bluuebunny/crossref_metadata_2025 huggingface dataset:
Ontogeny of neurotransmitter systems: Substrates for developmental disabilities?
Authors: Lauder Jean M.
Published: June 2005

This papaer provides an overview of the developmental characteristics of several major CNS neurotransmitter systems, specifically those involving serotonin, catecholamines, and GABA. These were chosen because of their putative importance in various aspects of brain development or plasticity, and the existence of clinically relevant sequelae linking these systems to developmental disorders and disabilities. Patterns of development of these neurotransmitter systems and their putative roles as developmental signals are discussed, as is their possible relevance to developmental disabilities such as autism, attention‐deficit/hyperactivity disorders, self‐injurious behaviour, and epilepsy. © 1995 Wiley‐Liss, Inc.
Prenatal exposure to opiates
Authors: DeCristofaro Joseph D. , Lagamma Edmund F.
Published: June 2005

Opiate use has been described for thousands of years. In this century, clinical features of the “neonatal abstinence syndrome” have been amply documented in the medical literature. Indeed, the abuse of “recreational” drugs continues at an alarming rate and results in a high number of adverse maternal‐fetal outcomes even as we near the end of the twentieth century. These consequences persist despite the myriad of medical advances that have resulted in the lowest perinatal mortality on record.

The effects of opiate exposure on the developing fetus have been extensively described in the literature on animal research, in which neurodevelopmental and behavioral abnormalities have been linked to brain region‐specific cellular and molecular findings. The human clinical literature clearly defines the symptoms, timing, and frequency of opiate withdrawal in infants exposed prenatally and documents treatment of withdrawal, which is dependent on the severity of symptoms. A panoply of similarities exist.

The adverse complications of maternal opiate addiction during the human prenatal and postnatal period are most significant for the fetus and infant, resulting in increased morbidity and mortality. Other consequences include stillbirth, premature birth, low birth weight, small head circumference at birth and during childhood, poor postnatal somatic growth, transient hypertonia, maladaptive responses to physiologic stresses of hypoxia and hypercarbia, and an increased rate of sudden infant death syndrome, as well as a variety of neurodevelopmental and cognitive delays. Although the factors relating to socioeconomic status, nutrition, and multisubstance abuse add to the challenges of acquiring reliable data, a vast amount of animal and human data suggest that opioids play a critical role in developmental processes that affect the vulnerability and plasticity of the immature brain. In addition, affected infants and children are subject to significant emotional, social, and environmental instability throughout their lives. This must certainly contribute to their neurobehavioral dysfunction. Regardless of these findings, opiates do not appear to have a specific teratogenic effect. © 1995 Wiley‐Liss, Inc.
Neurotransmitter alterations in attention‐deficit/hyperactivity disorder
Authors: Mercugliano Marianne
Published: June 2005

Attention‐deficit/hyperactivity disorder is a common neurodevelopmental disorder characterized by short attention span, distractibility, hyperactivity, and impulsivity, which begins in early childhood. The purpose of this review is threefold: to summarize early research suggesting that ADHD results from frontal‐striatal dysfunction and can be ameliorated by medications that increase dopaminergic and noradrenergic transmission: to describe recent functional imaging studies that allow in vivo testing of these hypotheses; and to discuss recent advances in the understanding of neurotransmitter function that may suggest new approaches to elucidating the neurochemical basis of this disorder.
Reduction of 6‐aminonicotinamide teratogenicity in mice by etherization,
Authors: Hamly Carole‐Ann , Trasler Daphne G. , Fraser F. C.
Published: June 2005

In an experiment involving selection for cleft lip in which pregnant mice were treated with 6‐aminonicotinamide (6‐AN) to induce this malformation, some were lightly anesthetized with ether to make them easier to handle at the time of treatment. In the first experiment etherization significantly lowered the frequency of malformed embryos from 51.7 to 26.2%, and of induced cleft lip from 23.9 to 3.3%. The resorption frequency was also significantly reduced from 38.5 to 22.4%. A second experiment under more controlled conditions in a later generation of the selection experiment gave results consistent with those of the first experiment. This finding must be taken into consideration whenever anesthesia is used in teratological experiments.
Relation between embryotoxicity of adenine in mice and day of prenatal treatment
Authors: Fujii Takaaki
Published: June 2005

Adenine (250 mg/kg) was given ip to ICR‐JCL mice on day 8, 9, 10, 11, or 12 of gestation. Near‐term fetuses were examined for external and skeletal malformations and the following noted. (1) A lethal effect occurred in all treatment groups except day 8 with the effect severest in day‐10 group. (2) The mean fetal weight was significantly decreased in all treatment groups, with this effect especially high in the day‐10 and −12 groups. (3) Day‐10 or −12 treatment caused high frequencies of external malformations. (4) Cleared specimens revealed that day‐8, −9, or −10 treatment induced a large number of vertebral malformations and there was a tendency of head‐to‐tail shift of malformations as time of administration advanced.
The Embryotoxic effects of 5‐fluoro‐2′‐deoxyuridine in mice
Authors: Kleinebrecht J.
Published: June 2005

