systems, appears to be intrinsically programmed from very early on to react in a responsive manner and to learn from environmental stimuli in order to adjust internal parameters of the developing embryo/fetus to its environment, i.e., to the maternal one. In this view, such an early programming aims at maintaining the fetal homeostasis. This permanent responsiveness to the context allows for a greater flexibility in the developmental trajectory and thus seems to have been selected through evolution for ensuring the survival both at the level of the individual and at the level of the species. However, there is a potential cost to this apparently endless flexibility: an increased risk for an adverse outcome if the stimulation exceeds the

<figure><img src="image_6.png" /><figcaption>FIGURE 4. Developmental environment and early programming. Environmental influences are often considered to begin after birth, however, the prenatal *in utero* environment plays also a fundamental role in the early programming of the physiological integrity of the fetus. Ever-changing environmental conditions can indeed produce different outcomes on the development of the organism by impacting the fetal brain. In particular, early stressful events during gestation might shape the developing brain, notably the HPA and HPG axis, as well as their common interface, namely the limbic system. Thus, any event occurring during the perinatal period may affect various aspects of the neuroendocrine programming. Such early environmental changes can be either advantageous and promote an optimal development, or deleterious and alter the development, subsequently programming modifications of cardiovascular system, immune function, GC regulation, behavior, cognition, memory, learning, emotion, sexual behavior, or levels of sexual hormones, etc. and ultimately leading to the development of adult diseases as initially suggested by Barker[17]. GC: glucocorticoids; HPA : hypothalamo-pituitary-adrenal axis; HPG : hypothalamo-pituitary-gonadotropic axis</figcaption></figure>

tolerable limits of the developing organisms. Nevertheless, this perspective should not mean that all
environmental changes are to be considered as deleterious for the fetus. Indeed, sometimes the
disturbance will be just salient enough to shift the regulatory set points of the physiological systems that
will mature later after birth. However, in other cases, the challenge is so potent that the trajectory of fetal
development is deviated towards pathology. In particular, numerous studies including our own indicate
that extended periods of maternal stress during gestation, and exposure of the fetus to alcohol or drugs
like DEX, are capable of leaving a lasting mark on behavior and physiology that can persist into
adulthood.

Moreover, one has also to keep in mind that most information gathered in the field of perinatal
programming emerged from animal-based studies. With regard to the relevance of these findings for our
species, we would like to suggest that human babies are somewhat more resilient to PS adverse
consequences, in part because of a greater reliance on the more protracted period of postnatal growth. In
this view, lactating rats (postnatal day 13) and monkey infants are born with a brain, respectively, 52 and
60% of the adult size, whereas the human neonate by comparison has a brain only 24% of the adult
volume [56,110]. Thus, a prenatal insult in rodents or monkeys is likely to have considerably more
developmental impact with less chance for postnatal recovery since the potential for neonatal plasticity
within the brain is more limited. However, the developing human central nervous system may be more
vulnerable to environmental perturbations than any other system. Indeed, it develops over a much longer
period of time (~18–20 years) as compared to other species, it has limited repair capacities, and the
programming of neurotransmitter systems during critical developmental periods might affect the
organism’s response to any subsequent experiences. Despite the significant and persistent effects of PS on
the neuroendocrine programming documented in the literature, most of these changes should be viewed as
being within a tolerable range of modulation, with little adverse consequences under undisturbed and
unprovoked conditions. It is only in the context of environmental challenge that one can really see the
potential vulnerability of PS organisms.

ACKNOWLEDGMENTS

The authors would like to acknowledge the warm support and critical reading of the manuscript by Drs. M.C. Chartier-Harlin and I. Wolowczuk.

REFERENCES

1. Abu-Akel, A. (2003) The neurochemical hypothesis of 'theory of mind'. *Med. Hypotheses* **60**, 382–386.

2. Akira, S., Uematsu, S., and Takeuchi, O. (2006) Pathogen recognition and innate immunity. *Cell* **124**, 783–801.

3. Albertsson-Wikland, K., Boguszewski, M., and Karlberg, J. (1998) Children born small-for-gestational age: postnatal growth and hormonal status. *Horm. Res.* **49**(Suppl 2), 7–13.

4. Antunes, V.R., Yao, S.T., Pickering, A.E., Murphy, D., and Paton, J.F. (2006) A spinal vasopressinergic mechanism mediates hyperosmolality-induced sympathoexcitation. *J. Physiol.* **576**, 569–583.

5. Arnold, A.P. and Gorski, R.A. (1984) Gonadal steroid induction of structural sex differences in the central nervous system. *Annu. Rev. Neurosci.* **7**, 413–442.

6. Ashton, I.K., Zapf, J., Einschenk, I., and MacKenzie, I.Z. (1985) Insulin-like growth factors (IGF) 1 and 2 in human foetal plasma and relationship to gestational age and foetal size during midpregnancy. *Acta Endocrinol. (Copenh.)* **110**, 558–563.

7. Asplund, K. (1973) Dynamics of insulin release from the foetal and neonatal rat pancreas. *Eur. J. Clin. Invest.* **3**, 338–344.

8. Auernhammer, C.J., Chesnokova, V., and Melmed, S. (1998) Leukemia inhibitory factor modulates interleukin-1beta-induced. *Endocrinology* **139**, 2201–2208.

9. Austin, M.P., Leader, L.R., and Reilly, N. (2005) Prenatal stress, the hypothalamic-pituitary-adrenal axis, and fetal and infant neurobehaviour. *Early Hum. Dev.* **81**, 917–926.

10. Avishai-Eliner, S., Brunson, K.L., Sandman, C.A., and Baram, T.Z. (2002) Stressed-out, or in (utero)? *Trends Neurosci.* **25**, 518–524.

11. Baker, J., Liu, J.P., Robertson, E.J., and Efstratiadis, A. (1993) Role of insulin-like growth factors in embryonic and postnatal growth. *Cell* **75**, 73–82.

12. Bakker, J.M., Schmidt, E.D., Kroes, H., Kavelaars, A., Heijnen, C.J., Tilders, F.J., and van Rees, E.P. (1995) Effects
will mature later after birth. However, in other cases, the challenge is so potent that the trajectory of fetal
development is deviated towards pathology. In particular, numerous studies including our own indicate
that extended periods of maternal stress during gestation, and exposure of the fetus to alcohol or drugs
like DEX, are capable of leaving a lasting mark on behavior and physiology that can persist into
adulthood.

Moreover, one has also to keep in mind that most information gathered in the field of perinatal
programming emerged from animal-based studies. With regard to the relevance of these findings for our
species, we would like to suggest that human babies are somewhat more resilient to PS adverse
consequences, in part because of a greater reliance on the more protracted period of postnatal growth. In
this view, lactating rats (postnatal day 13) and monkey infants are born with a brain, respectively, 52 and
60% of the adult size, whereas the human neonate by comparison has a brain only 24% of the adult
volume [56,110]. Thus, a prenatal insult in rodents or monkeys is likely to have considerably more
developmental impact with less chance for postnatal recovery since the potential for neonatal plasticity
within the brain is more limited. However, the developing human central nervous system may be more
vulnerable to environmental perturbations than any other system. Indeed, it develops over a much longer
period of time (~18-20 years) as compared to other species, it has limited repair capacities, and the
programming of neurotransmitter systems during critical developmental periods might affect the
organism's response to any subsequent experiences. Despite the significant and persistent effects of PS on
the neuroendocrine programming documented in the literature, most of these changes should be viewed as
being within a tolerable range of modulation, with little adverse consequences under undisturbed and
unprovoked conditions. It is only in the context of environmental challenge that one can really see the
potential vulnerability of PS organisms.

ACKNOWLEDGMENTS

The authors would like to acknowledge the warm support and critical reading of the manuscript by Drs. M.C. Chartier-Harlin and I. Wolowczuk.

REFERENCES

1. Abu-Akel, A. (2003) The neurochemical hypothesis of 'theory of mind'. *Med. Hypotheses* **60**, 382-386.

2. Akira, S., Uematsu, S., and Takeuchi, O. (2006) Pathogen recognition and innate immunity. *Cell* **124**, 783-801.

3. Albertsson-Wikland, K., Boguszewski, M., and Karlberg, J. (1998) Children born small-for-gestational age: postnatal growth and hormonal status. *Horm. Res.* **49**(Suppl 2), 7-13.

4. Antunes, V.R., Yao, S.T., Pickering, A.E., Murphy, D., and Paton, J.F. (2006) A spinal vasopressinergic mechanism mediates hyperosmolality-induced sympathoexcitation. *J. Physiol.* **576**, 569-583.

5. Arnold, A.P. and Gorski, R.A. (1984) Gonadal steroid induction of structural sex differences in the central nervous system. *Annu. Rev. Neurosci.* **7**, 413-442.

6. Ashton, I.K., Zapf, J., Einschenk, I., and MacKenzie, I.Z. (1985) Insulin-like growth factors (IGF) 1 and 2 in human foetal plasma and relationship to gestational age and foetal size during midpregnancy. *Acta Endocrinol. (Copenh.)* **110**, 558-563.

7. Asplund, K. (1973) Dynamics of insulin release from the foetal and neonatal rat pancreas. *Eur. J. Clin. Invest.* **3**, 338-344.

8. Auernhammer, C.J., Chesnokova, V., and Melmed, S. (1998) Leukemia inhibitory factor modulates interleukin-1beta-induced. *Endocrinology* **139**, 2201-2208.

9. Austin, M.P., Leader, L.R., and Reilly, N. (2005) Prenatal stress, the hypothalamic-pituitary-adrenal axis, and fetal and infant neurobehaviour. *Early Hum. Dev.* **81**, 917-926.

10. Avishai-Eliner, S., Brunson, K.L., Sandman, C.A., and Baram, T.Z. (2002) Stressed-out, or in (utero)? *Trends Neurosci.* **25**, 518-524.

11. Baker, J., Liu, J.P., Robertson, E.J., and Efstratiadis, A. (1993) Role of insulin-like growth factors in embryonic and postnatal growth. *Cell* **75**, 73-82.

12. Bakker, J.M., Schmidt, E.D., Kroes, H., Kavelaars, A., Heijnen, C.J., Tilders, F.J., and van Rees, E.P. (1995) Effects
of short-term dexamethasone treatment during pregnancy on the development of the immune system and the hypothalamo-pituitary adrenal axis in the rat. *J. Neuroimmunol.* **63**, 183–191.

13. Bakker, J.M., van den Dobbelsteen, G.P., Kroes, H., Kavelaars, A., Heijnen, C.J., Tilders, F.J., and van Rees, E.P. (1998) Long-term gender-specific effects of manipulation during pregnancy on immune and endocrine responsiveness in rat offspring. *J. Neuroimmunol.* **82**, 56–63.

14. Barbazanges, A., Vallee, M., Mayo, W., Day, J., Simon, H., Le, M.M., and Maccari, S. (1996) Early and later adoptions have different long-term effects on male rat offspring. *J. Neurosci.* **16**, 7783–7790.

15. Barbazanges, A., Piazza, P.V., Le, M.M., and Maccari, S. (1996) Maternal glucocorticoid secretion mediates long-term effects of prenatal stress. *J. Neurosci.* **16**, 3943–3949.

16. Barker, D.J., Osmond, C., Simmonds, S.J., and Wield, G.A. (1993) The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life. *BMJ* **306**, 422–426.

17. Barker, D.J. (1995) The Wellcome Foundation Lecture, 1994. The fetal origins of adult disease. *Proc. Biol. Sci.* **262**, 37–43.

18. Barreau, F., de Lahitte, J.D., Ferrier, L., Frexinos, J., Bueno, L., and Fioramonti, J. (2006) Neonatal maternal deprivation promotes Nippostrongylus brasiliensis infection in adult rats. *Brain Behav. Immun.* **20**, 254–260.

19. Barros, V.G., Berger, M.A., Martijena, I.D., Sarchi, M.I., Perez, A.A., Molina, V.A., Tarazi, F.I., and Antonelli, M.C. (2004) Early adoption modifies the effects of prenatal stress on dopamine and glutamate receptors in adult rat brain. *J. Neurosci. Res.* **76**, 488–496.

20. Barros, V.G., Rodriguez, P., Martijena, I.D., Perez, A., Molina, V.A., and Antonelli, M.C. (2006) Prenatal stress and early adoption effects on benzodiazepine receptors. *Synapse* **60**, 609–618.

21. Bateson, P., Barker, D., Clutton-Brock, T., Deb, D., D'Udine, B., Foley, R.A., Gluckman, P., Godfrey, K., Kirkwood, T., Lahr, M.M., McNamara, J., Metcalfe, N.B., Monaghan, P., Spencer, H.G., and Sultan, S.E. (2004) Developmental plasticity and human health. *Nature* **430**, 419–421.

22. Baumann, M.U., Deborde, S., and Illsley, N.P. (2002) Placental glucose transfer and fetal growth. *Endocrine* **19**, 13–22.

23. Besedovsky, H., Sorkin, E., Keller, M., and Muller, J. (1975) Changes in blood hormone levels during the immune response. *Proc. Soc. Exp. Biol. Med.* **150**, 466–470.

24. Bieswal, F., Ahn, M.T., Reusens, B., Holvoet, P., Raes, M., Rees, W.D., and Remacle, C. (2006) The importance of catch-up growth after early malnutrition for the programming of obesity in male rat. *Obesity (Silver Spring)* **14**, 1330–1343.

25. Blondeau, B., Lesage, J., Czernichow, P., Dupouy, J.P., and Breant, B. (2001) Glucocorticoids impair fetal beta-cell development in rats. *Am. J. Physiol Endocrinol. Metab.* **281**, E592–E599.

26. Bornstein, M.H. (1989) Sensitive periods in development: structural characteristics and causal interpretations. *Psychol. Bull.* **105**, 179–197.

27. Boudouresque, F., Guillaume, V., Grino, M., Strbak, V., Chautard, T., Conte-Devolx, B., and Oliver, C. (1988) Maturation of the pituitary-adrenal function in rat fetuses. *Neuroendocrinology* **48**, 417–422.

28. Bouret, S.G., Draper, S.J., and Simerly, R.B. (2004) Trophic action of leptin on hypothalamic neurons that regulate feeding. *Science* **304**, 108–110.

29. Bouret, S.G., Draper, S.J., and Simerly, R.B. (2004) Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. *J. Neurosci.* **24**, 2797–2805.

30. Brown, A.S., van Os, J., Driessens, C., Hoek, H.W., and Susser, E.S. (2000) Further evidence of relation between prenatal famine and major affective disorder. *Am. J. Psychiatry* **157**, 190–195.

31. Brown, R.W., Diaz, R., Robson, A.C., Kotelevtsev, Y.V., Mullins, J.J., Kaufman, M.H., and Seckl, J.R. (1996) The ontogeny of 11 beta-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development. *Endocrinology* **137**, 794–797.

32. Brussow, K.P., Schneider, F., Kanitz, E., Otten, W., and Tuchscherer, M. (2005) Alteration of reproductive hormone levels in pregnant sows induced by repeated ACTH application and its possible influence on pre- and post-natal hormone secretion of piglets. *J. Reprod. Dev.* **51**, 133–142.

33. Burton, P.J. and Waddell, B.J. (1999) Dual function of 11beta-hydroxysteroid dehydrogenase in placenta: modulating placental glucocorticoid passage and local steroid action. *Biol. Reprod.* **60**, 234–240.

34. Buss, C., Lord, C., Wadiwalla, M., Hellhammer, D.H., Lupien, S.J., Meaney, M.J., and Pruessner, J.C. (2007) Maternal care modulates the relationship between prenatal risk and hippocampal volume in women but not in men. *J. Neurosci.* **27**, 2592–2595.

35. Caldji, C., Tannenbaum, B., Sharma, S., Francis, D., Plotsky, P.M., and Meaney, M.J. (1998) Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. *Proc. Natl. Acad. Sci. U. S. A.* **95**, 5335–5340.

36. Caldji, C., Diorio, J., and Meaney, M.J. (2003) Variations in maternal care alter GABA(A) receptor subunit expression in brain regions associated with fear. *Neuropsychopharmacology* **28**, 1950–1959.

37. Cameron, N.M., Champagne, F.A., Parent, C., Fish, E.W., Ozaki-Kuroda, K., and Meaney, M.J. (2005) The programming of individual differences in defensive responses and reproductive strategies in the rat through variations in maternal care. *Neurosci. Biobehav. Rev.* **29**, 843–865.
of short-term dexamethasone treatment during pregnancy on the development of the immune system and the hypothalamo-pituitary adrenal axis in the rat. *J. Neuroimmunol.* **63**, 183–191.

13. Bakker, J.M., van den Dobbelsteen, G.P., Kroes, H., Kavelaars, A., Heijnen, C.J., Tilders, F.J., and van Rees, E.P. (1998) Long-term gender-specific effects of manipulation during pregnancy on immune and endocrine responsiveness in rat offspring. *J. Neuroimmunol.* **82**, 56–63.

14. Barbazanges, A., Vallee, M., Mayo, W., Day, J., Simon, H., Le, M.M., and Maccari, S. (1996) Early and later adoptions have different long-term effects on male rat offspring. *J. Neurosci.* **16**, 7783–7790.

15. Barbazanges, A., Piazza, P.V., Le, M.M., and Maccari, S. (1996) Maternal glucocorticoid secretion mediates long-term effects of prenatal stress. *J. Neurosci.* **16**, 3943–3949.

16. Barker, D.J., Osmond, C., Simmonds, S.J., and Wield, G.A. (1993) The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life. *BMJ* **306**, 422–426.

17. Barker, D.J. (1995) The Wellcome Foundation Lecture, 1994. The fetal origins of adult disease. *Proc. Biol. Sci.* **262**, 37–43.

18. Barreau, F., de Lahitte, J.D., Ferrier, L., Frexinos, J., Bueno, L., and Fioramonti, J. (2006) Neonatal maternal deprivation promotes Nippostrongylus brasiliensis infection in adult rats. *Brain Behav. Immun.* **20**, 254–260.

19. Barros, V.G., Berger, M.A., Martijena, I.D., Sarchi, M.I., Perez, A.A., Molina, V.A., Tarazi, F.I., and Antonelli, M.C. (2004) Early adoption modifies the effects of prenatal stress on dopamine and glutamate receptors in adult rat brain. *J. Neurosci. Res.* **76**, 488–496.

20. Barros, V.G., Rodriguez, P., Martijena, I.D., Perez, A., Molina, V.A., and Antonelli, M.C. (2006) Prenatal stress and early adoption effects on benzodiazepine receptors. *Synapse* **60**, 609–618.

21. Bateson, P., Barker, D., Clutton-Brock, T., Deb, D., D'Udine, B., Foley, R.A., Gluckman, P., Godfrey, K., Kirkwood, T., Lahr, M.M., McNamara, J., Metcalfe, N.B., Monaghan, P., Spencer, H.G., and Sultan, S.E. (2004) Developmental plasticity and human health. *Nature* **430**, 419–421.

22. Baumann, M.U., Deborde, S., and Illsley, N.P. (2002) Placental glucose transfer and fetal growth. *Endocrine* **19**, 13–22.

23. Besedovsky, H., Sorkin, E., Keller, M., and Muller, J. (1975) Changes in blood hormone levels during the immune response. *Proc. Soc. Exp. Biol. Med.* **150**, 466–470.

24. Bieswal, F., Ahn, M.T., Reusens, B., Holvoet, P., Raes, M., Rees, W.D., and Remacle, C. (2006) The importance of catch-up growth after early malnutrition for the programming of obesity in male rat. *Obesity (Silver Spring)* **14**, 1330–1343.

25. Blondeau, B., Lesage, J., Czernichow, P., Dupouy, J.P., and Breant, B. (2001) Glucocorticoids impair fetal beta-cell development in rats. *Am. J. Physiol Endocrinol. Metab.* **281**, E592–E599.

26. Bornstein, M.H. (1989) Sensitive periods in development: structural characteristics and causal interpretations. *Psychol. Bull.* **105**, 179–197.

27. Boudouresque, F., Guillaume, V., Grino, M., Strbak, V., Chautard, T., Conte-Devolx, B., and Oliver, C. (1988) Maturation of the pituitary-adrenal function in rat fetuses. *Neuroendocrinology* **48**, 417–422.

28. Bouret, S.G., Draper, S.J., and Simerly, R.B. (2004) Trophic action of leptin on hypothalamic neurons that regulate feeding. *Science* **304**, 108–110.

29. Bouret, S.G., Draper, S.J., and Simerly, R.B. (2004) Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. *J. Neurosci.* **24**, 2797–2805.

30. Brown, A.S., van Os, J., Driessens, C., Hoek, H.W., and Susser, E.S. (2000) Further evidence of relation between prenatal famine and major affective disorder. *Am. J. Psychiatry* **157**, 190–195.

31. Brown, R.W., Diaz, R., Robson, A.C., Kotelevtsev, Y.V., Mullins, J.J., Kaufman, M.H., and Seckl, J.R. (1996) The ontogeny of 11 beta-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development. *Endocrinology* **137**, 794–797.

32. Brussow, K.P., Schneider, F., Kanitz, E., Otten, W., and Tuchscherer, M. (2005) Alteration of reproductive hormone levels in pregnant sows induced by repeated ACTH application and its possible influence on pre- and post-natal hormone secretion of piglets. *J. Reprod. Dev.* **51**, 133–142.

33. Burton, P.J. and Waddell, B.J. (1999) Dual function of 11beta-hydroxysteroid dehydrogenase in placenta: modulating placental glucocorticoid passage and local steroid action. *Biol. Reprod.* **60**, 234–240.

34. Buss, C., Lord, C., Wadiwalla, M., Hellhammer, D.H., Lupien, S.J., Meaney, M.J., and Pruessner, J.C. (2007) Maternal care modulates the relationship between prenatal risk and hippocampal volume in women but not in men. *J. Neurosci.* **27**, 2592–2595.

35. Caldji, C., Tannenbaum, B., Sharma, S., Francis, D., Plotsky, P.M., and Meaney, M.J. (1998) Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. *Proc. Natl. Acad. Sci. U. S. A.* **95**, 5335–5340.

36. Caldji, C., Diorio, J., and Meaney, M.J. (2003) Variations in maternal care alter GABA(A) receptor subunit expression in brain regions associated with fear. *Neuropsychopharmacology* **28**, 1950–1959.

37. Cameron, N.M., Champagne, F.A., Parent, C., Fish, E.W., Ozaki-Kuroda, K., and Meaney, M.J. (2005) The programming of individual differences in defensive responses and reproductive strategies in the rat through variations in maternal care. *Neurosci. Biobehav. Rev.* **29**, 843–865.
38. Campbell, E.A., Linton, E.A., Wolfe, C.D., Scraggs, P.R., Jones, M.T., and Lowry, P.J. (1987) Plasma corticotropin-releasing hormone concentrations during pregnancy and parturition. *J. Clin. Endocrinol. Metab.* **64**, 1054-1059.

39. Cannon W.B. (1929) *Bodily Changes in Pain, Hunger, Fear, and Rage*. 2nd ed. D. Appleton and Co., New York and London.

40. Canu, M.H., Darnaudery, M., Falempin, M., Maccari, S., and Viltart, O. (2007) Effect of hindlimb unloading on motor activity in adult rats: impact of prenatal stress. *Behav. Neurosci.* **121**, 177-185.

41. Castonguay, T.W. (1991) Glucocorticoids as modulators in the control of feeding. *Brain Res. Bull.* **27**, 423-428.

42. Caudle, M.R., Harbert, G.M., Jr., and Singhas, C.A. (1981) Effect of betamethasone on fetal macrophage function: depression of adherence of immunoglobulin-coated red blood cells. *Am. J. Reprod. Immunol.* **1**, 182-184.

43. Challis, J.R., Sloboda, D., Matthews, S.G., Holloway, A., Alfaidy, N., Patel, F.A., Whittle, W., Fraser, M., Moss, T.J., and Newnham, J. (2001) The fetal placental hypothalamic-pituitary-adrenal (HPA) axis, parturition and post natal health. *Mol. Cell Endocrinol.* **185**, 135-144.

44. Champagne, F.A., Francis, D.D., Mar, A., and Meaney, M.J. (2003) Variations in maternal care in the rat as a mediating influence for the effects of environment on development. *Physiol. Behav.* **79**, 359-371.

45. Champagne, F.A. and Meaney, M.J. (2006) Stress during gestation alters postpartum maternal care and the development of the offspring in a rodent model. *Biol. Psychiatry* **59**, 1227-1235.

46. Chapillon, P., Patin, V., Roy, V., Vincent, A., and Caston, J. (2002) Effects of pre- and postnatal stimulation on developmental, emotional, and cognitive aspects in rodents: a review. *Dev. Psychobiol.* **41**, 373-387.

47. Charmandari, E., Kino, T., Souvatzoglou, E., and Chrousos, G.P. (2003) Pediatric stress: hormonal mediators and human development. *Horm. Res.* **59**, 161-179.

48. Chesnokova, V., Auernhammer, C.J., and Melmed, S. (1998) Murine leukemia inhibitory factor gene disruption attenuates the hypothalamo-pituitary-adrenal axis stress response. *Endocrinology* **139**, 2209-2216.

49. Cintra, A., Solfrini, V., Bunnemann, B., Okret, S., Bortolotti, F., Gustafsson, J.A., and Fuxe, K. (1993) Prenatal development of glucocorticoid receptor gene expression and immunoreactivity in the rat brain and pituitary gland: a combined in situ hybridization and immunocytochemical analysis. *Neuroendocrinology* **57**, 1133-1147.

50. Cleasby, M.E., Kelly, P.A., Walker, B.R., and Seckl, J.R. (2003) Programming of rat muscle and fat metabolism by in utero overexposure to glucocorticoids. *Endocrinology* **144**, 999-1007.

51. Coe, C.L., Kemnitz, J.W., and Schneider, M.L. (1993) Vulnerability of placental antibody transfer and fetal complement synthesis to disturbance of the pregnant monkey. *J. Med. Primatol.* **22**, 294-300.

52. Coe, C.L., Lubach, G.R., Karaszewski, J.W., and Ershler, W.B. (1996) Prenatal endocrine activation alters postnatal cellular immunity in infant monkeys. *Brain Behav. Immun.* **10**, 221-234.

53. Coe, C.L., Lubach, G.R., and Karaszewski, J.W. (1999) Prenatal stress and immune recognition of self and nonself in the primate neonate. *Biol. Neonate* **76**, 301-310.

54. Coe, C.L. and Lubach, G.R. (2000) Prenatal influences on neuroimmune set points in infancy. *Ann. N. Y. Acad. Sci.* **917**, 468-477.

55. Coe, C.L., Kramer, M., Kirschbaum, C., Netter, P., and Fuchs, E. (2002) Prenatal stress diminishes the cytokine response of leukocytes to endotoxin stimulation in juvenile rhesus monkeys. *J. Clin. Endocrinol. Metab.* **87**, 675-681.

56. Coe, C.L. and Lubach, G.R. (2005) Prenatal origins of individual variation in behavior and immunity. *Neurosci. Biobehav. Rev.* **29**, 39-49.

57. Coffman, R.L., Seymour, B.W., Hudak, S., Jackson, J., and Rennick, D. (1989) Antibody to interleukin-5 inhibits helminth-induced eosinophilia in mice. *Science* **245**, 308-310.

58. Conti, B., Tabarean, I., Andrei, C., and Bartfai, T. (2004) Cytokines and fever. *Front. Biosci.* **9**, 1433-1449.

59. Cooper, M.D. and Alder, M.N. (2006) The evolution of adaptive immune systems. *Cell* **124**, 815-822.

60. Corbier, P., Kerdelhue, B., Picon, R., and Roffi, J. (1978) Changes in testicular weight and serum gonadotropin and testosterone levels before, during, and after birth in the perinatal rat. *Endocrinology* **103**, 1985-1991.

61. Coussons-Read, M.E., Okun, M.L., Schmitt, M.P., and Giese, S. (2005) Prenatal stress alters cytokine levels in a manner that may endanger human pregnancy. *Psychosom. Med.* **67**, 625-631.

62. Coussons-Read, M.E., Okun, M.L., and Nettles, C.D. (2007) Psychosocial stress increases inflammatory markers and alters cytokine production across pregnancy. *Brain Behav. Immun.* **21**, 343-350.

63. Cratty, M.S., Ward, H.E., Johnson, E.A., Azzaro, A.J., and Birkle, D.L. (1995) Prenatal stress increases corticotropin-releasing factor (CRF) content and release in rat amygdala minces. *Brain Res.* **675**, 297-302.

64. Crespi, E.J. and Denver, R.J. (2005) Ancient origins of human developmental plasticity. *Am. J. Hum. Biol.* **17**, 44-54.

65. Csernus, V. (1986) Production of sexual steroids in rats during pre- and early postnatal life. *Exp. Clin. Endocrinol.* **88**, 1-5.

66. Cutfield, W.S., Hofman, P.L., Vickers, M., Breier, B., Blum, W.F., and Robinson, E.M. (2002) IGFs and binding proteins in short children with intrauterine growth retardation. *J. Clin. Endocrinol. Metab.* **87**, 235-239.

67. Dafny, N. and Yang, P.B. (2005) Interferon and the central nervous system. *Eur. J. Pharmacol.* **523**, 1-15.

68. Damoiseaux, J.G., Cautain, B., Bernard, I., Mas, M., van, B., V, Druet, P., Fournie, G., and Saoudi, A. (1999) A dominant role for the thymus and MHC genes in determining the peripheral CD4/CD8 T cell ratio in the rat. *J.*
38. Campbell, E.A., Linton, E.A., Wolfe, C.D., Scraggs, P.R., Jones, M.T., and Lowry, P.J. (1987) Plasma corticotropin-releasing hormone concentrations during pregnancy and parturition. *J. Clin. Endocrinol. Metab.* **64**, 1054-1059.

39. Cannon W.B. (1929) *Bodily Changes in Pain, Hunger, Fear, and Rage*. 2nd ed. D. Appleton and Co., New York and London.

40. Canu, M.H., Darnaudery, M., Falempin, M., Maccari, S., and Viltart, O. (2007) Effect of hindlimb unloading on motor activity in adult rats: impact of prenatal stress. *Behav. Neurosci.* **121**, 177-185.

41. Castonguay, T.W. (1991) Glucocorticoids as modulators in the control of feeding. *Brain Res. Bull.* **27**, 423-428.

42. Caudle, M.R., Harbert, G.M., Jr., and Singhas, C.A. (1981) Effect of betamethasone on fetal macrophage function: depression of adherence of immunoglobulin-coated red blood cells. *Am. J. Reprod. Immunol.* **1**, 182-184.

43. Challis, J.R., Sloboda, D., Matthews, S.G., Holloway, A., Alfaidy, N., Patel, F.A., Whittle, W., Fraser, M., Moss, T.J., and Newnham, J. (2001) The fetal placental hypothalamic-pituitary-adrenal (HPA) axis, parturition and post natal health. *Mol. Cell Endocrinol.* **185**, 135-144.

44. Champagne, F.A., Francis, D.D., Mar, A., and Meaney, M.J. (2003) Variations in maternal care in the rat as a mediating influence for the effects of environment on development. *Physiol. Behav.* **79**, 359-371.

45. Champagne, F.A. and Meaney, M.J. (2006) Stress during gestation alters postpartum maternal care and the development of the offspring in a rodent model. *Biol. Psychiatry* **59**, 1227-1235.

46. Chapillon, P., Patin, V., Roy, V., Vincent, A., and Caston, J. (2002) Effects of pre- and postnatal stimulation on developmental, emotional, and cognitive aspects in rodents: a review. *Dev. Psychobiol.* **41**, 373-387.

47. Charmandari, E., Kino, T., Souvatzoglou, E., and Chrousos, G.P. (2003) Pediatric stress: hormonal mediators and human development. *Horm. Res.* **59**, 161-179.

48. Chesnokova, V., Auernhammer, C.J., and Melmed, S. (1998) Murine leukemia inhibitory factor gene disruption attenuates the hypothalamo-pituitary-adrenal axis stress response. *Endocrinology* **139**, 2209-2216.

49. Cintra, A., Solfrini, V., Bunnemann, B., Okret, S., Bortolotti, F., Gustafsson, J.A., and Fuxe, K. (1993) Prenatal development of glucocorticoid receptor gene expression and immunoreactivity in the rat brain and pituitary gland: a combined in situ hybridization and immunocytochemical analysis. *Neuroendocrinology* **57**, 1133-1147.

50. Cleasby, M.E., Kelly, P.A., Walker, B.R., and Seckl, J.R. (2003) Programming of rat muscle and fat metabolism by in utero overexposure to glucocorticoids. *Endocrinology* **144**, 999-1007.

51. Coe, C.L., Kemnitz, J.W., and Schneider, M.L. (1993) Vulnerability of placental antibody transfer and fetal complement synthesis to disturbance of the pregnant monkey. *J. Med. Primatol.* **22**, 294-300.

52. Coe, C.L., Lubach, G.R., Karaszewski, J.W., and Ershler, W.B. (1996) Prenatal endocrine activation alters postnatal cellular immunity in infant monkeys. *Brain Behav. Immun.* **10**, 221-234.

53. Coe, C.L., Lubach, G.R., and Karaszewski, J.W. (1999) Prenatal stress and immune recognition of self and nonself in the primate neonate. *Biol. Neonate* **76**, 301-310.

54. Coe, C.L. and Lubach, G.R. (2000) Prenatal influences on neuroimmune set points in infancy. *Ann. N. Y. Acad. Sci.* **917**, 468-477.

55. Coe, C.L., Kramer, M., Kirschbaum, C., Netter, P., and Fuchs, E. (2002) Prenatal stress diminishes the cytokine response of leukocytes to endotoxin stimulation in juvenile rhesus monkeys. *J. Clin. Endocrinol. Metab.* **87**, 675-681.

56. Coe, C.L. and Lubach, G.R. (2005) Prenatal origins of individual variation in behavior and immunity. *Neurosci. Biobehav. Rev.* **29**, 39-49.

57. Coffman, R.L., Seymour, B.W., Hudak, S., Jackson, J., and Rennick, D. (1989) Antibody to interleukin-5 inhibits helminth-induced eosinophilia in mice. *Science* **245**, 308-310.

58. Conti, B., Tabarean, I., Andrei, C., and Bartfai, T. (2004) Cytokines and fever. *Front. Biosci.* **9**, 1433-1449.

59. Cooper, M.D. and Alder, M.N. (2006) The evolution of adaptive immune systems. *Cell* **124**, 815-822.

60. Corbier, P., Kerdelhue, B., Picon, R., and Roffi, J. (1978) Changes in testicular weight and serum gonadotropin and testosterone levels before, during, and after birth in the perinatal rat. *Endocrinology* **103**, 1985-1991.

61. Coussons-Read, M.E., Okun, M.L., Schmitt, M.P., and Giese, S. (2005) Prenatal stress alters cytokine levels in a manner that may endanger human pregnancy. *Psychosom. Med.* **67**, 625-631.

62. Coussons-Read, M.E., Okun, M.L., and Nettles, C.D. (2007) Psychosocial stress increases inflammatory markers and alters cytokine production across pregnancy. *Brain Behav. Immun.* **21**, 343-350.

63. Cratty, M.S., Ward, H.E., Johnson, E.A., Azzaro, A.J., and Birkle, D.L. (1995) Prenatal stress increases corticotropin-releasing factor (CRF) content and release in rat amygdala minces. *Brain Res.* **675**, 297-302.

64. Crespi, E.J. and Denver, R.J. (2005) Ancient origins of human developmental plasticity. *Am. J. Hum. Biol.* **17**, 44-54.

65. Csernus, V. (1986) Production of sexual steroids in rats during pre- and early postnatal life. *Exp. Clin. Endocrinol.* **88**, 1-5.

66. Cutfield, W.S., Hofman, P.L., Vickers, M., Breier, B., Blum, W.F., and Robinson, E.M. (2002) IGFs and binding proteins in short children with intrauterine growth retardation. *J. Clin. Endocrinol. Metab.* **87**, 235-239.

67. Dafny, N. and Yang, P.B. (2005) Interferon and the central nervous system. *Eur. J. Pharmacol.* **523**, 1-15.

68. Damoiseaux, J.G., Cautain, B., Bernard, I., Mas, M., van, B., V, Druet, P., Fournie, G., and Saoudi, A. (1999) A dominant role for the thymus and MHC genes in determining the peripheral CD4/CD8 T cell ratio in the rat. *J.*
Immunol. **163**, 2983-2989.