The embryolethal and teratogenic dose‐response relations of 5‐fluoro‐2′‐deoxyuridine (FUdR) were tested in mice at day VIII of pregnancy. FUdR was embryotoxic at dosages above 5 mg/kg maternal body weight. Types of resorptions and malformations were similar to those produced by 5‐fluoro‐2′‐deoxycytidine (FCdR) at day VIII (Degenhardt et al., '68; Kleinebrecht et al., '70). To produce the same frequency of resorptions or malformations the dosage of FUdR had to be about 2–4 times that of FCdR. These findings compared with data in rats (Chaube and Murphy, '69a) indicate a differential response to FUdR and FCdR in the two species.
Ossification of the rat and mouse skeleton in the perinatal period
Authors: Fritz Hans , Hess Robert
Published: June 2005

In the perinatal period the skeletal development of rats and mice showed transient stages of missing to incomplete or largely complete ossification. Alizarin red S staining revealed characteristic morphological patterns of maturation, which differed from one part of the skeleton to another. In the two species examined all the skeletal elements were ossified 2 days after birth. In about 12% of the rats and 90% of the mice an additional sternebra formed in the postnatal period. In a small number of cases abnormal ossification was observed. A few days after term the spontaneous rate of abnormally ossified bones was found to be 0.51% in the rats and 1.40% in the mice. A reduced rate of ossification at a given time of development which is never less within the normal range, may be indicative of a nonspecific retardation of fetal maturation.
Teratogenic and other effects produced in mice by norethynodrel and its 3‐hydroxymetabolites
Authors: Gidley J. T. , Christensen H. D. , Hall I. H. , Palmer K. H. , Wall M. E.
Published: June 2005

Cranial retardation was produced in the offspring of CF1 mice that were treated with norethynodrel [17α‐ethynyl‐estr‐5(10)‐en‐3‐on‐17β‐ol] or its metabolites [17α‐ethynyl‐estr‐5(10)‐ene‐3α,17β‐diol and the corresponding 3β,17β‐diol] on days 8–10 of gestation. The most active agent was the 3β,17β‐diol. Incomplete development of the parietal bones was observed in 64.1% of fetuses examined from mothers treated with 0.6 mg/kg of the 3β,17β‐diol. Five percent of all fetuses in this treatment group had exencephaly. An anomaly resembling cryptorchidism occurred when the diols were administered on gestation days 11–13.
Accelerated clearing and staining of teratologic specimens by heat and light
Authors: Schnell Viola , Newberne James W.
Published: June 2005

A technique is described for a more consistent and rapid method of clearing and alizarin staining rat and rabbit fetal skeletons. With the addition of heat and light several hundred teratological specimens can be rapidly processed in a controlled situation at one time. The method is also easily adapted to small numbers of animals. The entire procedure can be completed in 3 days for rats and 4 days for rabbits. The results are reproducible and predictable almost to the hour.
Influence of prenatal administration of busulfan on the postnatal development of mice. Production of a syndrome including hypoplasia of the thymus
Authors: Pinto‐machado J.
Published: June 2005

The alkylating agent busulfan (1,4‐butanediol dimethanesulfonate) was given to mice on day 1 to 18 of pregnancy, each animal receiving a single 30 mg/kg ip dose. Growth and mortality rates from birth to the end of the 8th week were observed in 510 young. Starting from the gestation day 9 treatment caused significant growth retardation in 51.2% of offspring. The frequency was highest when injections were given on day 10, 15, or 16. Treatment on day 9, 10, 15, 16, or 17 was associated with an overall death rate of 37.6%. There was a direct relation between retarded growth and premature death, and both occurred chiefly in animals treated during fetogenesis. In 23.8% of the young from females treated on day 10, 11, or 12 extreme stunting, wasting, abnormal hair, skeletal muscle weakness, and, in two cases, necrotic foci in the liver were associated with hypoplasia of the thymus; 30% of the animals died before the end of the 1st month. Damage of some or all the thymus cell precursor lines was probably the origin of the hypoplasia of this organ, which, in turn, was the likely cause of the other features of the syndrome. These results emphasize the need for studying postnatal development when testing embryopathic effects of drugs, and point to the possibility of using busulfan as an experimental model in the study of the thymus ontogenesis and development of immune responsiveness.
Influence of sex‐linked genes on embryonic sensitivity to cortisone in three strains of mice
Authors: Francis B. M.
Published: June 2005

It was postulated that sex‐linked genes affecting embryonic sensitivity to cortisone‐induced cleft palate and cortisone‐induced resorption might differ between inbred mouse strains showing pronounced reciprocal effects. The three strains tested were the A/J (A), C57BL/6J (B), and C3H/HeJ (C), whose sensitivities to cortisone‐induced cleft palate had been shown to be: A > C > B. The sensitivity of reciprocal A × B and B × C hybrid embryos was matroclinous; of reciprocal A × C embryos, patroclinous. Backcrosses of reciprocal F1 hybrid males to inbred females were used to test the hypothesis of sex‐linkage with respect to the incidence of cortisone‐induced cleft palate, cortisone‐induced resorption, and the overall level of cortisone‐induced fetal damage. The results were consistent with the hypothesis that sex‐linked genes affecting embryonic sensitivity to cortisone‐induced cleft palate, but not to cortisone‐induced resorption, differ in the three strains.
Absent and abnormal umbilical arteries
Authors: Monie I. W. , Khemmani M.
Published: June 2005