69. Darnaudery, M., Dutriez, I., Viltart, O., Morley-Fletcher, S., and Maccari, S. (2004) Stress during gestation induces lasting effects on emotional reactivity of the dam rat. *Behav. Brain Res.* **153**, 211–216.

70. Darnaudery, M., Koehl, M., Barbazanges, A., Cabib, S., Le, M.M., and Maccari, S. (2004) Early and later adoptions differently modify mother-pup interactions. *Behav. Neurosci.* **118**, 590–596.

71. Davis, E.C., Popper, P., and Gorski, R.A. (1996) The role of apoptosis in sexual differentiation of the rat sexually dimorphic nucleus of the preoptic area. *Brain Res.* **734**, 10–18.

72. de Kloet, E.R. and Oitzl, M.S. (2003) Who cares for a stressed brain? The mother, the kid or both? *Neurobiol. Aging* **24**(Suppl 1), S61-S65.

73. de Kloet, E.R., Joels, M., and Holsboer, F. (2005) Stress and the brain: from adaptation to disease. *Nat. Rev. Neurosci.* **6**, 463–475.

74. de Kloet, E.R., Sibug, R.M., Helmerhorst, F.M., and Schmidt, M.V. (2005) Stress, genes and the mechanism of programming the brain for later life. *Neurosci. Biobehav. Rev.* **29**, 271–281.

75. Deminiere, J.M., Piazza, P.V., Guegan, G., Abrous, N., Maccari, S., Le, M.M., and Simon, H. (1992) Increased locomotor response to novelty and propensity to intravenous amphetamine self-administration in adult offspring of stressed mothers. *Brain Res.* **586**, 135-139.

76. Desai, M., Gayle, D., Babu, J., and Ross, M.G. (2005) Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. *Am. J. Physiol. Regul. Integr. Comp. Physiol.* **288**, R91–R96.

77. Dhabhar, F.S. and McEwen, B.S. (1997) Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: a potential role for leukocyte trafficking. *Brain Behav. Immun.* **11**, 286-306.

78. Dhabhar, F.S. and McEwen, B.S. (1999) Enhancing versus suppressive effects of stress hormones on skin immune function. *Proc. Natl. Acad. Sci. U. S. A.* **96**, 1059–1064.

79. Dorner, G., Geier, T., Ahrens, L., Krell, L., Munx, G., Sieler, H., Kittner, E., and Muller, H. (1980) Prenatal stress as possible aetiogenetic factor of homosexuality in human males. *Endokrinologie* **75**, 365-368.

80. Dorner, G., Schenk, B., Schmiedel, B., and Ahrens, L. (1983) Stressful events in prenatal life of bi- and homosexual men. *Exp. Clin. Endocrinol.* **81**, 83-87.

81. Dudek, R.W., Kawabe, T., Brinn, J.E., O'Brien, K., Poole, M.C., and Morgan, C.R. (1984) Glucose affects in vitro maturation of fetal rat islets. *Endocrinology* **114**, 582-587.

82. Dutriez-Casteloot, I., Bernet, F., Dedieu, J.F., Croix, D., Laborie, C., Montel, V., Lesage, J., Beauvillain, J.C., and Dupouy, J.P. (1999) Hypothalamic-pituitary-adrenocortical and gonadal axes and sympathoadrenal activity of adult male rats prenatally exposed to morphine. *Neurosci. Lett.* **263**, 1-4.

83. Elenkov, I.J., Wilder, R.L., Chrousos, G.P., and Vizi, E.S. (2000) The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. *Pharmacol. Rev.* **52**, 595-638.

84. Fernandez-Twinn, D.S. and Ozanne, S.E. (2006) Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome. *Physiol. Behav.* **88**, 234-243.

85. Fletcher, A.J., Ma, X.H., Wu, W.X., Nathanielsz, P.W., McGarrigle, H.H., Fowden, A.L., and Giussani, D.A. (2004) Antenatal glucocorticoids reset the level of baseline and hypoxemia-induced pituitary-adrenal activity in the sheep fetus during late gestation. *Am. J. Physiol. Endocrinol. Metab.* **286**, E311-E319.

86. Flier, J.S., Harris, M., and Hollenberg, A.N. (2000) Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring. *J. Clin. Invest.* **105**, 859-861.

87. Forhead, A.J., Li, J., Gilmour, R.S., and Fowden, A.L. (1998) Control of hepatic insulin-like growth factor II gene expression by thyroid hormones in fetal sheep near term. *Am. J. Physiol.* **275**, E149-E156.

88. Forhead, A.J., Li, J., Saunders, J.C., Dauncey, M.J., Gilmour, R.S., and Fowden, A.L. (2000) Control of ovine hepatic growth hormone receptor and insulin-like growth factor I by thyroid hormones in utero. *Am. J. Physiol. Endocrinol. Metab.* **278**, E1166-E1174.

89. Fowden, A.L. (1995) Endocrine regulation of fetal growth. *Reprod. Fertil. Dev.* **7**, 351-363.

90. Fowden, A.L. (2003) The insulin-like growth factors and feto-placental growth. *Placenta* **24**, 803-812.

91. Fowden, A.L., Giussani, D.A., and Forhead, A.J. (2006) Intrauterine programming of physiological systems: causes and consequences. *Physiology (Bethesda)* **21**, 29-37.

92. Francis, D., Diorio, J., Liu, D., and Meaney, M.J. (1999) Nongenomic transmission across generations of maternal behavior and stress responses in the rat. *Science* **286**, 1155-1158.

93. Francis, D.D., Champagne, F.A., Liu, D., and Meaney, M.J. (1999) Maternal care, gene expression, and the development of individual differences in stress reactivity. *Ann. N. Y. Acad. Sci.* **896**, 66-84.

94. Francis, D.D., Caldji, C., Champagne, F., Plotsky, P.M., and Meaney, M.J. (1999) The role of corticotropin-releasing factor--norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress. *Biol. Psychiatry* **46**, 1153-1166.

95. Francis, D.D., Champagne, F.C., and Meaney, M.J. (2000) Variations in maternal behaviour are associated with differences in oxytocin receptor levels in the rat. *J. Neuroendocrinol.* **12**, 1145-1148.

96. Francis, D.D., Diorio, J., Plotsky, P.M., and Meaney, M.J. (2002) Environmental enrichment reverses the effects of maternal separation on stress reactivity. *J. Neurosci.* **22**, 7840-7843.

97. Frank, G.D. and Parnes, J.R. (1998) The level of CD4 surface protein influences T cell selection in the thymus. *J. Immunol.* **160**, 634-642.
Immunol. **163**, 2983–2989.

69. Darnaudery, M., Dutriez, I., Viltart, O., Morley-Fletcher, S., and Maccari, S. (2004) Stress during gestation induces lasting effects on emotional reactivity of the dam rat. *Behav. Brain Res.* **153**, 211–216.

70. Darnaudery, M., Koehl, M., Barbazanges, A., Cabib, S., Le, M.M., and Maccari, S. (2004) Early and later adoptions differently modify mother-pup interactions. *Behav. Neurosci.* **118**, 590–596.

71. Davis, E.C., Popper, P., and Gorski, R.A. (1996) The role of apoptosis in sexual differentiation of the rat sexually dimorphic nucleus of the preoptic area. *Brain Res.* **734**, 10–18.

72. de Kloet, E.R. and Oitzl, M.S. (2003) Who cares for a stressed brain? The mother, the kid or both? *Neurobiol. Aging* **24**(Suppl 1), S61–S65.

73. de Kloet, E.R., Joels, M., and Holsboer, F. (2005) Stress and the brain: from adaptation to disease. *Nat. Rev. Neurosci.* **6**, 463–475.

74. de Kloet, E.R., Sibug, R.M., Helmerhorst, F.M., and Schmidt, M.V. (2005) Stress, genes and the mechanism of programming the brain for later life. *Neurosci. Biobehav. Rev.* **29**, 271–281.

75. Deminiere, J.M., Piazza, P.V., Guegan, G., Abrous, N., Maccari, S., Le, M.M., and Simon, H. (1992) Increased locomotor response to novelty and propensity to intravenous amphetamine self-administration in adult offspring of stressed mothers. *Brain Res.* **586**, 135–139.

76. Desai, M., Gayle, D., Babu, J., and Ross, M.G. (2005) Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. *Am. J. Physiol. Regul. Integr. Comp. Physiol.* **288**, R91–R96.

77. Dhabhar, F.S. and McEwen, B.S. (1997) Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: a potential role for leukocyte trafficking. *Brain Behav. Immun.* **11**, 286–306.

78. Dhabhar, F.S. and McEwen, B.S. (1999) Enhancing versus suppressive effects of stress hormones on skin immune function. *Proc. Natl. Acad. Sci. U. S. A.* **96**, 1059–1064.

79. Dorner, G., Geier, T., Ahrens, L., Krell, L., Munx, G., Sieler, H., Kittner, E., and Muller, H. (1980) Prenatal stress as possible aetiogenetic factor of homosexuality in human males. *Endokrinologie* **75**, 365–368.

80. Dorner, G., Schenk, B., Schmiedel, B., and Ahrens, L. (1983) Stressful events in prenatal life of bi- and homosexual men. *Exp. Clin. Endocrinol.* **81**, 83–87.

81. Dudek, R.W., Kawabe, T., Brinn, J.E., O'Brien, K., Poole, M.C., and Morgan, C.R. (1984) Glucose affects in vitro maturation of fetal rat islets. *Endocrinology* **114**, 582–587.

82. Dutriez-Casteloot, I., Bernet, F., Dedieu, J.F., Croix, D., Laborie, C., Montel, V., Lesage, J., Beauvillain, J.C., and Dupouy, J.P. (1999) Hypothalamic-pituitary-adrenocortical and gonadal axes and sympathoadrenal activity of adult male rats prenatally exposed to morphine. *Neurosci. Lett.* **263**, 1–4.

83. Elenkov, I.J., Wilder, R.L., Chrousos, G.P., and Vizi, E.S. (2000) The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. *Pharmacol. Rev.* **52**, 595–638.

84. Fernandez-Twinn, D.S. and Ozanne, S.E. (2006) Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome. *Physiol. Behav.* **88**, 234–243.

85. Fletcher, A.J., Ma, X.H., Wu, W.X., Nathanielsz, P.W., McGarrigle, H.H., Fowden, A.L., and Giussani, D.A. (2004) Antenatal glucocorticoids reset the level of baseline and hypoxemia-induced pituitary-adrenal activity in the sheep fetus during late gestation. *Am. J. Physiol. Endocrinol. Metab.* **286**, E311–E319.

86. Flier, J.S., Harris, M., and Hollenberg, A.N. (2000) Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring. *J. Clin. Invest.* **105**, 859–861.

87. Forhead, A.J., Li, J., Gilmour, R.S., and Fowden, A.L. (1998) Control of hepatic insulin-like growth factor II gene expression by thyroid hormones in fetal sheep near term. *Am. J. Physiol.* **275**, E149–E156.

88. Forhead, A.J., Li, J., Saunders, J.C., Dauncey, M.J., Gilmour, R.S., and Fowden, A.L. (2000) Control of ovine hepatic growth hormone receptor and insulin-like growth factor I by thyroid hormones in utero. *Am. J. Physiol. Endocrinol. Metab.* **278**, E1166–E1174.

89. Fowden, A.L. (1995) Endocrine regulation of fetal growth. *Reprod. Fertil. Dev.* **7**, 351–363.

90. Fowden, A.L. (2003) The insulin-like growth factors and feto-placental growth. *Placenta* **24**, 803–812.

91. Fowden, A.L., Giussani, D.A., and Forhead, A.J. (2006) Intrauterine programming of physiological systems: causes and consequences. *Physiology (Bethesda)* **21**, 29–37.

92. Francis, D., Diorio, J., Liu, D., and Meaney, M.J. (1999) Nongenomic transmission across generations of maternal behavior and stress responses in the rat. *Science* **286**, 1155–1158.

93. Francis, D.D., Champagne, F.A., Liu, D., and Meaney, M.J. (1999) Maternal care, gene expression, and the development of individual differences in stress reactivity. *Ann. N. Y. Acad. Sci.* **896**, 66–84.

94. Francis, D.D., Caldji, C., Champagne, F., Plotsky, P.M., and Meaney, M.J. (1999) The role of corticotropin-releasing factor--norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress. *Biol. Psychiatry* **46**, 1153–1166.

95. Francis, D.D., Champagne, F.C., and Meaney, M.J. (2000) Variations in maternal behaviour are associated with differences in oxytocin receptor levels in the rat. *J. Neuroendocrinol.* **12**, 1145–1148.

96. Francis, D.D., Diorio, J., Plotsky, P.M., and Meaney, M.J. (2002) Environmental enrichment reverses the effects of maternal separation on stress reactivity. *J. Neurosci.* **22**, 7840–7843.

97. Frank, G.D. and Parnes, J.R. (1998) The level of CD4 surface protein influences T cell selection in the thymus. *J. Immunol.* **160**, 634–642.
98. Freyschmidt-Paul, P., McElwee, K.J., Hoffmann, R., Sundberg, J.P., Vitacolonna, M., Kissling, S., and Zoller, M. (2006) Interferon-gamma-deficient mice are resistant to the development of alopecia areata. *Br. J. Dermatol.* **155**, 515-521.

99. Fride, E. and Weinstock, M. (1984) The effects of prenatal exposure to predictable or unpredictable stress on early development in the rat. *Dev. Psychobiol.* **17**, 651-660.

100. Frye, C.A. and Orecki, Z.A. (2002) Prenatal stress alters reproductive responses of rats in behavioral estrus and paced mating of hormone-primed rats. *Horm. Behav.* **42**, 472-483.

101. Fujioka, A., Fujioka, T., Ishida, Y., Maekawa, T., and Nakamura, S. (2006) Differential effects of prenatal stress on the morphological maturation of hippocampal neurons. *Neuroscience* **141**, 907-915.

102. Fujioka, T., Sakata, Y., Yamaguchi, K., Shibasaki, T., Kato, H., and Nakamura, S. (1999) The effects of prenatal stress on the development of hypothalamic paraventricular neurons in fetal rats. *Neuroscience* **92**, 1079-1088.

103. Gafni, R.I. and Baron, J. (2000) Catch-up growth: possible mechanisms. *Pediatr. Nephrol.* **14**, 616-619.

104. Galler, J.R. and Tonkiss, J. (1991) Prenatal protein malnutrition and maternal behavior in Sprague-Dawley rats. *J. Nutr.* **121**, 762-769.

105. Gandelman, R., vom Saal, F.S., and Reinisch, J.M. (1977) Contiguity to male foetuses affects morphology and behaviour of female mice. *Nature* **266**, 722-724.

106. Garbrecht, M.R., Klein, J.M., Schmidt, T.J., and Snyder, J.M. (2006) Glucocorticoid metabolism in the human fetal lung: implications for lung development and the pulmonary surfactant system. *Biol. Neonate* **89**, 109-119.

107. Garofano, A., Czernichow, P., and Breant, B. (1997) In utero undernutrition impairs rat beta-cell development. *Diabetologia* **40**, 1231-1234.

108. Garofano, A., Czernichow, P., and Breant, B. (1998) Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat. *Diabetologia* **41**, 1114-1120.

109. Ge, R.S., Dong, Q., Niu, E.M., Sottas, C.M., Hardy, D.O., Catterall, J.F., Latif, S.A., Morris, D.J., and Hardy, M.P. (2005) 11{beta}-Hydroxysteroid dehydrogenase 2 in rat leydig cells: its role in blunting glucocorticoid action at physiological levels of substrate. *Endocrinology* **146**, 2657-2664.

110. Gefen, A., Gefen, N., Zhu, Q., Raghupathi, R., and Margulies, S.S. (2003) Age-dependent changes in material properties of the brain and braincase of the rat. *J. Neurotrauma* **20**, 1163-1177.

111. Gemmill, M.E., Eskay, R.L., Hall, N.L., Douglass, L.W., and Castonguay, T.W. (2003) Leptin suppresses food intake and body weight in corticosterone-replaced adrenalectomized rats. *J. Nutr.* **133**, 504-509.

112. Georgel, P. and Bahram, S. (2006)[Toll-dependent and toll-independent innate antiviral immunity]. *Med. Sci. (Paris)* **22**, 961-968.

113. Gerardin, D.C., Pereira, O.C., Kempinas, W.G., Florio, J.C., Moreira, E.G., and Bernardi, M.M. (2005) Sexual behavior, neuroendocrine, and neurochemical aspects in male rats exposed prenatally to stress. *Physiol. Behav.* **84**, 97-104.

114. Gitau, R., Fisk, N.M., and Glover, V. (2004) Human fetal and maternal corticotrophin releasing hormone responses to acute stress. *Arch. Dis. Child. Fetal Neonatal Ed.* **89**, F29-F32.

115. Gluckman, P.D., Butler, J.H., Comline, R., and Fowden, A. (1987) The effects of pancreatectomy on the plasma concentrations of insulin-like growth factors 1 and 2 in the sheep fetus. *J. Dev. Physiol.* **9**, 79-88.

116. Gluckman, P.D. and Harding, J.E. (1997) The physiology and pathophysiology of intrauterine growth retardation. *Horm. Res.* **48**(Suppl 1), 11-16.

117. Gohlke, B.C., Huber, A., Bartmann, P., Fimmers, R., Hecher, K., Bouret, S.G., and Roth, C.L. (2006) Cord blood leptin and IGF-I in relation to birth weight differences and head circumference in monozygotic twins. *J. Pediatr. Endocrinol. Metab.* **19**, 3-9.

118. Gorski, R.A., Gordon, J.H., Shryne, J.E., and Southam, A.M. (1978) Evidence for a morphological sex difference within the medial preoptic area of the rat brain. *Brain Res.* **148**, 333-346.

119. Gorski, R.A., Harlan, R.E., Jacobson, C.D., Shryne, J.E., and Southam, A.M. (1980) Evidence for the existence of a sexually dimorphic nucleus in the preoptic area of the rat. *J. Comp. Neurol.* **193**, 529-539.

120. Gotz, A.A. and Stefanski, V. (2007) Psychosocial maternal stress during pregnancy affects serum corticosterone, blood immune parameters and anxiety behaviour in adult male rat offspring. *Physiol. Behav.* **90**, 108-115.