Umbilical arteries were not found in some fetuses from female rats given retinoic (vitamin A) acid by gavage on day 10 of gestation. It was felt that fetomaternal exchange in them must have been maintained either by the vitelline placenta alone, or by the allantoic placenta supplied by branches of the vitelline artery. In control rat embryos the vitelline and umbilical arteries communicated until day 11 after which the two circulations became separate. In young from females given retinoic acid during gestation, however, this communication (vitelloumbilical anastomosis) persisted and the definitive umbilical arteries failed to develop completely. This resulted in the normally formed single umbilical artery of the cord and its branches to the allantoic placenta receiving blood from the aorta through the vitelline or superior mesenteric artery. Thus, although the intra‐abdominal portions of the umbilical arteries were missing, the allantoic placental circulation was maintained. The vitelline placental circulation was normal. In other experimental embryos persistent primary umbilical arteries were frequently seen alone or accompanied by definitive umbilical arteries. In normal human embryos a vitelloumbilical anastomosis apparently does not form and the single umbilical artery seen in fetuses with symmelia is most likely a persistent primary umbilical artery, as suggested by Dawson. However, the possibility of a vitelloumbilical anastomosis occasionally arising as an abnormality in human embryos cannot be overlooked.
Appendicular skeletal and visceral malformations induced by thalidomide in bonnet monkeys
Authors: Hendrickx Andrew G. , Newman Lois
Published: June 2005

Twenty‐nine pregnancies were obtained in 21 female bonnet monkeys. The females were housed individually and were mated for a 2‐h period, usually 2 days before midcycle. The day of mating was designated as day o of pregnancy. After pregnancy was confirmed by rectal palpation the animals each received 5, 10, or 30 mg/kg thalidomide orally, either as single doses on days 24, 25, 26, 27, 28, or 29 or once per day on days 25–27 or 41–44. With 5 and 10 mg/kg only malformations of the forelimbs were observed, characterized by total absence (amelia) or partial absence (meromelia) of the free limb. In all cases the malformations were more severe on the left side than the right. No craniocaudal developmental gradient was noted with 10 mg/kg. With 30 mg/kg forelimb and hindlimb malformations occurred, although the hindlimb malformations were mild and consisted essentially of either bowing or partial absence of the femur. A craniocaudal developmental gradient was evident with 30 mg/kg. Treatment during the time of palate closure (days 41–44) did not affect normal palate development. Absence and/or malformations of the uterus, ovaries, kidney, heart, brain, spleen, and umbilical arteries also occurred.
Postnatal effects in rats of prenatal treatment with hydroxyurea
Authors: Butcher Richard E. , Scott William J. , Kazmaier Kathy , Ritter Edmond J.
Published: June 2005

The offspring of pregnant female rats treated with 375 or 500 mg/kg hydroxyurea (HU) on day 12 of gestation were tested for exploratory activity and maze‐learning ability beginning at 30 days of age. Experimental subjects were retarded in growth and had locomotor abnormalities, tail defects not noted at birth, and impaired maze learning. Thus, HU at doses that produce only minor malformations in 20‐day fetuses alters the postnatal functional capacity of rats treated prenatally.
Cleft palate formation: The effects of fasting and lodoacetic acid on mice
Authors: Miller Tony Jasper
Published: June 2005

A 24 h fast of pregnant CFW mice on day 11, 13, or 14 of gestation produced 2, 16, and 1% cleft palate (CP), respectively. A 48 h fast on days 11–12 gave 8% CP, and a 72 h fast on days 11–13 gave 58%. A maximal response to fasting thus occurred during day 13. The CP incidence induced by fasting was reduced with drinking solutions containing glucose or glucose plus ammonium chloride. Ip administration of glucose or succinate decreased the incidence of affected offspring, but ammonium chloride and pyruvate did not. lodoacetic acid also produced CP, 5% on day 11 of gestation, 8% on day 13, 8% on days 11–13, and 14% on days 12–14. The incidence of iodoacetic acid‐induced CP was reduced with succinate. Administering iodoacetic acid to fasting mice produced results indicating that both teratogens acted on the same metabolic pathway.
Congenital brain cysts in infancy: Diagnosis, treatment, and follow‐up
Authors: Shurtleff David B. , Eliason B. Clair , Oakland James A.
Published: June 2005

Eleven cases of congenital brain cysts—two encephaloclastic intracerebral, five noncommunicating pia‐arachnoid, and four either communicating pia‐arachnoid or intracranial meningoencephalocele congenital type cysts—were diagnosed in infancy based on suspicious cephalomegaly, skull asymmetry, and abnormal transillumination. Complete diagnosis differentiated primary congenital cysts from trauma and infection, both of which complicate congenital cysts as well as being etiologic for brain cyst formation. Early diagnosis coupled with surgical exploration and cerebrospinal fluid shunting have allowed seven to live in a functional, socially acceptable way to the age of 11/2 to 121/2 years. Two of the remaining four are now dead, and two are severely retarded. Retardation was due to congenital malformation and a shunt obstruction. Death resulted from infectious epiglottis and cardiac arrest during cystostomy.
Abnormal segregation and sex ratio and reduced litter size associated with the siren phenotype in mice
Authors: Hoornbeek Frank K. , Schreiner Ceinwen
Published: June 2005

Abnormal segregation ratios in +/srn intercrosses found at term were due to prenatal loss of siren embryos. Litters without sirens were smaller than those with sirens; litters with sirens were smaller than control litters. There was a significant excess of prenatal resorptions in +/srn intercross litters compared with control litters, suggesting reduced reproductive fitness of +/srn females. The abnormal siren sex ratio at term may have been due to excessive prenatal loss of siren females.
Canine teratogenesis with an estrogen antagonist
Authors: Schardein James L. , Reutner Thomas F. , Fitzgerald James E. , Kurtz Stanley M.
Published: June 2005

A nonsteroidal estrogen antagonist, CI‐628, was administered orally to female beagle dogs on days 1–15 following mating. Dosages of 0.5, 1, 2, and 5 mg/kg effectively blocked pregnancy; six litters were whelped after 0.125 or 0.25 mg/kg in which various defects were present in pups of three litters.
Teratogenic effects of 5‐bromodeoxyuridine on the external morphology of Drosophila melanogaster
Authors: Gilbert Enid F. , Pitot Henry C. , Bruyere Harold J. , Cheung Alphonsus L.
Published: June 2005

Various anomalies were induced in Drosophila melanogaster by dietary administration of 5‐bromodeoxyuridine (5‐BUdR). Contraction of the proboscis was the most conspicuous effect. Others included wings that resembled those of a vestigial wing mutant, twisted and/or deformed (occasionally fused) rear legs, and twin spots on the posterior half of the pterothorax. In view of many studies that have demonstrated that 5‐BUdR incorporation into DNA is the main determinant of the biological activity of this compound, the altered patterns of differentiation produced by this treatment suggest interference with certain metabolic pathways. Teratogenic effects induced by 5‐BUdR in other systems and possible causes for the observed defects are discussed.
The community of human malformation syndromes that shares ectodermal dysplasia and deformities of the hands and feet
Authors: Pinsky Leonard
Published: June 2005

Syndromes of human congenital malformation may be classified by recognizing communities of syndromes that share multiple phenotypic similarities involving their principal diagnostic features. A community of syndromes that shares various expressions of ectodermal dysplasia and various deformities of the hands and feet is proposed; these syndromes are divisible into two classes according to the presence or absence of anomalies in the nasal or labial regions of the face. The dysmorphogenetic validity of the division is supported by the fact that the syndromes without nasal or labial anomalies have a high frequency of sensorineural deafness as one expression of ectodermal dysplasia whereas those without such anomalies do not. The usefulness of such a syndromal community as a base for evolving a taxonomic scheme of dysmorphogenetic relatedness amongst different syndromes is illustrated.
Incorporation of a phospholipid precursor into the hemochorionic and yolk sac placentas associated with 9‐methylpteroylglutamic acid‐treated rat embryos
Authors: Chepenik Kenneth P. , Waite B. Moseley
Published: June 2005

Pregnant Long‐Evans rats were subjected to a teratogenic regimen, i.e., were fed a synthetic diet lacking folic acid and containing 9‐methyl‐pteroylglutamic acid on the llth to 14th days of gestation. Experimental and control pregnant rats injected with 10 μCi of [2‐14C] ethanolamine on the 14th day were killed 1 or 2 days later. The total radioactivity and radioactivities of phosphatidylethanolamine (PE), phosphatidylcholine (PC), and lysophosphatidylethanolamine (LPE) were determined in chloroform extracts of homogenates and subcellular fractions prepared from hemochorionic and yolk sac placentas and maternal liver. The distribution of radioisotope into PC and PE of control and experimental yolk sac placentas was similar, and paralleled the distribution in maternal liver. However, the distribution of radioisotope into PC and PE of the hemochorionic placentas did not parallel that of the maternal liver, and radiolabeled PC accumulated faster in experimental placentas than in controls. We suggest that the ability of the hemochorionic placenta to synthesize PC from PE was impaired by the teratogenic regimen, and that the organ took up relatively more PC from the maternal plasma. We propose that this teratogen‐induced shift from placental lecithin synthesis to selective lecithin uptake underlies the previous finding of an increased accumulation of radio‐labeled PC in embryos from pregnant females subjected to this teratogenic regimen (Chepenik and Waite, '73).
Primary congenital aphakia and the rubella syndrome
Authors: Vermeij‐Keers Christl
Published: June 2005

Four embryos from women infected by rubella virus early in pregnancy were investigated histologically. In three of the patients the serological tests were positive; in the fourth the diagnosis of rubella was based solely on the clinical picture. Three of the four embryos showed unilateral severe microphthalmia and primary congenital aphakia. In addition to this defect the right eye of one of the embryos showed a central liquefaction of the lens (cataract). Damage to the internal ear in the form of discontinuities in the epithelium of the cochlear duct were also observed (in two of the three embryos; in the fourth both internal ears were absent in the curettage material). In three of the four hearts there were cells in the myocardium with a markedly eosinophilic cytoplasm.
Histological effects of 6‐mercaptopurine on the fetal rat central nervous system: A light‐microscopic study
Authors: Adhami H. , Noack W.
Published: June 2005