121. Gray, L.E., Jr., Ostby, J.S., and Kelce, W.R. (1994) Developmental effects of an environmental antiandrogen: the fungicide vinclozolin alters sex differentiation of the male rat. *Toxicol. Appl. Pharmacol.* **129**, 46-52.

122. Gray, L.E., Jr. and Ostby, J. (1998) Effects of pesticides and toxic substances on behavioral and morphological reproductive development: endocrine versus nonendocrine mechanisms. *Toxicol. Ind. Health* **14**, 159-184.

123. Grisham, W., Kerchner, M., and Ward, I.L. (1991) Prenatal stress alters sexually dimorphic nuclei in the spinal cord of male rats. *Brain Res.* **551**, 126-131.

124. Hahn, T., Barth, S., Graf, R., Engelmann, M., Beslagic, D., Reul, J.M., Holsboer, F., Dohr, G., and Desoye, G. (1999) Placental glucose transporter expression is regulated by glucocorticoids. *J. Clin. Endocrinol. Metab.* **84**, 1445-1452.

125. Hales, C.N., Barker, D.J., Clark, P.M., Cox, L.J., Fall, C., Osmond, C., and Winter, P.D. (1991) Fetal and infant growth and impaired glucose tolerance at age 64. *BMJ* **303**, 1019-1022.

126. Hales, C.N. and Barker, D.J. (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. *Diabetologia* **35**, 595-601.
98. Freyschmidt-Paul, P., McElwee, K.J., Hoffmann, R., Sundberg, J.P., Vitacolonna, M., Kissling, S., and Zoller, M. (2006) Interferon-gamma-deficient mice are resistant to the development of alopecia areata. *Br. J. Dermatol.* **155**, 515-521.

99. Fride, E. and Weinstock, M. (1984) The effects of prenatal exposure to predictable or unpredictable stress on early development in the rat. *Dev. Psychobiol.* **17**, 651-660.

100. Frye, C.A. and Orecki, Z.A. (2002) Prenatal stress alters reproductive responses of rats in behavioral estrus and paced mating of hormone-primed rats. *Horm. Behav.* **42**, 472-483.

101. Fujioka, A., Fujioka, T., Ishida, Y., Maekawa, T., and Nakamura, S. (2006) Differential effects of prenatal stress on the morphological maturation of hippocampal neurons. *Neuroscience* **141**, 907-915.

102. Fujioka, T., Sakata, Y., Yamaguchi, K., Shibasaki, T., Kato, H., and Nakamura, S. (1999) The effects of prenatal stress on the development of hypothalamic paraventricular neurons in fetal rats. *Neuroscience* **92**, 1079-1088.

103. Gafni, R.I. and Baron, J. (2000) Catch-up growth: possible mechanisms. *Pediatr. Nephrol.* **14**, 616-619.

104. Galler, J.R. and Tonkiss, J. (1991) Prenatal protein malnutrition and maternal behavior in Sprague-Dawley rats. *J. Nutr.* **121**, 762-769.

105. Gandelman, R., vom Saal, F.S., and Reinisch, J.M. (1977) Contiguity to male foetuses affects morphology and behaviour of female mice. *Nature* **266**, 722-724.

106. Garbrecht, M.R., Klein, J.M., Schmidt, T.J., and Snyder, J.M. (2006) Glucocorticoid metabolism in the human fetal lung: implications for lung development and the pulmonary surfactant system. *Biol. Neonate* **89**, 109-119.

107. Garofano, A., Czernichow, P., and Breant, B. (1997) In utero undernutrition impairs rat beta-cell development. *Diabetologia* **40**, 1231-1234.

108. Garofano, A., Czernichow, P., and Breant, B. (1998) Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat. *Diabetologia* **41**, 1114-1120.

109. Ge, R.S., Dong, Q., Niu, E.M., Sottas, C.M., Hardy, D.O., Catterall, J.F., Latif, S.A., Morris, D.J., and Hardy, M.P. (2005) 11{beta}-Hydroxysteroid dehydrogenase 2 in rat leydig cells: its role in blunting glucocorticoid action at physiological levels of substrate. *Endocrinology* **146**, 2657-2664.

110. Gefen, A., Gefen, N., Zhu, Q., Raghupathi, R., and Margulies, S.S. (2003) Age-dependent changes in material properties of the brain and braincase of the rat. *J. Neurotrauma* **20**, 1163-1177.

111. Gemmill, M.E., Eskay, R.L., Hall, N.L., Douglass, L.W., and Castonguay, T.W. (2003) Leptin suppresses food intake and body weight in corticosterone-replaced adrenalectomized rats. *J. Nutr.* **133**, 504-509.

112. Georgel, P. and Bahram, S. (2006)[Toll-dependent and toll-independent innate antiviral immunity]. *Med. Sci. (Paris)* **22**, 961-968.

113. Gerardin, D.C., Pereira, O.C., Kempinas, W.G., Florio, J.C., Moreira, E.G., and Bernardi, M.M. (2005) Sexual behavior, neuroendocrine, and neurochemical aspects in male rats exposed prenatally to stress. *Physiol. Behav.* **84**, 97-104.

114. Gitau, R., Fisk, N.M., and Glover, V. (2004) Human fetal and maternal corticotrophin releasing hormone responses to acute stress. *Arch. Dis. Child. Fetal Neonatal Ed.* **89**, F29-F32.

115. Gluckman, P.D., Butler, J.H., Comline, R., and Fowden, A. (1987) The effects of pancreatectomy on the plasma concentrations of insulin-like growth factors 1 and 2 in the sheep fetus. *J. Dev. Physiol.* **9**, 79-88.

116. Gluckman, P.D. and Harding, J.E. (1997) The physiology and pathophysiology of intrauterine growth retardation. *Horm. Res.* **48**(Suppl 1), 11-16.

117. Gohlke, B.C., Huber, A., Bartmann, P., Fimmers, R., Hecher, K., Bouret, S.G., and Roth, C.L. (2006) Cord blood leptin and IGF-I in relation to birth weight differences and head circumference in monozygotic twins. *J. Pediatr. Endocrinol. Metab.* **19**, 3-9.

118. Gorski, R.A., Gordon, J.H., Shryne, J.E., and Southam, A.M. (1978) Evidence for a morphological sex difference within the medial preoptic area of the rat brain. *Brain Res.* **148**, 333-346.

119. Gorski, R.A., Harlan, R.E., Jacobson, C.D., Shryne, J.E., and Southam, A.M. (1980) Evidence for the existence of a sexually dimorphic nucleus in the preoptic area of the rat. *J. Comp. Neurol.* **193**, 529-539.

120. Gotz, A.A. and Stefanski, V. (2007) Psychosocial maternal stress during pregnancy affects serum corticosterone, blood immune parameters and anxiety behaviour in adult male rat offspring. *Physiol. Behav.* **90**, 108-115.

121. Gray, L.E., Jr., Ostby, J.S., and Kelce, W.R. (1994) Developmental effects of an environmental antiandrogen: the fungicide vinclozolin alters sex differentiation of the male rat. *Toxicol. Appl. Pharmacol.* **129**, 46-52.

122. Gray, L.E., Jr. and Ostby, J. (1998) Effects of pesticides and toxic substances on behavioral and morphological reproductive development: endocrine versus nonendocrine mechanisms. *Toxicol. Ind. Health* **14**, 159-184.

123. Grisham, W., Kerchner, M., and Ward, I.L. (1991) Prenatal stress alters sexually dimorphic nuclei in the spinal cord of male rats. *Brain Res.* **551**, 126-131.

124. Hahn, T., Barth, S., Graf, R., Engelmann, M., Beslagic, D., Reul, J.M., Holsboer, F., Dohr, G., and Desoye, G. (1999) Placental glucose transporter expression is regulated by glucocorticoids. *J. Clin. Endocrinol. Metab.* **84**, 1445-1452.

125. Hales, C.N., Barker, D.J., Clark, P.M., Cox, L.J., Fall, C., Osmond, C., and Winter, P.D. (1991) Fetal and infant growth and impaired glucose tolerance at age 64. *BMJ* **303**, 1019-1022.

126. Hales, C.N. and Barker, D.J. (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. *Diabetologia* **35**, 595-601.
127. Hales, C.N. and Ozanne, S.E. (2003) The dangerous road of catch-up growth. *J. Physiol.* **547**, 5–10.

128. Hales, C.N. and Ozanne, S.E. (2003) For debate: fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure. *Diabetologia* **46**, 1013–1019.

129. Hashimoto, M., Watanabe, T., Fujioka, T., Tan, N., Yamashita, H., and Nakamura, S. (2001) Modulating effects of prenatal stress on hyperthermia induced in adult rat offspring by restraint or LPS-induced stress. *Physiol. Behav.* **73**, 125–132.

130. Hattersley, A.T. and Tooke, J.E. (1999) The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. *Lancet* **353**, 1789–1792.

131. Hayashi, A., Nagaoka, M., Yamada, K., Ichitani, Y., MIAKE, Y., and Okado, N. (1998) Maternal stress induces synaptic loss and developmental disabilities of offspring. Int. *J. Dev. Neurosci.* **16**, 209–216.

132. Henry, C., Kabbaj, M., Simon, H., Le, M.M., and Maccari, S. (1994) Prenatal stress increases the hypothalamo-pituitary-adrenal axis response in young and adult rats. *J. Neuroendocrinol.* **6**, 341–345.

133. Henry, C., Arsaut, J., Arnauld, E., and Demotes-Mainard, J. (1996) Transient neonatal elevation in hypothalamic estrogen receptor mRNA in prenatally-stressed male rats. *Neurosci. Lett.* **216**, 141–145.

134. Hermann, G., Tovar, C.A., Beck, F.M., and Sheridan, J.F. (1994) Kinetics of glucocorticoid response to restraint stress and/or experimental influenza viral infection in two inbred strains of mice. *J. Neuroimmunol.* **49**, 25–33.

135. Herrenkohl, L.R. (1979) Prenatal stress reduces fertility and fecundity in female offspring. *Science* **206**, 1097–1099.

136. Herrenkohl, L.R. and Scott, S. (1984) Prenatal stress and postnatal androgen: effects on reproduction in female rats. *Experientia* **40**, 101–103.

137. Hinde, R.A. (1986) Some implication of evolutionary theory and comparative data for the study of human prosocial and aggressive behaviour. In *Development of Anti-Social and Prosocial Behavior*, Eds D. Olweus, J. Block, and M. Radke-Yarrow, Academic Press, Orlando, 13-32.

138. Hines, M., Johnston, K.J., Golombok, S., Rust, J., Stevens, M., and Golding, J. (2002) Prenatal stress and gender role behavior in girls and boys: a longitudinal, population study. *Horm. Behav.* **42**, 126–134.

139. Hng, T.M., Cheung, N.W., and McLean, M. (2005) Growth hormone and cortisol dynamic function in relation to birth weight: a study in adult twins. *J. Clin. Endocrinol. Metab.* **90**, 2781–2786.

140. Holmes, M.C., Abrahamsen, C.T., French, K.L., Paterson, J.M., Mullins, J.J., and Seckl, J.R. (2006) The mother or the fetus? 11beta-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids. *J. Neurosci.* **26**, 3840–3844.

141. Holt, R.I. (2002) Fetal programming of the growth hormone-insulin-like growth factor axis. *Trends Endocrinol. Metab.* **13**, 392–397.

142. Horton, T.H. (2005) Fetal origins of developmental plasticity: animal models of induced life history variation. *Am. J. Hum. Biol.* **17**, 34–43.

143. Hotchkiss, A.K., Ostby, J.S., Vandenburgh, J.G., and Gray, L.E., Jr. (2002) Androgens and environmental antiandrogens affect reproductive development and play behavior in the Sprague-Dawley rat. *Environ. Health Perspect.* **110**(Suppl 3), 435–439.

144. Huck, U.W., Labov, J.B., and Lisk, R.D. (1987) Food-restricting first generation juvenile female hamsters (Mesocricetus auratus) affects sex ratio and growth of third generation offspring. *Biol. Reprod.* **37**, 612–617.

145. Hulshoff Pol, H.E., Hoek, H.W., Susser, E., Brown, A.S., Dingemans, A., Schnack, H.G., van Haren, N.E., Pereira Ramos, L.M., Gispen-de Wied, C.C., and Kahn, R.S. (2000) Prenatal exposure to famine and brain morphology in schizophrenia. *Am. J. Psychiatry* **157**, 1170–1172.

146. Humm, J.L., Lambert, K.G., and Kinsley, C.H. (1995) Paucity of c-fos expression in the medial preoptic area of prenatally stressed male rats following exposure to sexually receptive females. *Brain Res. Bull.* **37**, 363–368.

147. Igosheva, N., Klimova, O., Anishchenko, T., and Glover, V. (2004) Prenatal stress alters cardiovascular responses in adult rats. *J. Physiol.* **557**, 273–285.

148. Jacobson, C.D., Csernus, V.J., Shryne, J.E., and Gorski, R.A. (1981) The influence of gonadectomy, androgen exposure, or a gonadal graft in the neonatal rat on the volume of the sexually dimorphic nucleus of the preoptic area. *J. Neurosci.* **1**, 1142–1147.

149. Jara, L.J., Navarro, C., Medina, G., Vera-Lastra, O., and Blanco, F. (2006) Immune-neuroendocrine interactions and autoimmune diseases. *Clin. Dev. Immunol.* **13**, 109–123.

150. Joost, H.G. and Thorens, B. (2001) The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members (review). *Mol. Membr. Biol.* **18**, 247–256.

151. Kaffman, A. and Meaney, M.J. (2007) Neurodevelopmental sequelae of postnatal maternal care in rodents: clinical and research implications of molecular insights. *J. Child Psychol. Psychiatry* **48**, 224–244.

152. Kallapur, S.G., Kramer, B.W., Moss, T.J., Newnham, J.P., Jobe, A.H., Ikegami, M., and Bachurski, C.J. (2003) Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm lambs. *Am. J. Physiol. Lung Cell. Mol. Physiol.* **284**, L633–L642.

153. Kanaka-Gantenbein, C., Mastorakos, G., and Chrousos, G.P. (2003) Endocrine-related causes and consequences of intrauterine growth retardation. *Ann. N. Y. Acad. Sci.* **997**, 150–157.

154. Kavelaars, A., van der, P.G., Bakker, J.M., van Hasselt, P.M., Cats, B., Visser, G.H., and Heijnen, C.J. (1999) Altered immune function in human newborns after prenatal administration of betamethasone: enhanced natural killer cell activity and decreased T cell proliferation in cord blood. *Pediatr. Res.* **45**, 306–312.
127. Hales, C.N. and Ozanne, S.E. (2003) The dangerous road of catch-up growth. *J. Physiol.* **547**, 5–10.

128. Hales, C.N. and Ozanne, S.E. (2003) For debate: fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure. *Diabetologia* **46**, 1013–1019.

129. Hashimoto, M., Watanabe, T., Fujioka, T., Tan, N., Yamashita, H., and Nakamura, S. (2001) Modulating effects of prenatal stress on hyperthermia induced in adult rat offspring by restraint or LPS-induced stress. *Physiol. Behav.* **73**, 125–132.

130. Hattersley, A.T. and Tooke, J.E. (1999) The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. *Lancet* **353**, 1789–1792.

131. Hayashi, A., Nagaoka, M., Yamada, K., Ichitani, Y., MIAKE, Y., and Okado, N. (1998) Maternal stress induces synaptic loss and developmental disabilities of offspring. Int. J. Dev. Neurosci. **16**, 209–216.

132. Henry, C., Kabbaj, M., Simon, H., Le, M.M., and Maccari, S. (1994) Prenatal stress increases the hypothalamo-pituitary-adrenal axis response in young and adult rats. *J. Neuroendocrinol.* **6**, 341–345.

133. Henry, C., Arsaut, J., Arnauld, E., and Demotes-Mainard, J. (1996) Transient neonatal elevation in hypothalamic estrogen receptor mRNA in prenatally-stressed male rats. *Neurosci. Lett.* **216**, 141–145.

134. Hermann, G., Tovar, C.A., Beck, F.M., and Sheridan, J.F. (1994) Kinetics of glucocorticoid response to restraint stress and/or experimental influenza viral infection in two inbred strains of mice. *J. Neuroimmunol.* **49**, 25–33.

135. Herrenkohl, L.R. (1979) Prenatal stress reduces fertility and fecundity in female offspring. *Science* **206**, 1097–1099.

136. Herrenkohl, L.R. and Scott, S. (1984) Prenatal stress and postnatal androgen: effects on reproduction in female rats. *Experientia* **40**, 101–103.

137. Hinde, R.A. (1986) Some implication of evolutionary theory and comparative data for the study of human prosocial and aggressive behaviour. In *Development of Anti-Social and Prosocial Behavior*, Eds D. Olweus, J. Block, and M. Radke-Yarrow, Academic Press, Orlando, 13-32.

138. Hines, M., Johnston, K.J., Golombok, S., Rust, J., Stevens, M., and Golding, J. (2002) Prenatal stress and gender role behavior in girls and boys: a longitudinal, population study. *Horm. Behav.* **42**, 126–134.

139. Hng, T.M., Cheung, N.W., and McLean, M. (2005) Growth hormone and cortisol dynamic function in relation to birth weight: a study in adult twins. *J. Clin. Endocrinol. Metab.* **90**, 2781–2786.

140. Holmes, M.C., Abrahamsen, C.T., French, K.L., Paterson, J.M., Mullins, J.J., and Seckl, J.R. (2006) The mother or the fetus? 11beta-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids. *J. Neurosci.* **26**, 3840–3844.

141. Holt, R.I. (2002) Fetal programming of the growth hormone-insulin-like growth factor axis. *Trends Endocrinol. Metab.* **13**, 392–397.

142. Horton, T.H. (2005) Fetal origins of developmental plasticity: animal models of induced life history variation. *Am. J. Hum. Biol.* **17**, 34–43.

143. Hotchkiss, A.K., Ostby, J.S., Vandenburgh, J.G., and Gray, L.E., Jr. (2002) Androgens and environmental antiandrogens affect reproductive development and play behavior in the Sprague-Dawley rat. *Environ. Health Perspect.* **110**(Suppl 3), 435–439.

144. Huck, U.W., Labov, J.B., and Lisk, R.D. (1987) Food-restricting first generation juvenile female hamsters (Mesocricetus auratus) affects sex ratio and growth of third generation offspring. *Biol. Reprod.* **37**, 612–617.

145. Hulshoff Pol, H.E., Hoek, H.W., Susser, E., Brown, A.S., Dingemans, A., Schnack, H.G., van Haren, N.E., Pereira Ramos, L.M., Gispen-de Wied, C.C., and Kahn, R.S. (2000) Prenatal exposure to famine and brain morphology in schizophrenia. *Am. J. Psychiatry* **157**, 1170–1172.

146. Humm, J.L., Lambert, K.G., and Kinsley, C.H. (1995) Paucity of c-fos expression in the medial preoptic area of prenatally stressed male rats following exposure to sexually receptive females. *Brain Res. Bull.* **37**, 363–368.

147. Igosheva, N., Klimova, O., Anishchenko, T., and Glover, V. (2004) Prenatal stress alters cardiovascular responses in adult rats. *J. Physiol.* **557**, 273–285.

148. Jacobson, C.D., Csernus, V.J., Shryne, J.E., and Gorski, R.A. (1981) The influence of gonadectomy, androgen exposure, or a gonadal graft in the neonatal rat on the volume of the sexually dimorphic nucleus of the preoptic area. *J. Neurosci.* **1**, 1142–1147.

149. Jara, L.J., Navarro, C., Medina, G., Vera-Lastra, O., and Blanco, F. (2006) Immune-neuroendocrine interactions and autoimmune diseases. *Clin. Dev. Immunol.* **13**, 109–123.

150. Joost, H.G. and Thorens, B. (2001) The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members (review). *Mol. Membr. Biol.* **18**, 247–256.

151. Kaffman, A. and Meaney, M.J. (2007) Neurodevelopmental sequelae of postnatal maternal care in rodents: clinical and research implications of molecular insights. *J. Child Psychol. Psychiatry* **48**, 224–244.

152. Kallapur, S.G., Kramer, B.W., Moss, T.J., Newnham, J.P., Jobe, A.H., Ikegami, M., and Bachurski, C.J. (2003) Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm lambs. *Am. J. Physiol. Lung Cell. Mol. Physiol.* **284**, L633–L642.

153. Kanaka-Gantenbein, C., Mastorakos, G., and Chrousos, G.P. (2003) Endocrine-related causes and consequences of intrauterine growth retardation. *Ann. N. Y. Acad. Sci.* **997**, 150–157.

154. Kavelaars, A., van der, P.G., Bakker, J.M., van Hasselt, P.M., Cats, B., Visser, G.H., and Heijnen, C.J. (1999) Altered immune function in human newborns after prenatal administration of betamethasone: enhanced natural killer cell activity and decreased T cell proliferation in cord blood. *Pediatr. Res.* **45**, 306–312.
155. Kavelaars, A., Kuis, W., Knook, L., Sinnema, G., and Heijnen, C.J. (2000) Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome. *J. Clin. Endocrinol. Metab.* **85**, 692–696.

156. Kay, G., Tarcic, N., Poltyrev, T., and Weinstock, M. (1998) Prenatal stress depresses immune function in rats. *Physiol. Behav.* **63**, 397–402.

157. Kerchner, M., Malsbury, C.W., Ward, O.B., and Ward, I.L. (1995) Sexually dimorphic areas in the rat medial amygdala: resistance to the demasculinizing effect of prenatal stress. *Brain Res.* **672**, 251–260.

158. Kerman, I.A., Akil, H., and Watson, S.J. (2006) Rostral elements of sympatho-motor circuitry: a virally mediated transsynaptic tracing study. *J. Neurosci.* **26**, 3423–3433.

159. Keshet, G.I. and Weinstock, M. (1995) Maternal naltrexone prevents morphological and behavioral alterations induced in rats by prenatal stress. *Pharmacol. Biochem. Behav.* **50**, 413–419.

160. Kinsley, C. and Svare, B. (1986) Prenatal stress effects: are they mediated by reductions in maternal food and water intake and body weight gain? *Physiol. Behav.* **37**, 191–193.

161. Kinsley, C.H., Mann, P.E., and Bridges, R.S. (1992) Diminished luteinizing hormone release in prenatally stressed male rats after exposure to sexually receptive females. *Physiol. Behav.* **52**, 925–928.

162. Kjaer, A. (1993) Vasopressin as a neuroendocrine regulator of anterior pituitary hormone secretion. *Acta Endocrinol. (Copenh.)* **129**, 489–496.

163. Klein, S.L. and Rager, D.R. (1995) Prenatal stress alters immune function in the offspring of rats. *Dev. Psychobiol.* **28**, 321–336.

164. Koenig, J.I., Elmer, G.I., Shepard, P.D., Lee, P.R., Mayo, C., Joy, B., Hercher, E., and Brady, D.L. (2005) Prenatal exposure to a repeated variable stress paradigm elicits behavioral and neuroendocrinological changes in the adult offspring: potential relevance to schizophrenia. *Behav. Brain Res.* **156**, 251–261.

165. Komatsu, S., Yamamoto, M., Arishima, K., and Eguchi, Y. (1998) Maternal adrenocortical hormones maintain the early development of pancreatic B cells in the fetal rat. *J. Anat.* **193**(Pt 4), 551–557.

166. Koo, J.W., Park, C.H., Choi, S.H., Kim, N.J., Kim, H.S., Choe, J.C., and Suh, Y.H. (2003) The postnatal environment can counteract prenatal effects on cognitive ability, cell proliferation, and synaptic protein expression. *FASEB J.* **17**, 1556–1558.

167. Korgun, E.T., Celik-Ozenci, C., Seval, Y., Desoye, G., and Demir, R. (2005) Do glucose transporters have other roles in addition to placental glucose transport during early pregnancy? *Histochem. Cell Biol.* **123**, 621–629.

168. Kuzawa, C.W. (2005) Fetal origins of developmental plasticity: are fetal cues reliable predictors of future nutritional environments? *Am. J. Hum. Biol.* **17**, 5–21.

169. Laborie, C., Dutriez-Casteloot, I., Montel, V., ckes-Coopman, A., Lesage, J., and Vieau, D. (2005) Prenatal morphine exposure affects sympathoadrenal axis activity and serotonin metabolism in adult male rats both under basal conditions and after an ether inhalation stress. *Neurosci. Lett.* **381**, 211–216.

170. Lalau, J.D., Aubert, M.L., Carmignac, D.F., Gregoire, I., and Dupouy, J.P. (1990) Reduction in testicular function in rats. II. Reduction by dexamethasone in fetal and neonatal rats. *Neuroendocrinology* **51**, 289–293.

171. Langley-Evans, S.C., Gardner, D.S., and Jackson, A.A. (1996) Maternal protein restriction influences the programming of the rat hypothalamic-pituitary-adrenal axis. *J. Nutr.* **126**, 1578–1585.

172. Langley-Evans, S.C. (1997) Hypertension induced by foetal exposure to a maternal low-protein diet, in the rat, is prevented by pharmacological blockade of maternal glucocorticoid synthesis. *J. Hypertens.* **15**, 537–544.

173. Langley-Evans, S.C. (2001) Fetal programming of cardiovascular function through exposure to maternal undernutrition. *Proc. Nutr. Soc.* **60**, 505–513.

174. Langley-Evans, S.C., Bellinger, L., and McMullen, S. (2005) Animal models of programming: early life influences on appetite and feeding behaviour. *Matern. Child Nutr.* **1**, 142–148.

175. Lassarre, C., Hardouin, S., Daffos, F., Forestier, F., Frankenne, F., and Binoux, M. (1991) Serum insulin-like growth factors and insulin-like growth factor binding proteins in the human fetus. Relationships with growth in normal subjects and in subjects with intrauterine growth retardation. *Pediatr. Res.* **29**, 219–225.

176. Latimer, A.M., Hausman, G.J., McCusker, R.H., and Buonomo, F.C. (1993) The effects of thyroxine on serum and tissue concentrations of insulin-like growth factors (IGF-I and -II) and IGF-binding proteins in the fetal pig. *Endocrinology* **133**, 1312–1319.

177. Laviola, G., Rea, M., Morley-Fletcher, S., Di, C.S., Bacosi, A., De, S.R., Bertini, M., and Pacifici, R. (2004) Beneficial effects of enriched environment on adolescent rats from stressed pregnancies. *Eur. J. Neurosci.* **20**, 1655–1664.

178. Lazzarin, A., Luerti, M., Capsoni, F., Galli, M., Uberti-Foppa, C., Zavattini, G., and Corbella, E. (1986) A study of cellular immunity in newborns after prevention of respiratory distress syndrome (RDS). *Int. J. Tissue React.* **8**, 157–165.

179. Le Roith D (1999) Insulin-like growth factor. *Horm. Metab. Res.* **31**, 41–42.

180. Le Roith D., Scavo, L., and Butler, A. (2001) What is the role of circulating IGF-I? *Trends Endocrinol. Metab.* **12**, 48–52.

181. Leckman, J.F. and Herman, A.E. (2002) Maternal behavior and developmental psychopathology. *Biol. Psychiatry* **51**, 27–43.

182. Lemaire, V., Lamarque, S., Le, M.M., Piazza, P.V., and Abrous, D.N. (2006) Postnatal stimulation of the pups counteracts prenatal stress-induced deficits in hippocampal neurogenesis. *Biol. Psychiatry* **59**, 786–792.
155. Kavelaars, A., Kuis, W., Knook, L., Sinnema, G., and Heijnen, C.J. (2000) Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome. *J. Clin. Endocrinol. Metab.* **85**, 692-696.

156. Kay, G., Tarcic, N., Poltyrev, T., and Weinstock, M. (1998) Prenatal stress depresses immune function in rats. *Physiol. Behav.* **63**, 397-402.

157. Kerchner, M., Malsbury, C.W., Ward, O.B., and Ward, I.L. (1995) Sexually dimorphic areas in the rat medial amygdala: resistance to the demasculinizing effect of prenatal stress. *Brain Res.* **672**, 251-260.

158. Kerman, I.A., Akil, H., and Watson, S.J. (2006) Rostral elements of sympatho-motor circuitry: a virally mediated transsynaptic tracing study. *J. Neurosci.* **26**, 3423-3433.

159. Keshet, G.I. and Weinstock, M. (1995) Maternal naltrexone prevents morphological and behavioral alterations induced in rats by prenatal stress. *Pharmacol. Biochem. Behav.* **50**, 413-419.

160. Kinsley, C. and Svare, B. (1986) Prenatal stress effects: are they mediated by reductions in maternal food and water intake and body weight gain? *Physiol. Behav.* **37**, 191-193.

161. Kinsley, C.H., Mann, P.E., and Bridges, R.S. (1992) Diminished luteinizing hormone release in prenatally stressed male rats after exposure to sexually receptive females. *Physiol. Behav.* **52**, 925-928.

162. Kjaer, A. (1993) Vasopressin as a neuroendocrine regulator of anterior pituitary hormone secretion. *Acta Endocrinol. (Copenh.)* **129**, 489-496.

163. Klein, S.L. and Rager, D.R. (1995) Prenatal stress alters immune function in the offspring of rats. *Dev. Psychobiol.* **28**, 321-336.

164. Koenig, J.I., Elmer, G.I., Shepard, P.D., Lee, P.R., Mayo, C., Joy, B., Hercher, E., and Brady, D.L. (2005) Prenatal exposure to a repeated variable stress paradigm elicits behavioral and neuroendocrinological changes in the adult offspring: potential relevance to schizophrenia. *Behav. Brain Res.* **156**, 251-261.

165. Komatsu, S., Yamamoto, M., Arishima, K., and Eguchi, Y. (1998) Maternal adrenocortical hormones maintain the early development of pancreatic B cells in the fetal rat. *J. Anat.* **193**(Pt 4), 551-557.

166. Koo, J.W., Park, C.H., Choi, S.H., Kim, N.J., Kim, H.S., Choe, J.C., and Suh, Y.H. (2003) The postnatal environment can counteract prenatal effects on cognitive ability, cell proliferation, and synaptic protein expression. *FASEB J.* **17**, 1556-1558.

167. Korgun, E.T., Celik-Ozenci, C., Seval, Y., Desoye, G., and Demir, R. (2005) Do glucose transporters have other roles in addition to placental glucose transport during early pregnancy? *Histochem. Cell Biol.* **123**, 621-629.

168. Kuzawa, C.W. (2005) Fetal origins of developmental plasticity: are fetal cues reliable predictors of future nutritional environments? *Am. J. Hum. Biol.* **17**, 5-21.

169. Laborie, C., Dutriez-Casteloot, I., Montel, V., ckes-Coopman, A., Lesage, J., and Vieau, D. (2005) Prenatal morphine exposure affects sympathoadrenal axis activity and serotonin metabolism in adult male rats both under basal conditions and after an ether inhalation stress. *Neurosci. Lett.* **381**, 211-216.

170. Lalau, J.D., Aubert, M.L., Carmignac, D.F., Gregoire, I., and Dupouy, J.P. (1990) Reduction in testicular function in rats. II. Reduction by dexamethasone in fetal and neonatal rats. *Neuroendocrinology* **51**, 289-293.

171. Langley-Evans, S.C., Gardner, D.S., and Jackson, A.A. (1996) Maternal protein restriction influences the programming of the rat hypothalamic-pituitary-adrenal axis. *J. Nutr.* **126**, 1578-1585.

172. Langley-Evans, S.C. (1997) Hypertension induced by foetal exposure to a maternal low-protein diet, in the rat, is prevented by pharmacological blockade of maternal glucocorticoid synthesis. *J. Hypertens.* **15**, 537-544.

173. Langley-Evans, S.C. (2001) Fetal programming of cardiovascular function through exposure to maternal undernutrition. *Proc. Nutr. Soc.* **60**, 505-513.

174. Langley-Evans, S.C., Bellinger, L., and McMullen, S. (2005) Animal models of programming: early life influences on appetite and feeding behaviour. *Matern. Child Nutr.* **1**, 142-148.

175. Lassarre, C., Hardouin, S., Daffos, F., Forestier, F., Frankenne, F., and Binoux, M. (1991) Serum insulin-like growth factors and insulin-like growth factor binding proteins in the human fetus. Relationships with growth in normal subjects and in subjects with intrauterine growth retardation. *Pediatr. Res.* **29**, 219-225.

176. Latimer, A.M., Hausman, G.J., McCusker, R.H., and Buonomo, F.C. (1993) The effects of thyroxine on serum and tissue concentrations of insulin-like growth factors (IGF-I and -II) and IGF-binding proteins in the fetal pig. *Endocrinology* **133**, 1312-1319.

177. Laviola, G., Rea, M., Morley-Fletcher, S., Di, C.S., Bacosi, A., De, S.R., Bertini, M., and Pacifici, R. (2004) Beneficial effects of enriched environment on adolescent rats from stressed pregnancies. *Eur. J. Neurosci.* **20**, 1655-1664.

178. Lazzarin, A., Luerti, M., Capsoni, F., Galli, M., Uberti-Foppa, C., Zavattini, G., and Corbella, E. (1986) A study of cellular immunity in newborns after prevention of respiratory distress syndrome (RDS). *Int. J. Tissue React.* **8**, 157-165.

179. Le Roith D (1999) Insulin-like growth factor. *Horm. Metab. Res.* **31**, 41-42.

180. Le Roith D., Scavo, L., and Butler, A. (2001) What is the role of circulating IGF-I? *Trends Endocrinol. Metab.* **12**, 48-52.

181. Leckman, J.F. and Herman, A.E. (2002) Maternal behavior and developmental psychopathology. *Biol. Psychiatry* **51**, 27-43.

182. Lemaire, V., Lamarque, S., Le, M.M., Piazza, P.V., and Abrous, D.N. (2006) Postnatal stimulation of the pups counteracts prenatal stress-induced deficits in hippocampal neurogenesis. *Biol. Psychiatry* **59**, 786-792.
183. Leong, N.M., Mignone, L.I., Newcomb, P.A., Titus-Ernstoff, L., Baron, J.A., Trentham-Dietz, A., Stampfer, M.J., Willett, W.C., and Egan, K.M. (2003) Early life risk factors in cancer: the relation of birth weight to adult obesity. *Int. J. Cancer* **103**, 789-791.

184. Lesage, J., Grino, M., Bernet, F., Dutriez-Casteloot, I., Montel, V., and Dupouy, J.P. (1998) Consequences of prenatal morphine exposure on the hypothalamo-pituitary-adrenal axis in the newborn rat: effect of maternal adrenalectomy. *J. Neuroendocrinol.* **10**, 331-342.

185. Lesage, J., Del-Favero, F., Leonhardt, M., Louvart, H., Maccari, S., Vieau, D., and Darnaudery, M. (2004) Prenatal stress induces intrauterine growth restriction and programmes glucose intolerance and feeding behaviour disturbances in the aged rat. *J. Endocrinol.* **181**, 291-296.

186. Levine, S. (1956) A further study of infantile handling and adult avoidance learning. *J. Pers.* **25**, 70-80.

187. Levine, S. (2000) Influence of psychological variables on the activity of the hypothalamic-pituitary-adrenal axis. *Eur. J. Pharmacol.* **405**, 149-160.

188. Lewis, M.H. (2004) Environmental complexity and central nervous system development and function. *Ment. Retard. Dev. Disabil. Res. Rev.* **10**, 91-95.

189. Li, Y.F., Jackson, K.L., Stern, J.E., Rabeler, B., and Patel, K.P. (2006) Interaction between glutamate and GABA systems in the integration of sympathetic outflow by the paraventricular nucleus of the hypothalamus. *Am. J. Physiol. Heart Circ. Physiol.* **291**, H2847-H2856.

190. Lindsay, R.S., Lindsay, R.M., Waddell, B.J., and Seckl, J.R. (1996) Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone. *Diabetologia* **39**, 1299-1305.

191. Liu, D., Diorio, J., Tannenbaum, B., Caldji, C., Francis, D., Freedman, A., Sharma, S., Pearson, D., Plotsky, P.M., and Meaney, M.J. (1997) Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. *Science* **277**, 1659-1662.

192. Llorente, E., Brito, M.L., Machado, P., and Gonzalez, M.C. (2002) Effect of prenatal stress on the hormonal response to acute and chronic stress and on immune parameters in the offspring. *J. Physiol. Biochem.* **58**, 143-149.