Wistar rats were administered single doses of 16 or 50 mg/kg 6‐mercaptopurine (6‐MP) on day 12 of pregnancy. Necrosis in the fetal forebrain and spinal cord was studied by light microscope 6, 12, 14, 48, 72, and 81 h and 8 days afterward. The extent of necrosis was dose dependent. The first necroses were seen after 24 h, regardless of location (brain, spinal cord) or dose; but the extent was greatest after 48 h. All necrotic cells had a typical appearance; they were ballooned and often fragmented, their nuclei were darkly colored and frequently pyknotic, and they were often karyorhexic. Necroses appeared almost exclusively at sites of beginning cellular differentiation, i.e., in the intermediate zone. In the spinal cord the ventricular zone was also necrotic and the alar plate (dorsal horn) always affected. Phagocytizing cells (macrophages) appeared in the spinal cord after 48 h and in the brain after 72 h. After 81 h all the necrotic material had been phagocytized. at which time there was a massive congestion of the extra‐ and intracerebral vessels. Hemorrhages appeared in denned localizations. Eight days after exposure to 16 mg/kg 6‐MP fetuses no longer showed any visible deviations. Fetuses exposed to 50 mg/kg showed deviations in the cytoarchitecture of the neopallium: an extremely broadened ventricular zone, few cells in the intermediate zone, and extensive rarefaction of cells in the cortical plate with no clear layer structure. In the spinal cord, cleft formations were especially noticeable in the dorsal‐horn region. All fetuses showed a hydrocephalus externus after 50 mg/kg. The mechanism leading to necrosis is discussed.
Comparative teratogenicity of selected glucocorticoids applied ocularly in mice
Authors: Ballard Paul D. , Hearney Elaine F. , Smith Marvin B.
Published: June 2005

Three glucocorticoids (dexamethasone, hydrocortisone, and prednisolone) were ocularly applied to pregnant CD‐1 mice on days 10‐13 of gestation. The drug concentrations were various multiples of the common therapeutic dose levels and were applied to both eyes in 1‐μl drops five times a day. Eighteen‐day fetuses were examined for malformations. A significant increase in the incidence of cleft palate was observed in fetuses treated with each of these glucocorticoids. There appeared to be a dose related effect on cleft palate width among fetuses from both dexamethasone and prednisolone treated dams. The incidence of sex organ anomalies, although lower than the incidence of cleft palate, also showed a positive dose relationship. Analysis of variance was used to compare the teratogenic effects of these glucocorticoids ocularly applied in equipotent anti‐inflammatory concentrations. Our results indicate that dexamethasone produces a higher incidence of cleft palate, than either of the other two drugs when given in equipotent concentrations. It appears that the teratogenic potency of these ocularly applied glucocorticoids cannot be predicted on the basis of anti‐inflammatory potency.
A note on the epidemiology of acardiac monsters
Authors: James William H.
Published: June 2005

The literature on acardiac monsters has been reviewed. The following conclusions were drawn:

The probability of their appearance seems considerably higher among monoamniotic than diamniotic monochorionic twin pairs.

They seem more likely to occur within monozygotic (MZ) pairs in higher multiple births than in MZ twins.

The data are consistent with the suggestion that there is a slight female excess among them.
Response of early chick embryos to busulfan
Authors: Swartz William J.
Published: June 2005

Busulfan, suspended in peanut oil, was injected into the yolk sac of white Leghorn chick embryos in dosages of 0.1 mg, 0.5 mg, or 1.0 mg. Embryos received a single injection of busulfan either prior to incubation, at 24, 48, 72, or 96 hours of incubation. Surviving embryos were sacrificed when they reached five days of incubation. Some embryos exposed to busulfan at 96 hours were allowed to develop to nine days of incubation to determine whether the time of initial exposure or the length of exposure to busulfan was more critical. The embryo required 48 hours to manifest the deleterious effects of busulfan. Abnormalities such as defects in the formation of the limb buds and cephalic hematomas were commonly seen in survivors no matter when exposed to busulfan. Some embryos injected at 96 hours and allowed to develop to nine days displayed edema of the body cavities. The role of busulfan in eliciting these malfomations is discussed.
Cell cycle phase specificity of hydroxyurea and its effects on the cell kinetics in embryonic spinal cord
Authors: Herken R.
Published: June 2005

Pregnant mice (NMRI) received an intravenous injection of 500 mg/kg of hydroxyurea (HU) on day 10 of gestation. The animals were killed 1, 1.5, 2, 2.5, 4, 6, 8 or 10 h after application of the drug and the embryos removed. Forty‐five min. prior to sacrifice, the animals were given an intraperitoneal injection of 5 μ Ci/g 3H‐thymidine (specific activity 5 Ci/mmol). From autoradiographs of the embryos the percentage of mitoses, necroses and labelled cells of the spinal cord was determined at the various time intervals. It was observed that HU inhibited DNA‐synthesis in all S‐phase cells for more than 4 hours. All cells damaged by HU did not start DNA ‐synthesis again and became necrotic. Only cells entering the S‐phase after the influence of HU could replicate their DNA in a normal manner. It is assumed that HU possibly blocks cells in the G2‐phase and in the mitosis for a certain period of time.
A glucocorticoid receptor in fetal mouse: Its relationship to cleft palate formation
Authors: Hackney John F.
Published: June 2005

Fetal mouse tissue was investigated for a glucocorticoid binding receptor which might be responsible for cleft palate formation. Fetal mouse heads contain a soluble component which binds the glucocorticoid triamcinolone acetonide in vitro with high affinity. This binding component is present in small finite amounts. Other glucocorticoids compete with triamcinolone acetonide for the binding site in a manner consistent with their potency ranking as cleft palate teratogens. Several mineralocorticoids and progestins also compete when administered in vitro but not when administered in vivo. Triamcinolone acetonide binding was determined in three mouse strains, A/J C3H, and C57BL, which are listed in decreasing order of cleft palate susceptibility to cortisone. No positive correlation was found between cortisone cleft palate susceptibility and either triamcinolone acetonide binding affinity or binding amout in fetuses from these strains. Cleft palate dose response curves for triamcinolone acetonide were determined in these strains, but they were not parallel to each other as they were for cortisone. This suggests that triamcinolone acetonide may cause cleft palate by different mechanisms in these strains. Thus, fetal mouse tissue contains and apparent glucocorticoid receptor, but its relationship to cleft palate formation in mice is not clear.
Ectopic pregnancy and myoma uteri: Teratogenic effects and maternal characteristics
Authors: Matsunaga Ei , Shiota Kohei
Published: June 2005