193. Lockwood, C.J., Radunovic, N., Nastic, D., Petkovic, S., Aigner, S., and Berkowitz, G.S. (1996) Corticotropin-releasing hormone and related pituitary-adrenal axis hormones in fetal and maternal blood during the second half of pregnancy. *J. Perinat. Med.* **24**, 243-251.

194. Loewy, A.D. (1981) Descending pathways to sympathetic and parasympathetic preganglionic neurons. *J. Auton. Nerv. Syst.* **3**, 265-275.

195. Lordi, B., Protais, P., Mellier, D., and Caston, J. (1997) Acute stress in pregnant rats: effects on growth rate, learning, and memory capabilities of the offspring. *Physiol. Behav.* **62**, 1087-1092.

196. Lordi, B., Patin, V., Protais, P., Mellier, D., and Caston, J. (2000) Chronic stress in pregnant rats: effects on growth rate, anxiety and memory capabilities of the offspring. *Int. J. Psychophysiol.* **37**, 195-205.

197. Louey, S. and Thornburg, K.L. (2005) The prenatal environment and later cardiovascular disease. *Early Hum. Dev.* **81**, 745-751.

198. Lovejoy, D.A. and Jahan, S. (2006) Phylogeny of the corticotropin-releasing factor family of peptides in the metazoa. *Gen. Comp Endocrinol.* **146**, 1-8.

199. Lucas, A. (1991) Programming by early nutrition in man. *Ciba Found. Symp.* **156**, 38-50; discussion 50-55 38-55.

200. Lummaa, V. (2003) Early developmental conditions and reproductive success in humans: downstream effects of prenatal famine, birthweight, and timing of birth. *Am. J. Hum. Biol.* **15**, 370-379.

201. Lupien, S.J., de Leon, M., de Santi, S., Convit, A., Tarshish, C., Nair, N.P., Thakur, M., McEwen, B.S., Hauger, R.L., and Meaney, M.J. (1998) Cortisol levels during human aging predict hippocampal atrophy and memory deficits. *Nat. Neurosci.* **1**, 69-73.

202. Maccari, S., Piazza, P.V., Kabbaj, M., Barbazanges, A., Simon, H., and Le, M.M. (1995) Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress. *J. Neurosci.* **15**, 110-116.

203. Maccari, S., Darnaudery, M., Morley-Fletcher, S., Zuena, A.R., Cinque, C., and Van, R.O. (2003) Prenatal stress and long-term consequences: implications of glucocorticoid hormones. *Neurosci. Biobehav. Rev.* **27**, 119-127.

204. Mairesse, J., Lesage, J., Breton, C., Breant, B., Hahn, T., Darnaudery, M., Dickson, S.L., Seckl, J., Blondeau, B., Vieau, D., Maccari, S., and Viltart, O. (2007) Maternal stress alters endocrine function of the feto-placental unit in rats. *Am. J. Physiol Endocrinol. Metab.* **292**(6), E1526-533.

205. Mann, D.R. and Fraser, H.M. (1996) The neonatal period: a critical interval in male primate development. *J. Endocrinol.* **149**, 191-197.

206. Martin, D.S. and Haywood, J.R. (1992) Sympathetic nervous system activation by glutamate injections into the paraventricular nucleus. *Brain Res.* **577**, 261-267.

207. Mazur-Kolecka, B., Kubera, M., Skowron-Cendrzak, A., Basta-Kaim, A., and Shani, J. (1996) Effect of prenatal stress on ontogenesis of immunoregulatory cell maturation in mice. *Pol. J. Pharmacol.* **48**, 621-625.

208. McEwen, B.S., Lieberburg, I., Chaptal, C., and Krey, L.C. (1977) Aromatization: important for sexual differentiation of the neonatal rat brain. *Horm. Behav.* **9**, 249-263.

209. McEwen, B.S. (1998) Protective and damaging effects of stress mediators. *N. Engl. J. Med.* **338**, 171-179.

210. McTernan, C.L., Draper, N., Nicholson, H., Chalder, S.M., Driver, P., Hewison, M., Kilby, M.D., and Stewart, P.M. (2001) Reduced placental 11beta-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies
183. Leong, N.M., Mignone, L.I., Newcomb, P.A., Titus-Ernstoff, L., Baron, J.A., Trentham-Dietz, A., Stampfer, M.J., Willett, W.C., and Egan, K.M. (2003) Early life risk factors in cancer: the relation of birth weight to adult obesity. *Int. J. Cancer* **103**, 789-791.

184. Lesage, J., Grino, M., Bernet, F., Dutriez-Casteloot, I., Montel, V., and Dupouy, J.P. (1998) Consequences of prenatal morphine exposure on the hypothalamo-pituitary-adrenal axis in the newborn rat: effect of maternal adrenalectomy. *J. Neuroendocrinol.* **10**, 331-342.

185. Lesage, J., Del-Favero, F., Leonhardt, M., Louvart, H., Maccari, S., Vieau, D., and Darnaudery, M. (2004) Prenatal stress induces intrauterine growth restriction and programmes glucose intolerance and feeding behaviour disturbances in the aged rat. *J. Endocrinol.* **181**, 291-296.

186. Levine, S. (1956) A further study of infantile handling and adult avoidance learning. *J. Pers.* **25**, 70-80.

187. Levine, S. (2000) Influence of psychological variables on the activity of the hypothalamic-pituitary-adrenal axis. *Eur. J. Pharmacol.* **405**, 149-160.

188. Lewis, M.H. (2004) Environmental complexity and central nervous system development and function. *Ment. Retard. Dev. Disabil. Res. Rev.* **10**, 91-95.

189. Li, Y.F., Jackson, K.L., Stern, J.E., Rabeler, B., and Patel, K.P. (2006) Interaction between glutamate and GABA systems in the integration of sympathetic outflow by the paraventricular nucleus of the hypothalamus. *Am. J. Physiol. Heart Circ. Physiol.* **291**, H2847-H2856.

190. Lindsay, R.S., Lindsay, R.M., Waddell, B.J., and Seckl, J.R. (1996) Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone. *Diabetologia* **39**, 1299-1305.

191. Liu, D., Diorio, J., Tannenbaum, B., Caldji, C., Francis, D., Freedman, A., Sharma, S., Pearson, D., Plotsky, P.M., and Meaney, M.J. (1997) Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. *Science* **277**, 1659-1662.

192. Llorente, E., Brito, M.L., Machado, P., and Gonzalez, M.C. (2002) Effect of prenatal stress on the hormonal response to acute and chronic stress and on immune parameters in the offspring. *J. Physiol. Biochem.* **58**, 143-149.

193. Lockwood, C.J., Radunovic, N., Nastic, D., Petkovic, S., Aigner, S., and Berkowitz, G.S. (1996) Corticotropin-releasing hormone and related pituitary-adrenal axis hormones in fetal and maternal blood during the second half of pregnancy. *J. Perinat. Med.* **24**, 243-251.

194. Loewy, A.D. (1981) Descending pathways to sympathetic and parasympathetic preganglionic neurons. *J. Auton. Nerv. Syst.* **3**, 265-275.

195. Lordi, B., Protais, P., Mellier, D., and Caston, J. (1997) Acute stress in pregnant rats: effects on growth rate, learning, and memory capabilities of the offspring. *Physiol. Behav.* **62**, 1087-1092.

196. Lordi, B., Patin, V., Protais, P., Mellier, D., and Caston, J. (2000) Chronic stress in pregnant rats: effects on growth rate, anxiety and memory capabilities of the offspring. *Int. J. Psychophysiol.* **37**, 195-205.

197. Louey, S. and Thornburg, K.L. (2005) The prenatal environment and later cardiovascular disease. *Early Hum. Dev.* **81**, 745-751.

198. Lovejoy, D.A. and Jahan, S. (2006) Phylogeny of the corticotropin-releasing factor family of peptides in the metazoa. *Gen. Comp Endocrinol.* **146**, 1-8.

199. Lucas, A. (1991) Programming by early nutrition in man. *Ciba Found. Symp.* **156**, 38-50; discussion 50-55 38-55.

200. Lummaa, V. (2003) Early developmental conditions and reproductive success in humans: downstream effects of prenatal famine, birthweight, and timing of birth. *Am. J. Hum. Biol.* **15**, 370-379.

201. Lupien, S.J., de Leon, M., de Santi, S., Convit, A., Tarshish, C., Nair, N.P., Thakur, M., McEwen, B.S., Hauger, R.L., and Meaney, M.J. (1998) Cortisol levels during human aging predict hippocampal atrophy and memory deficits. *Nat. Neurosci.* **1**, 69-73.

202. Maccari, S., Piazza, P.V., Kabbaj, M., Barbazanges, A., Simon, H., and Le, M.M. (1995) Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress. *J. Neurosci.* **15**, 110-116.

203. Maccari, S., Darnaudery, M., Morley-Fletcher, S., Zuena, A.R., Cinque, C., and Van, R.O. (2003) Prenatal stress and long-term consequences: implications of glucocorticoid hormones. *Neurosci. Biobehav. Rev.* **27**, 119-127.

204. Mairesse, J., Lesage, J., Breton, C., Breant, B., Hahn, T., Darnaudery, M., Dickson, S.L., Seckl, J., Blondeau, B., Vieau, D., Maccari, S., and Viltart, O. (2007) Maternal stress alters endocrine function of the feto-placental unit in rats. *Am. J. Physiol Endocrinol. Metab.* **292**(6), E1526-533.

205. Mann, D.R. and Fraser, H.M. (1996) The neonatal period: a critical interval in male primate development. *J. Endocrinol.* **149**, 191-197.

206. Martin, D.S. and Haywood, J.R. (1992) Sympathetic nervous system activation by glutamate injections into the paraventricular nucleus. *Brain Res.* **577**, 261-267.

207. Mazur-Kolecka, B., Kubera, M., Skowron-Cendrzak, A., Basta-Kaim, A., and Shani, J. (1996) Effect of prenatal stress on ontogenesis of immunoregulatory cell maturation in mice. *Pol. J. Pharmacol.* **48**, 621-625.

208. McEwen, B.S., Lieberburg, I., Chaptal, C., and Krey, L.C. (1977) Aromatization: important for sexual differentiation of the neonatal rat brain. *Horm. Behav.* **9**, 249-263.

209. McEwen, B.S. (1998) Protective and damaging effects of stress mediators. *N. Engl. J. Med.* **338**, 171-179.

210. McTernan, C.L., Draper, N., Nicholson, H., Chalder, S.M., Driver, P., Hewison, M., Kilby, M.D., and Stewart, P.M. (2001) Reduced placental 11beta-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies
complicated by intrauterine growth restriction: an analysis of possible mechanisms. *J. Clin. Endocrinol. Metab.* **86**, 4979–4983.

211. Meaney, M.J. and Szyf, M. (2005) Maternal care as a model for experience-dependent chromatin plasticity? *Trends Neurosci.* **28**, 456–463.

212. Meyer, U., Schwendener, S., Feldon, J., and Yee, B.K. (2006) Prenatal and postnatal maternal contributions in the infection model of schizophrenia. *Exp. Brain Res.* **173**, 243–257.

213. Millan, S., Gonzalez-Quijano, M.I., Giordano, M., Soto, L., Martin, A.I., and Lopez-Calderon, A. (1996) Short and long restraint differentially affect humoral and cellular immune functions. *Life Sci.* **59**, 1431–1442.

214. Morley-Fletcher, S., Rea, M., Maccari, S., and Laviola, G. (2003) Environmental enrichment during adolescence reverses the effects of prenatal stress on play behaviour and HPA axis reactivity in rats. *Eur. J. Neurosci.* **18**, 3367–3374.

215. Morley-Fletcher, S., Darnaudery, M., Koehl, M., Casolini, P., Van, R.O., and Maccari, S. (2003) Prenatal stress in rats predicts immobility behavior in the forced swim test. Effects of a chronic treatment with tianeptine. *Brain Res.* **989**, 246–251.

216. Morley-Fletcher, S., Darnaudery, M., Mocaer, E., Froger, N., Lanfumey, L., Laviola, G., Casolini, P., Zuena, A.R., Marzano, L., Hamon, M., and Maccari, S. (2004) Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT(1A) receptor mRNA in prenatally stressed rats. *Neuropharmacology* **47**, 841–847.

217. Mueller, B.R. and Bale, T.L. (2006) Impact of prenatal stress on long term body weight is dependent on timing and maternal sensitivity. *Physiol. Behav.* **88**, 605–614.

218. Munck, A. and Guyre, P.M. (1986) Glucocorticoid physiology, pharmacology and stress. *Adv. Exp. Med. Biol.* **196**, 81–96.

219. Mune, T., Rogerson, F.M., Nikkila, H., Agarwal, A.K., and White, P.C. (1995) Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase. *Nat. Genet.* **10**, 394–399.

220. Muneoka, K., Mikuni, M., Ogawa, T., Kitera, K., Kamei, K., Takigawa, M., and Takahashi, K. (1997) Prenatal dexamethasone exposure alters brain monoamine metabolism and adrenocortical response in rat offspring. *Am. J. Physiol.* **273**, R1669–R1675.

221. Murase, T. (1994)[The effects of maternal stress on the aromatase activity in the perinatal rat brain]. *Nippon Naibunpi Gakkai Zasshi* **70**, 95–104.

222. Musselman, D.L. and Nemeroff, C.B. (1996) Depression and endocrine disorders: focus on the thyroid and adrenal system. *Br. J. Psychiatry Suppl.* **123**–128.

223. Nathanielsz, P.W. (2006) Animal models that elucidate basic principles of the developmental origins of adult diseases. *ILAR J.* **47**, 73–82.

224. Newburg, D.S. and Walker, W.A. (2007) Protection of the neonate by the innate immune system of developing gut and of human milk. *Pediatr. Res.* **61**, 2–8.

225. Nolan, L.A., Hart, E.J., Windle, R.J., Wood, S.A., Hu, X.W., Levi, A.J., Ingram, C.D., and Levy, A. (2001) Lack of effect of protein deprivation-induced intrauterine growth retardation on behavior and corticosterone and growth hormone secretion in adult male rats: a long-term follow-up study. *Endocrinology* **142**, 2996–3005.

226. Noorlander, C.W., De Graan, P.N., Middeldorp, J., Van Beers, J.J., and Visser, G.H. (2006) Ontogeny of hippocampal corticosteroid receptors: effects of antenatal glucocorticoids in human and mouse. *J. Comp. Neurol.* **499**, 924–932.

227. Nordeen, E.J., Nordeen, K.W., Sengelaub, D.R., and Arnold, A.P. (1985) Androgens prevent normally occurring cell death in a sexually dimorphic spinal nucleus. *Science* **229**, 671–673.

228. Nwagwu, M.O., Cook, A., and Langley-Evans, S.C. (2000) Evidence of progressive deterioration of renal function in rats exposed to a maternal low-protein diet in utero. *Br. J. Nutr.* **83**, 79–85.

229. Nyirenda, M.J., Lindsay, R.S., Kenyon, C.J., Burchell, A., and Seckl, J.R. (1998) Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. *J. Clin. Invest.* **101**, 2174–2181.

230. O'Connor, T.G., Ben-Shlomo, Y., Heron, J., Golding, J., Adams, D., and Glover, V. (2005) Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children. *Biol. Psychiatry* **58**, 211–217.

231. O'Connor, T.G., Caprariello, P., Blackmore, E.R., Gregory, A.M., Glover, V., and Fleming, P. (2006) Prenatal mood disturbance predicts sleep problems in infancy and toddlerhood. *Early Hum. Dev.* **83(7)**, 451–458.

232. Oliver, M.H., Harding, J.E., Breier, B.H., Evans, P.C., and Gluckman, P.D. (1993) Glucose but not a mixed amino acid infusion regulates plasma insulin-like growth factor-I concentrations in fetal sheep. *Pediatr. Res.* **34**, 62–65.

233. Ong, K.K. and Dunger, D.B. (2004) Birth weight, infant growth and insulin resistance. *Eur. J. Endocrinol.* **151**(Suppl 3), U131–U139.

234. Otten, W., Kanitz, E., Tuchscherer, M., Schneider, F., and Brussow, K.P. (2004) Effects of adrenocorticotropin stimulation on cortisol dynamics of pregnant gilts and their fetuses: implications for prenatal stress studies. *Theriogenology* **61**, 1649–1659.

235. Owen, D., Andrews, M.H., and Matthews, S.G. (2005) Maternal adversity, glucocorticoids and programming of neuroendocrine function and behaviour. *Neurosci. Biobehav. Rev.* **29**, 209–226.

236. Owens, J.A. (1991) Endocrine and substrate control of fetal growth: placental and maternal influences and insulin-
complicated by intrauterine growth restriction: an analysis of possible mechanisms. *J. Clin. Endocrinol. Metab.* **86**, 4979-4983.

211. Meaney, M.J. and Szyf, M. (2005) Maternal care as a model for experience-dependent chromatin plasticity? *Trends Neurosci.* **28**, 456-463.

212. Meyer, U., Schwendener, S., Feldon, J., and Yee, B.K. (2006) Prenatal and postnatal maternal contributions in the infection model of schizophrenia. *Exp. Brain Res.* **173**, 243-257.

213. Millan, S., Gonzalez-Quijano, M.I., Giordano, M., Soto, L., Martin, A.I., and Lopez-Calderon, A. (1996) Short and long restraint differentially affect humoral and cellular immune functions. *Life Sci.* **59**, 1431-1442.

214. Morley-Fletcher, S., Rea, M., Maccari, S., and Laviola, G. (2003) Environmental enrichment during adolescence reverses the effects of prenatal stress on play behaviour and HPA axis reactivity in rats. *Eur. J. Neurosci.* **18**, 3367-3374.

215. Morley-Fletcher, S., Darnaudery, M., Koehl, M., Casolini, P., Van, R.O., and Maccari, S. (2003) Prenatal stress in rats predicts immobility behavior in the forced swim test. Effects of a chronic treatment with tianeptine. *Brain Res.* **989**, 246-251.

216. Morley-Fletcher, S., Darnaudery, M., Mocaer, E., Froger, N., Lanfumey, L., Laviola, G., Casolini, P., Zuena, A.R., Marzano, L., Hamon, M., and Maccari, S. (2004) Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT(1A) receptor mRNA in prenatally stressed rats. *Neuropharmacology* **47**, 841-847.

217. Mueller, B.R. and Bale, T.L. (2006) Impact of prenatal stress on long term body weight is dependent on timing and maternal sensitivity. *Physiol. Behav.* **88**, 605-614.