Morphological data from 3,614 well‐preserved human embryos derived from artificial termination of pregnancy were used to determine whether ectopic implantation or enlarged myomas could enhance the prevalence of localized malformations of the embryo. The frequency of malformed embryos was 11.6% among 43 recovered from ectopic pregnancies, 6.2% among 97 from myomatous pregnancies, and 3.3% among 3,474 from normally implanted pregnancies not complicated by myomas. Unilateral amelia in the ectopic cases and caudal dysplasia in the myoma cases were significantly increased. Both malformations were quite unusual in the control group. It is argued that spatial restrictions could be a teratogenic agent in human embryos. Mothers of both ectopic and myoma cases were on average much older than mothers of the control specimens, and those with myomas had a higher frequency of previous pregnancy wastages. Ectopic pregnancy was found to be associated with lowered parity, previous ectopic pregnancy, and maternal smoking and drinking. These associations are discussed and interpreted in relation to etilogy of each of the two conditions.
Syndromes of cardiovascular malformations induced by copper citrate in hamsters
Authors: Dicarlo Frederick J.
Published: June 2005

Pregnant golden hamsters were injected intraperitoneally on the morning of the eighth day of gestation with a solution of copper citrate (2.7 mg/kg) or deionized water. Embryos were removed from the mothers by laparotomy on the 12th and 13th days of gestation, serially sectioned through the thorax, and examined for cardiac malformations. Twenty‐one of the 37 edematous embryos from copper‐treated mothers were affected with a total of 58 major cardiac anomalies. Sixteen of these embryos were affected with double outlet right ventricle in association with a membranous ventricular septal defect, two embryos contained hearts with overriding aortas, and three embryos were affected with isolated ventricular septal defects. Eleven of the 16 embryos with double outlet right ventricle were also affected with pulmonary trunk hypoplasia. The concept that these cardiac anomalies arise from a common pathogenetic basis is supported by the present model.
Potentiating effects of caffeine of teratogenicity of alkylating agents in mice
Authors: Fujii Takaaki , Nakatsuka Toshio
Published: June 2005

Teratogenic to subteratogenic doses of x‐ray, mitomycin C, MNNG, thio‐TEPA, cyclophosphamide, and chlorambucil were administered to pregnant ICR mice together with caffeine at doses of 12.5, 25, or 50 mg/kg on day 11 of gestation. Fetuses were examined for gross malformations on day 18 of gestation. The teratogenicity of mitomycin C was significantly potentiated by caffeine at a dose as low as 12.5 mg/kg. The teratogenicity of chlorambucil was also significantly potentiated by caffeine at 50 mg/kg, but similar potentiation was not observed for x‐ray, MNNG, thio‐TEPA, and cyclophosphamide.
Craniofacial and central nervous system malformations induced by triamcinolone acetonide in nonhuman primates: II. Craniofacial pathogenesis
Authors: Parker R. M. , Hendrickx A. G.
Published: June 2005

This study further defines the craniofacial malformations induced by triamcinolone acetonide in the rhesus monkey. Ten timed‐mated pregnant rhesus monkeys (Macaca mulatta) received intramuscular injections of 10 mg/kg TAC on days 23, 25, 27, 29, and 31 of gestation. Results of previous experiments with rhesus and bonnet monkeys and baboons indicated that specific craniofacial and brain malformations could be induced with TAC during this period of pregnancy (Hendrickx et al., '80). Stage‐matched TAC‐treated and control embryos (stages 17–18 and 22) and age‐matched TAC‐treated and control fetuses (50, 60, and 70 days gestation) were removed by hysterotomy. Stage 17–18 TAC embryos appeared grossly normal but histologic evaluation revealed a shortened anlage of the posterior cranial base. Stage 22 TAC embryos and all TAC fetuses exhibited craniofacial dysmorphia and encephalocele. The developing sphenoid was the earliest affected and most severely malformed bone. Its defects included reduced anterioposterior and transverse dimensions, reduced orbitosphenoid and alisphenoid, abnormal pituitary fossa, and reduced dorsum and tuberculum sellae. In addition, shortening of the posterior cranial base and decreased cranial base angle was a consistent finding in the treated embryos and fetuses. Decreased ossification and remodeling in the facial bones and abnormal position due to the malformed sphenoid occurred.
Forebrain damage in chick embryos exposed to carbon monoxide
Authors: Daughtrey Wayne C. , Newby‐Schmidt M. B. , Norton Stata
Published: June 2005

The consequences of CO‐induced hypoxia to the forebrain of seven‐day‐old chick embryos were investigated. Exposure of embryos to CO for three hours caused hemorrhages in developing forebrain areas. Carboxyhemoglobin levels reached about 50% in the embryos. Two weeks later, about one day prior to hatching, morphology of large neurons in the paleostriatum primitivum was evaluated. In Golgi‐stained sections examined under the light microscope, the CO‐exposed chicks were found to have reduced branching of the dendritic tree. In addition, the nuclear size of the paleostriatum primitivum neurons was reduced in the CO‐exposed chicks. These findings in chick embryos are comparable to results in previous experiments with fetal rats.
Detection of teratogens in the Drosophila embryonic cell culture test: Assay of 100 chemicals
Authors: Bournias‐Vardiabasis Nicole , Teplitz Raymond L. , Chernoff Gerald F. , Seecof Robert L.
Published: June 2005