218. Munck, A. and Guyre, P.M. (1986) Glucocorticoid physiology, pharmacology and stress. *Adv. Exp. Med. Biol.* **196**, 81-96.

219. Mune, T., Rogerson, F.M., Nikkila, H., Agarwal, A.K., and White, P.C. (1995) Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase. *Nat. Genet.* **10**, 394-399.

220. Muneoka, K., Mikuni, M., Ogawa, T., Kitera, K., Kamei, K., Takigawa, M., and Takahashi, K. (1997) Prenatal dexamethasone exposure alters brain monoamine metabolism and adrenocortical response in rat offspring. *Am. J. Physiol.* **273**, R1669-R1675.

221. Murase, T. (1994)[The effects of maternal stress on the aromatase activity in the perinatal rat brain]. *Nippon Naibunpi Gakkai Zasshi* **70**, 95-104.

222. Musselman, D.L. and Nemeroff, C.B. (1996) Depression and endocrine disorders: focus on the thyroid and adrenal system. *Br. J. Psychiatry Suppl.* **123-128**.

223. Nathanielsz, P.W. (2006) Animal models that elucidate basic principles of the developmental origins of adult diseases. *ILAR J.* **47**, 73-82.

224. Newburg, D.S. and Walker, W.A. (2007) Protection of the neonate by the innate immune system of developing gut and of human milk. *Pediatr. Res.* **61**, 2-8.

225. Nolan, L.A., Hart, E.J., Windle, R.J., Wood, S.A., Hu, X.W., Levi, A.J., Ingram, C.D., and Levy, A. (2001) Lack of effect of protein deprivation-induced intrauterine growth retardation on behavior and corticosterone and growth hormone secretion in adult male rats: a long-term follow-up study. *Endocrinology* **142**, 2996-3005.

226. Noorlander, C.W., De Graan, P.N., Middeldorp, J., Van Beers, J.J., and Visser, G.H. (2006) Ontogeny of hippocampal corticosteroid receptors: effects of antenatal glucocorticoids in human and mouse. *J. Comp. Neurol.* **499**, 924-932.

227. Nordeen, E.J., Nordeen, K.W., Sengelaub, D.R., and Arnold, A.P. (1985) Androgens prevent normally occurring cell death in a sexually dimorphic spinal nucleus. *Science* **229**, 671-673.

228. Nwagwu, M.O., Cook, A., and Langley-Evans, S.C. (2000) Evidence of progressive deterioration of renal function in rats exposed to a maternal low-protein diet in utero. *Br. J. Nutr.* **83**, 79-85.

229. Nyirenda, M.J., Lindsay, R.S., Kenyon, C.J., Burchell, A., and Seckl, J.R. (1998) Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. *J. Clin. Invest.* **101**, 2174-2181.

230. O'Connor, T.G., Ben-Shlomo, Y., Heron, J., Golding, J., Adams, D., and Glover, V. (2005) Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children. *Biol. Psychiatry* **58**, 211-217.

231. O'Connor, T.G., Caprariello, P., Blackmore, E.R., Gregory, A.M., Glover, V., and Fleming, P. (2006) Prenatal mood disturbance predicts sleep problems in infancy and toddlerhood. *Early Hum. Dev.* **83(7)**, 451-458.

232. Oliver, M.H., Harding, J.E., Breier, B.H., Evans, P.C., and Gluckman, P.D. (1993) Glucose but not a mixed amino acid infusion regulates plasma insulin-like growth factor-I concentrations in fetal sheep. *Pediatr. Res.* **34**, 62-65.

233. Ong, K.K. and Dunger, D.B. (2004) Birth weight, infant growth and insulin resistance. *Eur. J. Endocrinol.* **151**(Suppl 3), U131-U139.

234. Otten, W., Kanitz, E., Tuchscherer, M., Schneider, F., and Brussow, K.P. (2004) Effects of adrenocorticotropin stimulation on cortisol dynamics of pregnant gilts and their fetuses: implications for prenatal stress studies. *Theriogenology* **61**, 1649-1659.

235. Owen, D., Andrews, M.H., and Matthews, S.G. (2005) Maternal adversity, glucocorticoids and programming of neuroendocrine function and behaviour. *Neurosci. Biobehav. Rev.* **29**, 209-226.

236. Owens, J.A. (1991) Endocrine and substrate control of fetal growth: placental and maternal influences and insulin-
like growth factors. *Reprod. Fertil. Dev.* **3**, 501–517.

237. Ozanne, S.E. and Hales, C.N. (2002) Early programming of glucose-insulin metabolism. *Trends Endocrinol. Metab.* **13**, 368–373.

238. Ozanne, S.E. and Hales, C.N. (2004) Lifespan: catch-up growth and obesity in male mice. *Nature* **427**, 411–412.

239. Pacak, K. and Palkovits, M. (2001) Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. *Endocr. Rev.* **22**, 502–548.

240. Painter, R.C., de Rooij, S.R., Bossuyt, P.M., de Groot, E., Stok, W.J., Osmond, C., Barker, D.J., Bleker, O.P., and Roseboom, T.J. (2007) Maternal nutrition during gestation and carotid arterial compliance in the adult offspring: the Dutch famine birth cohort. *J. Hypertens.* **25**, 533–540.

241. Pancer, Z. and Cooper, M.D. (2006) The evolution of adaptive immunity. *Annu. Rev. Immunol.* **24**, 497–518.

242. Patel, K.P. (2000) Role of paraventricular nucleus in mediating sympathetic outflow in heart failure. *Heart Fail. Rev.* **5**, 73–86.

243. Pechnick, R.N., Chesnokova, V.M., Kariagina, A., Price, S., Bresee, C.J., and Poland, R.E. (2004) Reduced immobility in the forced swim test in mice with a targeted deletion of the leukemia inhibitory factor (LIF) gene. *Neuropsychopharmacology* **29**, 770–776.

244. Pechnick, R.N., Kariagina, A., Hartvig, E., Bresee, C.J., Poland, R.E., and Chesnokova, V.M. (2006) Developmental exposure to corticosterone: behavioral changes and differential effects on leukemia inhibitory factor (LIF) and corticotropin-releasing hormone (CRH) gene expression in the mouse. *Psychopharmacology (Berl.)* **185**, 76–83.

245. Penke, Z., Felszeghy, K., Fernette, B., Sage, D., Nyakas, C., and Burlet, A. (2001) Postnatal maternal deprivation produces long-lasting modifications of the stress response, feeding and stress-related behaviour in the rat. *Eur. J. Neurosci.* **14**, 747–755.

246. Pereira, O.C., Arena, A.C., Yasuhara, F., and Kempinas, W.G. (2003) Effects of prenatal hydrocortisone acetate exposure on fertility and sexual behavior in male rats. *Regul. Toxicol. Pharmacol.* **38**, 36–42.

247. Pereira, O.C., Bernardi, M.M., and Gerardin, D.C. (2006) Could neonatal testosterone replacement prevent alterations induced by prenatal stress in male rats? *Life Sci.* **78**, 2767–2771.

248. Peteranderl, C., Antonijevic, I.A., Steiger, A., Murck, H., Held, K., Frieboes, R.M., Uhr, M., and Schaaf, L. (2002) Nocturnal secretion of TSH and ACTH in male patients with depression and healthy controls. *J. Psychiatr. Res.* **36**, 189–196.

249. Peyronnet, J., Dalmaz, Y., Ehrstrom, M., Mamet, J., Roux, J.C., Pequignot, J.M., Thoren, H.P., and Lagercrantz, H. (2002) Long-lasting adverse effects of prenatal hypoxia on developing autonomic nervous system and cardiovascular parameters in rats. *Pflugers Arch.* **443**, 858–865.

250. Phillips, D.I. and Jones, A. (2006) Fetal programming of autonomic and HPA function: do people who were small babies have enhanced stress responses? *J. Physiol.* **572**, 45–50.

251. Phillips, N.K., Hammen, C.L., Brennan, P.A., Najman, J.M., and Bor, W. (2005) Early adversity and the prospective prediction of depressive and anxiety disorders in adolescents. *J. Abnorm. Child Psychol.* **33**, 13–24.

252. Phoojaroenchanachai, M., Sriussadaporn, S., Peerapatdit, T., Vannasaeng, S., Nitiyanant, W., Boonnamsiri, V., and Vichayanrat, A. (2001) Effect of maternal hyperthyroidism during late pregnancy on the risk of neonatal low birth weight. *Clin. Endocrinol. (Oxf.)* **54**, 365–370.

253. Phornphutkul, C., Frick, G.P., Goodman, H.M., Berry, S.A., and Gruppuso, P.A. (2000) Hepatic growth hormone signaling in the late gestation fetal rat. *Endocrinology* **141**, 3527–3533.

254. Piccinini, M.P., Maggi, E., and Romagnani, S. (2000) Role of hormone-controlled T-cell cytokines in the maintenance of pregnancy. *Biochem. Soc. Trans.* **28**, 212–215.

255. Pollard, I. (1986) Prenatal stress effects over two generations in rats. *J. Endocrinol.* **109**, 239–244.

256. Poltyrev, T., Keshet, G.I., Kay, G., and Weinstock, M. (1996) Role of experimental conditions in determining differences in exploratory behavior of prenatally stressed rats. *Dev. Psychobiol.* **29**, 453–462.

257. Porter, T.E. (2005) Regulation of pituitary somatotroph differentiation by hormones of peripheral endocrine glands. *Domest. Anim. Endocrinol.* **29**, 52–62.

258. Porterfield, S.P. (1985) Prenatal exposure of the fetal rat to excessive L-thyroxine or 3,5-dimethyl-3'-isopropyl-thyronine produces persistent changes in the thyroid control system. *Horm. Metab. Res.* **17**, 655–659.

259. Poulsen, P., Vaag, A., and Beck-Nielsen, H. (1999) Does zygosity influence the metabolic profile of twins? A population based cross sectional study. *BMJ* **319**, 151–154.

260. Prayer, D., Brugger, P.C., Kasprian, G., Witzani, L., Helmer, H., Dietrich, W., Eppel, W., and Langer, M. (2006) MRI of fetal acquired brain lesions. *Eur. J. Radiol.* **57**, 233–249.

261. Prentice, A.M. (2005) Early influences on human energy regulation: thrifty genotypes and thrifty phenotypes. *Physiol. Behav.* **86**, 640–645.

262. Previc, F.H. (2007) Prenatal influences on brain dopamine and their relevance to the rising incidence of autism. *Med. Hypotheses* **68**, 46–60.

263. Proulx, K., Richard, D., and Walker, C.D. (2002) Leptin regulates appetite-related neuropeptides in the hypothalamus of developing rats without affecting food intake. *Endocrinology* **143**, 4683–4692.

264. Pryce, C.R., Bettschen, D., and Feldon, J. (2001) Comparison of the effects of early handling and early deprivation on maternal care in the rat. *Dev. Psychobiol.* **38**, 239–251.

265. Pyner, S. and Coote, J.H. (1994) Evidence that sympathetic preganglionic neurones are arranged in target-specific
like growth factors. *Reprod. Fertil. Dev.* **3**, 501–517.

237. Ozanne, S.E. and Hales, C.N. (2002) Early programming of glucose-insulin metabolism. *Trends Endocrinol. Metab.* **13**, 368–373.

238. Ozanne, S.E. and Hales, C.N. (2004) Lifespan: catch-up growth and obesity in male mice. *Nature* **427**, 411–412.

239. Pacak, K. and Palkovits, M. (2001) Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. *Endocr. Rev.* **22**, 502–548.

240. Painter, R.C., de Rooij, S.R., Bossuyt, P.M., de Groot, E., Stok, W.J., Osmond, C., Barker, D.J., Bleker, O.P., and Roseboom, T.J. (2007) Maternal nutrition during gestation and carotid arterial compliance in the adult offspring: the Dutch famine birth cohort. *J. Hypertens.* **25**, 533–540.

241. Pancer, Z. and Cooper, M.D. (2006) The evolution of adaptive immunity. *Annu. Rev. Immunol.* **24**, 497–518.

242. Patel, K.P. (2000) Role of paraventricular nucleus in mediating sympathetic outflow in heart failure. *Heart Fail. Rev.* **5**, 73–86.

243. Pechnick, R.N., Chesnokova, V.M., Kariagina, A., Price, S., Bresee, C.J., and Poland, R.E. (2004) Reduced immobility in the forced swim test in mice with a targeted deletion of the leukemia inhibitory factor (LIF) gene. *Neuropsychopharmacology* **29**, 770–776.

244. Pechnick, R.N., Kariagina, A., Hartvig, E., Bresee, C.J., Poland, R.E., and Chesnokova, V.M. (2006) Developmental exposure to corticosterone: behavioral changes and differential effects on leukemia inhibitory factor (LIF) and corticotropin-releasing hormone (CRH) gene expression in the mouse. *Psychopharmacology (Berl.)* **185**, 76–83.

245. Penke, Z., Felszeghy, K., Fernette, B., Sage, D., Nyakas, C., and Burlet, A. (2001) Postnatal maternal deprivation produces long-lasting modifications of the stress response, feeding and stress-related behaviour in the rat. *Eur. J. Neurosci.* **14**, 747–755.

246. Pereira, O.C., Arena, A.C., Yasuhara, F., and Kempinas, W.G. (2003) Effects of prenatal hydrocortisone acetate exposure on fertility and sexual behavior in male rats. *Regul. Toxicol. Pharmacol.* **38**, 36–42.

247. Pereira, O.C., Bernardi, M.M., and Gerardin, D.C. (2006) Could neonatal testosterone replacement prevent alterations induced by prenatal stress in male rats? *Life Sci.* **78**, 2767–2771.

248. Peteranderl, C., Antonijevic, I.A., Steiger, A., Murck, H., Held, K., Frieboes, R.M., Uhr, M., and Schaaf, L. (2002) Nocturnal secretion of TSH and ACTH in male patients with depression and healthy controls. *J. Psychiatr. Res.* **36**, 189–196.

249. Peyronnet, J., Dalmaz, Y., Ehrstrom, M., Mamet, J., Roux, J.C., Pequignot, J.M., Thoren, H.P., and Lagercrantz, H. (2002) Long-lasting adverse effects of prenatal hypoxia on developing autonomic nervous system and cardiovascular parameters in rats. *Pflugers Arch.* **443**, 858–865.

250. Phillips, D.I. and Jones, A. (2006) Fetal programming of autonomic and HPA function: do people who were small babies have enhanced stress responses? *J. Physiol.* **572**, 45–50.

251. Phillips, N.K., Hammen, C.L., Brennan, P.A., Najman, J.M., and Bor, W. (2005) Early adversity and the prospective prediction of depressive and anxiety disorders in adolescents. *J. Abnorm. Child Psychol.* **33**, 13–24.

252. Phoojaroenchanachai, M., Sriussadaporn, S., Peerapatdit, T., Vannasaeng, S., Nitiyanant, W., Boonnamsiri, V., and Vichayanrat, A. (2001) Effect of maternal hyperthyroidism during late pregnancy on the risk of neonatal low birth weight. *Clin. Endocrinol. (Oxf.)* **54**, 365–370.

253. Phornphutkul, C., Frick, G.P., Goodman, H.M., Berry, S.A., and Gruppuso, P.A. (2000) Hepatic growth hormone signaling in the late gestation fetal rat. *Endocrinology* **141**, 3527–3533.

254. Piccinini, M.P., Maggi, E., and Romagnani, S. (2000) Role of hormone-controlled T-cell cytokines in the maintenance of pregnancy. *Biochem. Soc. Trans.* **28**, 212–215.

255. Pollard, I. (1986) Prenatal stress effects over two generations in rats. *J. Endocrinol.* **109**, 239–244.

256. Poltyrev, T., Keshet, G.I., Kay, G., and Weinstock, M. (1996) Role of experimental conditions in determining differences in exploratory behavior of prenatally stressed rats. *Dev. Psychobiol.* **29**, 453–462.

257. Porter, T.E. (2005) Regulation of pituitary somatotroph differentiation by hormones of peripheral endocrine glands. *Domest. Anim. Endocrinol.* **29**, 52–62.

258. Porterfield, S.P. (1985) Prenatal exposure of the fetal rat to excessive L-thyroxine or 3,5-dimethyl-3'-isopropyl-thyronine produces persistent changes in the thyroid control system. *Horm. Metab. Res.* **17**, 655–659.

259. Poulsen, P., Vaag, A., and Beck-Nielsen, H. (1999) Does zygosity influence the metabolic profile of twins? A population based cross sectional study. *BMJ* **319**, 151–154.

260. Prayer, D., Brugger, P.C., Kasprian, G., Witzani, L., Helmer, H., Dietrich, W., Eppel, W., and Langer, M. (2006) MRI of fetal acquired brain lesions. *Eur. J. Radiol.* **57**, 233–249.

261. Prentice, A.M. (2005) Early influences on human energy regulation: thrifty genotypes and thrifty phenotypes. *Physiol. Behav.* **86**, 640–645.

262. Previc, F.H. (2007) Prenatal influences on brain dopamine and their relevance to the rising incidence of autism. *Med. Hypotheses* **68**, 46–60.

263. Proulx, K., Richard, D., and Walker, C.D. (2002) Leptin regulates appetite-related neuropeptides in the hypothalamus of developing rats without affecting food intake. *Endocrinology* **143**, 4683–4692.

264. Pryce, C.R., Bettschen, D., and Feldon, J. (2001) Comparison of the effects of early handling and early deprivation on maternal care in the rat. *Dev. Psychobiol.* **38**, 239–251.

265. Pyner, S. and Coote, J.H. (1994) Evidence that sympathetic preganglionic neurones are arranged in target-specific
columns in the thoracic spinal cord of the rat. *J. Comp. Neurol.* **342**, 15–22.

266. Rabadan-Diehl, C., Lolait, S.J., and Aguilera, G. (1995) Regulation of pituitary vasopressin V1b receptor mRNA during stress in the rat. *J. Neuroendocrinol.* **7**, 903–910.

267. Raikkonen, K., Pesonen, A.K., Jarvenpaa, A.L., and Strandberg, T.E. (2004) Sweet babies: chocolate consumption during pregnancy and infant temperament at six months. *Early Hum. Dev.* **7**, 139–145.

268. Ravelli, G.P., Stein, Z.A., and Susser, M.W. (1976) Obesity in young men after famine exposure in utero and early infancy. *N. Engl. J Med.* **295**, 349–353.

269. Reul, J.M. and de Kloet, E.R. (1985) Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. *Endocrinology* **117**, 2505–2511.

270. Reul, J.M., Stec, I., Wiegers, G.J., Labeur, M.S., Linthorst, A.C., Arzt, E., and Holsboer, F. (1994) Prenatal immune challenge alters the hypothalamic-pituitary-adrenocortical axis in adult rats. *J. Clin. Invest.* **93**, 2600–2607.

271. Reul, J.M. and Holsboer, F. (2002) Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. *Curr. Opin. Pharmacol.* **2**, 23–33.

272. Rhees, R.W., Kirk, B.A., Sephton, S., and Lephart, E.D. (1997) Effects of prenatal testosterone on sexual behavior, reproductive morphology and LH secretion in the female rat. *Dev. Neurosci.* **19**, 430–437.

273. Ridley, R.M. and Baker, H.F. (1982) Stereotypy in monkeys and humans. *Psychol. Med.* **12**, 61–72.

274. Rivier, C.L. and Plotsky, P.M. (1986) Mediation by corticotropin releasing factor (CRF) of adenohypophysial hormone secretion. *Annu. Rev. Physiol.* **48**, 475–494.

275. Robey, E.A., Ramsdell, F., Kioussis, D., Sha, W., Loh, D., Axel, R., and Fowlkes, B.J. (1992) The level of CD8 expression can determine the outcome of thymic selection. *Cell* **69**, 1089–1096.

276. Rook, G.A. and Stanford, J.L. (1998) Give us this day our daily germs. *Immunol. Today* **19**, 113–116.

277. Roseboom, T., de Rooij, S., and Painter, R. (2006) The Dutch famine and its long-term consequences for adult health. *Early Hum. Dev.* **82**, 485–491.

278. Rosella, G., Zajac, J.D., Kaczmarczyk, S.J., Andrikopoulos, S., and Proietto, J. (1993) Impaired suppression of gluconeogenesis induced by overexpression of a noninsulin-responsive phosphoenolpyruvate carboxykinase gene. *Mol. Endocrinol.* **7**, 1456–1462.

279. Ross, M.G. and Desai, M. (2005) Gestational programming: population survival effects of drought and famine during pregnancy. *Am. J. Physiol. Regul. Integr. Comp. Physiol.* **288**, R25–R33.

280. Roszman, T.L. and Brooks, W.H. (1997) Interactive signaling pathways of the neuroendocrine-immune network. *Chem. Immunol.* **69**, 203–222.

281. Royer, C., Lachuer, J., Crouzoulon, G., Roux, J., Peyronnet, J., Mamet, J., Pequignot, J., and Dalmaz, Y. (2000) Effects of gestational hypoxia on mRNA levels of Glut3 and Glut4 transporters, hypoxia inducible factor-1 and thyroid hormone receptors in developing rat brain. *Brain Res.* **856**, 119–128.

282. Ryan, B.C. and Vandenbergh, J.G. (2002) Intrauterine position effects. *Neurosci. Biobehav. Rev.* **26**, 665–678.

283. Salm, A.K., Pavelko, M., Krouse, E.M., Webster, W., Kraszpulski, M., and Birkle, D.L. (2004) Lateral amygdaloid nucleus expansion in adult rats is associated with exposure to prenatal stress. *Brain Res. Dev. Brain Res.* **148**, 159–167.

284. Salome, N., Viltart, O., Leman, S., and Sequeira, H. (2001) Activation of ventrolateral medullary neurons projecting to spinal autonomic areas after chemical stimulation of the central nucleus of amygdala: a neuroanatomical study in the rat. *Brain Res.* **890**, 287–295.

285. Salome, N., Viltart, O., Lesage, J., Landgraf, R., Vieau, D., and Laborie, C. (2006) Altered hypothalamo-pituitary-adrenal and sympatho-adrenomedullary activities in rats bred for high anxiety: central and peripheral correlates. *Psychoneuroendocrinology* **31**, 724–735.

286. Samuelsson, A.M., Ohrn, I., Dahlgren, J., Eriksson, E., Angelin, B., Folkow, B., and Holmang, A. (2004) Prenatal exposure to interleukin-6 results in hypertension and increased hypothalamic-pituitary-adrenal axis activity in adult rats. *Endocrinology* **145**, 4897–4911.

287. Sapolsky, R.M. (1992) Do glucocorticoid concentrations rise with age in the rat? *Neurobiol. Aging* **13**, 171–174.

288. Sapolsky, R.M., Romero, L.M., and Munck, A.U. (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. *Endocr. Rev.* **21**, 55–89.

289. Schneider, M.L. (1992) Prenatal stress exposure alters postnatal behavioral expression under conditions of novelty challenge in rhesus monkey infants. *Dev. Psychobiol.* **25**, 529–540.

290. Schneider, T., Turczak, J., and Przewlocki, R. (2006) Environmental enrichment reverses behavioral alterations in rats prenatally exposed to valproic acid: issues for a therapeutic approach in autism. *Neuropsychopharmacology* **31**, 36–46.

291. Schwartz, M.W., Woods, S.C., Porte, D., Jr., Seeley, R.J., and Baskin, D.G. (2000) Central nervous system control of food intake. *Nature* **404**, 661–671.

292. Sebaai, N., Lesage, J., Breton, C., Vieau, D., and Deloof, S. (2004) Perinatal food deprivation induces marked alterations of the hypothalamo-pituitary-adrenal axis in 8-month-old male rats both under basal conditions and after a dehydration period. *Neuroendocrinology* **79**, 163–173.

293. Seckl, J.R. (1997) Glucocorticoids, feto-placental 11 beta-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. *Steroids* **62**, 89–94.

294. Seckl, J.R. (2001) Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. *Mol.*
columns in the thoracic spinal cord of the rat. *J. Comp. Neurol.* **342**, 15–22.

266. Rabadan-Diehl, C., Lolait, S.J., and Aguilera, G. (1995) Regulation of pituitary vasopressin V1b receptor mRNA during stress in the rat. *J. Neuroendocrinol.* **7**, 903–910.

267. Raikkonen, K., Pesonen, A.K., Jarvenpaa, A.L., and Strandberg, T.E. (2004) Sweet babies: chocolate consumption during pregnancy and infant temperament at six months. *Early Hum. Dev.* **7**, 139–145.

268. Ravelli, G.P., Stein, Z.A., and Susser, M.W. (1976) Obesity in young men after famine exposure in utero and early infancy. *N. Engl. J Med.* **295**, 349–353.

269. Reul, J.M. and de Kloet, E.R. (1985) Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. *Endocrinology* **117**, 2505–2511.

270. Reul, J.M., Stec, I., Wiegers, G.J., Labeur, M.S., Linthorst, A.C., Arzt, E., and Holsboer, F. (1994) Prenatal immune challenge alters the hypothalamic-pituitary-adrenocortical axis in adult rats. *J. Clin. Invest.* **93**, 2600–2607.

271. Reul, J.M. and Holsboer, F. (2002) Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. *Curr. Opin. Pharmacol.* **2**, 23–33.

272. Rhees, R.W., Kirk, B.A., Sephton, S., and Lephart, E.D. (1997) Effects of prenatal testosterone on sexual behavior, reproductive morphology and LH secretion in the female rat. *Dev. Neurosci.* **19**, 430–437.

273. Ridley, R.M. and Baker, H.F. (1982) Stereotypy in monkeys and humans. *Psychol. Med.* **12**, 61–72.

274. Rivier, C.L. and Plotsky, P.M. (1986) Mediation by corticotropin releasing factor (CRF) of adenohypophysial hormone secretion. *Annu. Rev. Physiol.* **48**, 475–494.

275. Robey, E.A., Ramsdell, F., Kioussis, D., Sha, W., Loh, D., Axel, R., and Fowlkes, B.J. (1992) The level of CD8 expression can determine the outcome of thymic selection. *Cell* **69**, 1089–1096.

276. Rook, G.A. and Stanford, J.L. (1998) Give us this day our daily germs. *Immunol. Today* **19**, 113–116.

277. Roseboom, T., de Rooij, S., and Painter, R. (2006) The Dutch famine and its long-term consequences for adult health. *Early Hum. Dev.* **82**, 485–491.

278. Rosella, G., Zajac, J.D., Kaczmarczyk, S.J., Andrikopoulos, S., and Proietto, J. (1993) Impaired suppression of gluconeogenesis induced by overexpression of a noninsulin-responsive phosphoenolpyruvate carboxykinase gene. *Mol. Endocrinol.* **7**, 1456–1462.

279. Ross, M.G. and Desai, M. (2005) Gestational programming: population survival effects of drought and famine during pregnancy. *Am. J. Physiol. Regul. Integr. Comp. Physiol.* **288**, R25–R33.

280. Roszman, T.L. and Brooks, W.H. (1997) Interactive signaling pathways of the neuroendocrine-immune network. *Chem. Immunol.* **69**, 203–222.

281. Royer, C., Lachuer, J., Crouzoulon, G., Roux, J., Peyronnet, J., Mamet, J., Pequignot, J., and Dalmaz, Y. (2000) Effects of gestational hypoxia on mRNA levels of Glut3 and Glut4 transporters, hypoxia inducible factor-1 and thyroid hormone receptors in developing rat brain. *Brain Res.* **856**, 119–128.

282. Ryan, B.C. and Vandenbergh, J.G. (2002) Intrauterine position effects. *Neurosci. Biobehav. Rev.* **26**, 665–678.

283. Salm, A.K., Pavelko, M., Krouse, E.M., Webster, W., Kraszpulski, M., and Birkle, D.L. (2004) Lateral amygdaloid nucleus expansion in adult rats is associated with exposure to prenatal stress. *Brain Res. Dev. Brain Res.* **148**, 159–167.

284. Salome, N., Viltart, O., Leman, S., and Sequeira, H. (2001) Activation of ventrolateral medullary neurons projecting to spinal autonomic areas after chemical stimulation of the central nucleus of amygdala: a neuroanatomical study in the rat. *Brain Res.* **890**, 287–295.

285. Salome, N., Viltart, O., Lesage, J., Landgraf, R., Vieau, D., and Laborie, C. (2006) Altered hypothalamo-pituitary-adrenal and sympatho-adrenomedullary activities in rats bred for high anxiety: central and peripheral correlates. *Psychoneuroendocrinology* **31**, 724–735.

286. Samuelsson, A.M., Ohrn, I., Dahlgren, J., Eriksson, E., Angelin, B., Folkow, B., and Holmang, A. (2004) Prenatal exposure to interleukin-6 results in hypertension and increased hypothalamic-pituitary-adrenal axis activity in adult rats. *Endocrinology* **145**, 4897–4911.

287. Sapolsky, R.M. (1992) Do glucocorticoid concentrations rise with age in the rat? *Neurobiol. Aging* **13**, 171–174.

288. Sapolsky, R.M., Romero, L.M., and Munck, A.U. (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. *Endocr. Rev.* **21**, 55–89.

289. Schneider, M.L. (1992) Prenatal stress exposure alters postnatal behavioral expression under conditions of novelty challenge in rhesus monkey infants. *Dev. Psychobiol.* **25**, 529–540.

290. Schneider, T., Turczak, J., and Przewlocki, R. (2006) Environmental enrichment reverses behavioral alterations in rats prenatally exposed to valproic acid: issues for a therapeutic approach in autism. *Neuropsychopharmacology* **31**, 36–46.

291. Schwartz, M.W., Woods, S.C., Porte, D., Jr., Seeley, R.J., and Baskin, D.G. (2000) Central nervous system control of food intake. *Nature* **404**, 661–671.

292. Sebaai, N., Lesage, J., Breton, C., Vieau, D., and Deloof, S. (2004) Perinatal food deprivation induces marked alterations of the hypothalamo-pituitary-adrenal axis in 8-month-old male rats both under basal conditions and after a dehydration period. *Neuroendocrinology* **79**, 163–173.

293. Seckl, J.R. (1997) Glucocorticoids, feto-placental 11 beta-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. *Steroids* **62**, 89–94.

294. Seckl, J.R. (2001) Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. *Mol.*
*Cell. Endocrinol.* **185**, 61–71.

295. Seckl, J.R. (2004) Prenatal glucocorticoids and long-term programming. *Eur. J. Endocrinol.* **151**(Suppl 3), U49–U62.

296. Selye, H. (1936) A syndrome produced by diverse nocuous agents. *Nature* **138**, 32.

297. Selye, H. (1976) Forty years of stress research: principal remaining problems and misconceptions. *Can. Med. Assoc. J.* **115**, 53–56.

298. Shepherd, P.R., Crowther, N.J., Desai, M., Hales, C.N., and Ozanne, S.E. (1997) Altered adipocyte properties in the offspring of protein malnourished rats. *Br. J. Nutr.* **78**, 121–129.

299. Shishkina, G.T. and Bykova, T.S. (1989) The postnatal development of the genital system in male rats following the prenatal administration of corticosterone. *Ontogenez* **20**, 431–434.

300. Shono, T. and Suita, S. (2003) Disturbed pituitary-testicular axis inhibits testicular descent in the prenatal rat. *BJU Int.* **92**, 641–643.

301. Sibley, C., Glazier, J., and D'Souza, S. (1997) Placental transporter activity and expression in relation to fetal growth. *Exp. Physiol.* **82**, 389–402.

302. Sibley, C.P., Turner, M.A., Cetin, I., Ayuk, P., Boyd, C.A., D'Souza, S.W., Glazier, J.D., Greenwood, S.L., Jansson, T., and Powell, T. (2005) Placental phenotypes of intrauterine growth. *Pediatr. Res.* **58**, 827–832.

303. Simerly, R.B., Chang, C., Muramatsu, M., and Swanson, L.W. (1990) Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. *J. Comp. Neurol.* **294**, 76–95.

304. Singhal, A., Cole, T.J., Fewtrell, M., Kennedy, K., Stephenson, T., Elias-Jones, A., and Lucas, A. (2007) Promotion of faster weight gain in infants born small for gestational age: is there an adverse effect on later blood pressure? *Circulation* **115**, 213–220.

305. Sinha, P., Halasz, I., Choi, J.F., McGivern, R.F., and Redei, E. (1997) Maternal adrenalectomy eliminates a surge of plasma dehydroepiandrosterone in the mother and attenuates the prenatal testosterone surge in the male fetus. *Endocrinology* **138**, 4792–4797.

306. Slone-Wilcoxon, J. and Redei, E.E. (2004) Maternal-fetal glucocorticoid milieu programs hypothalamic-pituitary-thyroid function of adult offspring. *Endocrinology* **145**, 4068–4072.

307. Smith, J.W., Seckl, J.R., Evans, A.T., Costall, B., and Smythe, J.W. (2004) Gestational stress induces post-partum depression-like behaviour and alters maternal care in rats. *Psychoneuroendocrinology* **29**, 227–244.

308. Sobrian, S.K., Vaughn, V.T., Bloch, E.F., and Burton, L.E. (1992) Influence of prenatal maternal stress on the immunocompetence of the offspring. *Pharmacol. Biochem. Behav.* **43**, 537–547.

309. Sobrian, S.K., Vaughn, V.T., Ashe, W.K., Markovic, B., Djuric, V., and Jankovic, B.D. (1997) Gestational exposure to loud noise alters the development and postnatal responsiveness of humoral and cellular components of the immune system in offspring. *Environ. Res.* **73**, 227–241.

310. Solomon, G.F., Levine, S., and Kraft, J.K. (1968) Early experience and immunity. *Nature* **220**, 821–822.

311. Speirs, H.J., Seckl, J.R., and Brown, R.W. (2004) Ontogeny of glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development. *J. Endocrinol.* **181**, 105–116.

312. Stearns, S. (1991) *The Evolution of Life Histories*. Oxford University Press.

313. Sterling, P. and Eyer, J. (1988) Allostasis: a new paradigm to explain arousal pathology. In *Handbook of Life Stress, Cognition and Health*. Fisher, S. and Reason, J., Eds. John Wiley & Sons, New York. pp. 629–649.

314. Stewart, P.M., Rogerson, F.M., and Mason, J.I. (1995) Type 2 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal adrenal steroidogenesis. *J. Clin. Endocrinol. Metab.* **80**, 885–890.

315. Strachan, D.P. (1994) Is allergic disease programmed in early life? *Clin. Exp. Allergy* **24**, 603–605.

316. Sugden, M.C., Langdown, M.L., Munns, M.J., and Holness, M.J. (2001) Maternal glucocorticoid treatment modulates placental leptin and leptin receptor expression and materno-fetal leptin physiology during late pregnancy, and elicits hypertension associated with hyperleptinaemia in the early-growth-retarded adult offspring. *Eur. J. Endocrinol.* **145**, 529–539.

317. Susser, E., Neugebauer, R., Hoek, H.W., Brown, A.S., Lin, S., Labovitz, D., and Gorman, J.M. (1996) Schizophrenia after prenatal famine. Further evidence. *Arch. Gen. Psychiatry* **53**, 25–31.

318. Susser, E., Brown, A.S., Klonowski, E., Allen, R.H., and Lindenbaum, J. (1998) Schizophrenia and impaired homocysteine metabolism: a possible association. *Biol. Psychiatry* **44**, 141–143.

319. Suzue, K., Asai, T., Takeuchi, T., and Koyasu, S. (2003) In vivo role of IFN-gamma produced by antigen-presenting cells in early host defense against intracellular pathogens. *Eur. J. Immunol.* **33**, 2666–2675.

320. Szuran, T., Zimmermann, E., and Welzl, H. (1994) Water maze performance and hippocampal weight of prenatally stressed rats. *Behav. Brain Res.* **65**, 153–155.

321. Takahashi, L.K., Turner, J.G., and Kalin, N.H. (1992) Prenatal stress alters brain catecholaminergic activity and potentiates stress-induced behavior in adult rats. *Brain Res.* **574**, 131–137.

322. Takahashi, L.K., Turner, J.G., and Kalin, N.H. (1998) Prolonged stress-induced elevation in plasma corticosterone during pregnancy in the rat: implications for prenatal stress studies. *Psychoneuroendocrinology* **23**, 571–581.

323. Teixeira, J.M., Fisk, N.M., and Glover, V. (1999) Association between maternal anxiety in pregnancy and increased uterine artery resistance index: cohort based study. *BMJ* **318**, 153–157.