An in vitro assay of teratogenesis has been developed that utilizes Drosophila embryonic cell cultures. The endpoint selected in assessing the teratogenic potential of any substance involves detection of interference with normal muscle and/or neuron differentiation. In the validation phase of this project, 100 chemicals were tested. With drugs for which extensive reliable mammalian data are available, the results in the Drosophila assay equate rather favorably with those observed in animals and humans (i.e., a low percentage of false positives and false negatives has been obtained). In an effort to determine if strain differences exist and also to establish that the system shows a dose response, cultures from three wild‐type Drosophila strains (Canton S, Canton S109, and Oregon R) were tested. Dose‐response differences were observed when diethylstilbestrol, diphenylhydantoin, imipramine, testosterone, and tolbutamide were added to the cultures. These results suggest that the Drosophila assay, with further testing and refinements, might be capable of identifying agents of high teratogenic potential by their effect on neurons and muscle differentiation. Furthermore, sensitive strains might be used to study mechanisms of abnormal development and gene involvement in teratogenic resistance.
Ultrastructure of trypan blue induced ocular defects: I. Retina and lens
Authors: Schmidt Karmen L. , Milner Karen , Hilburn Pamela J. , Schmidt Waldemar A.
Published: June 2005

The histological and cytological basis of trypan blue–induced ocular defects were studied using scanning and transmission electron microscopy. Microphthalmic and anophthalmic eyes of 16‐day rat fetuses were utilized from dams exposed to a teratogenic dose of trypan blue. Retinal and lenticular anlagen were specifically examined for architectural and cellular changes. Nearly all severely abnormal eyes showed no evidence of retina development: Of 41 such eyes, only two retinal rudiments were observed. Those eyes with mild microphthalmia always demonstrated retinae although architectural changes were present. In every abnormal eye, some degree of lenticular morphogenesis was always present. Lenses were small, displaced in the eye field, and arrested at the lens vesicle stage. Lens cells were markedly undifferentiated and thus lacked most of the cytological features normally present at this developmental stage. Neither retinal nor lenticular rudiments were necrotic despite major architectural and cytological disturbances. The data offer three conclusions: First, the absence of necrosis suggests that trypan blue causes developmental arrest in this eye model; second, absence of retinae is most likely due to primary failure of optic vesicle development; third, lack of lens differentiation is attributed to absence of the retina, the primary lens inducer.
Prune perineum syndrome: Report of a second case
Authors: Williams David A. , Weiss Terry , Wade Elizabeth , Dignan Peter
Published: June 2005

A child is reported with a constellation of anomalies which include acetabular dysplasia with bilateral dislocated hips, persistent cloaca, hypoplastic kidney, two umbilical vessels, anal atresia and no obvious external genitalia. These anomalies are strikingly similar to a case reported by Peeden et al ('79) which was referred to as prune perineum. A discussion on possible underlying cause(s) of caudal dysplasia is included.
Embryotoxic effects of doxorubicin and N‐trifluoroacetyladriamycin‐14‐valerate (AD‐32)
Authors: Zirvi Karimullah A. , Gilani Shamshad H. , Hill George J
Published: June 2005

Anthracyclines are mutagenic, carcinogenic, and also cardiotoxic. Concern has been shown over the use of anthracycline anticancer drugs during pregnancy as these may be teratogenic to the human fetus. We have performed a series of experiments using the chick embryo to investigate and compare the toxic and teratogenic effects of doxorubicin (DX) and its new analog N‐trifluoroacetyladriamycin‐4‐valerate (AD‐32). DX and AD‐32, dissolved in 1:1 emulphor/ethanol and diluted to 1:4 with water, were injected into the air sac of white leghorn chick eggs at dose levels of 1‐20 μg (DX) and 5–100 μg (AD‐32) per egg. Eggs received a single injection of the drugs on days 1 and 2 of incubation. Control eggs were injected with an equivalent volume of the drug vehicle (0.05 ml per egg). Both of the drugs caused embryonic death, stunted growth, and various gross morphological malformations. Surviving embryos were sacrificed when they reached 13 days of incubation. The LD50 values for days 1 and 2 were as follows: (DX, 2.5 μg/egg on day 1 and 0.9 μg/egg on day 2; AD‐32, 10.6 μg/egg on day 1 and 11.8 μg/egg on day 2). Stunting of growth, a common anomaly with both drugs, decreased sharply from day 1 to day 2. The studies demonstrate that both DX and AD‐32 are toxic and teratogenic during the period of early organogenesis in the chick embryos. However, the toxic and teratogenic potentials of DX and AD‐32 differ quantitatively. AD‐32 is a more potent teratogen than DX when injected on day 1.
A comparative study of the effects or retinoic acid given during the critical period for inducing spina bifida in mice and hamsters
Authors: Tibbles L. , Wiley M. J.
Published: June 2005

Spina bifida occurred in the offspring of golden Syrian hamsters treated on day 8 of gestation, and CD‐1 mice treated on day 9, with 80 mg/kg of retinoic acid. Light microscopic examination of term fetuses demonstrated that myeloschisis was the characteristic form of the defect in mice, whereas myelocystocele was the predominant type of spina bifida induced in the hamster. To investigate the pathogenesis of these defects, a comparative study was undertaken by light microscopy and scanning electron microscopy of the changes occurring in caudal embryonic tissues during the initial 48 hr following maternal treatment. Within 18 hr of exposure, similar effects were observed in both species. These included distortion of the neural folds at the level of the posterior neuropore, vascular damage and hematoma formation, malformation of the notochord, and abnormalities of secondary neurulation. No differences were observed that we thought could account for the apparent variation in the pattern of malformations seen in the term litters. Rather, the dissimilarity may reflect species differences in the position of the posterior neuropore in the neuraxis and in the extent to which secondary neurulation contributes to the development of the lumbosacral cord segments.
First‐trimester hemoglobin A1 and risk for major malformation and spontaneous abortion in diabetic pregnancy
Authors: Greene Michael F. , Hare John W. , Cloherty John P. , Benacerraf Beryl R. , Soeldner J. Stuart
Published: June 2005

The relationship between the level of hemoglobin A1 (Hb A1) in the first trimester and major malformations and spontaneous abortions was examined in 303 insulin‐requiring diabetic gravidas. During the study period, all patients with insulin‐requiring diabetes mellitus antedating pregnancy who registered for prenatal care prior to 12 weeks' gestation and who had a known outcome were included. Thirty‐five percent of the patients entered with a first‐trimester Hb A1 of greater than 11.0% of total hemoglobin (9 standard deviations above the mean for a nondiabetic population). A broad spectrum of glycemic control was therefore represented. The risk of spontaneous abortion was 12.4% with first‐trimester Hb A1 ⩽ 9.3% and 37.5% with Hb A1 > 14.4% (risk ratio 3.0; 95% confidence interval 1.3–7.0). The risk for major malformation was 3.0% with Hb A1 ⩽ 9.3% and 40% with Hb A1 > 14.4% (risk ratio 13.2; 95% confidence interval 4.3–40.4). Although the risks for both adverse outcomes were markedly elevated following a first trimester in very poor metabolic control, there was a broad range of control over which the risks were not substantially elevated. To keep malformations and spontaneous abortions to a minimum among diabetic women does not require “excellent” control; there seems to be a fairly broad range of “acceptable” control.
Transplacental estrogen responses in the fetal rat: Increased uterine weight and ornithine decarboxylase activity
Authors: Harmon James R. , Branham William S. , Sheehan Daniel M.
Published: June 2005

The synthetic estrogens, diethylstibestrol (DES) and ethynylestradiol (EE2), are more potent than 17β‐estradiol (E2) in inducing uterine weight gain in the neonatal rat, due to the binding of E2 to serum α‐fetoprotein (AFP). However, all three hormones are equipotent in inducing neonatal uterine ornithine decarboxylase (ODC) activity. The present study assessed estrogen potency in fetal rats. Pregnant CD rats were injected sc. daily on gestation days (GD) 16–20 with DES, EE2, or E2 in sesame oil. Both DES and EE2, but not E2, significantly increased uterine weight at birth, to more than twice that of controls. In addition, implants which continuously release E2 only slightly increased uterine weight at birth. Alternatively, dams were given a single estrogen injection on GD 20 and were sacrificed at various times after injection. Peak fetal uterine ODC activity occurred at 6–8 hours after maternal injection for all three estrogens. E2 had a relative potency about tenfold less than either DES or EE2 in stimulating fetal ODC activity, in contrast to equal potencies of the three estrogens in the postnatal rat uterus. Similar patterns were found following direct fetal injection with E2 or DES. In summary, these data demonstrate a transplacental induction of fetal uterine ODC activity and uterine weight gain by both DES and EE2. In addition, the lack of correlation between these endpoints in response to E2 suggests that they may be useful as selective indicators of potential toxicity of both natural and synthetic estrogens.
Ethylenethiourea‐induced hydrocephalus in vivo and in vitro with a note on the use of a constant gaseous atmosphere for rat embryo cultures
Authors: Khera K. S.
Published: June 2005

Embryos were studied either after direct exposure to ethylenethiourea (ETU) during incubation of embryo cultures or after maternal ETU dosing and subsequent embryonic development in utero with a view to assess the similarity of these two systems to produce hydrocephalus. Ten‐day‐old rat embryos were incubated with nutrient media containing 0–2.0 mM of ETU in a constant gasseous environment following a newly modified method. The cultured embryos showed hydrocephalus in the form of dilated rhombencephalon and other anomalies at the 1.5 and 2.0 mM of ETU after 26 hours of incubation. No anomalies were seen in the control group. In in vivo studies, dilated rhombencephalon or hydrocephalus was not observed when dams, orally dosed with ETU on gestation day 10, were either killed daily for three postdosing days to examine embryos or killed at term to evaluate fetuses. This discrepancy in dilatation that was incidental to the rhombencephalon in the two systems pointed out that the fourth ventricle of the cranial neural tube responded by dilatation in vitro but remained unaffected in vivo following ETU exposure. ETU dosing of dams on the 12th day of pregnancy, when embryos are known to be sensitive to ETU‐induced hydrocephalus, followed by serial gross examination of embryos, suggested that edema occurred in a generalized form but only after the appearance of both hydrocephalus (dilatation primarily in mesencephalon) and, the previously reported, neuroblastic necrosis.