bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperthermia as a teratogen: Parameters determining hyperthermia‐induced head defects in the rat
Authors: Germain Mary‐Ann , Webster William S. , Edwards Marshall J.
Published: June 2005

This study determined the relationship between the duration and extent of temperature elevation, during a critical period of rat embryonic development, and the induction of congenital malformations. Pregnant Sprague‐Dawley rats, at 9 days 12 hours gestation (gastrulation stage), were partially immersed in a water bath until their core temperature, monitored by a rectal thermistor probe, was elevated to a nominated temperature. Seven temperatures were tested from 40.5°C to 43.5°C, elevations of 2.0–5.0°C in core temperature. Various durations at each of these temperatures were tested for potential teratogenicity. A single elevation of 5.0°C or 4.5°C needed only a “spike” in duration to be teratogenic, 4.0°C was teratogenic within 5 minutes, 3.5°C within 10 minutes, 3.0°C within 20 minutes, and 2.5°C within 1 hour. An elevation of 2.0°C for 8 hours was not teratogenic. Microphthalmia was the most common malformation at all teratogenic temperatures and was frequently the only malformation seen at the shortest time exposure for a particular temperature. Encephalocele, facial clefting, and maxillary hypoplasia were the other frequently seen malformations. Five control rats were placed in the water bath for 2 hours at 38°C so that their core temperature was not elevated. All the control fetuses were normal. An elevation of 2.5°C for 1 hour was the threshold combination for teratogenesis. As the temperature increased above a 2.5°C elevation the necessary duration of exposure for teratogenesis decreased.
Experimental induction of microphthalmia in the chick embryo with a single dose of cisplatin
Authors: Narbaitz Roberto , Marino Irma
Published: June 2005

Chick embryos were injected on the fifth day of incubation with 75 ng cis‐diamminedichlorplatinum II (cisplatin) and killed at daily intervals. Bilateral microphthalmia appeared in 88% of the surviving embryos; the decrease in eye size was noticeable 2 or 3 days after injection. Coinciding with this, macroscopic, histological, and ultrastructural changes started to appear in the ciliary body: ciliary processes failed to form and the cells in the inner layer of the ciliary epithelium underwent degenerative changes.

Changes in the retina appeared somewhat later. Despite the decreased growth rate of the whole eye the neural layer of the retina continued to grow rapidly; as a result, it formed numerous folds and acquired a glandular appearance. In the most severe cases the rapidly growing retina would invade the ciliary region and replace completely the degenerated inner layer of the ciliary epithelium.

It has been shown by previous authors that intraocular pressure is a determinant of eye expansion and also that the secretion of water and ions by the ciliary epithelium is important for the maintenance of that intraocular pressure. On this basis, our results are interpreted as indicating that the primary lesion induced by cisplatin was in the ciliary epithelium and that microphthalmia was the consequence of decreased pressure. It is also concluded that the retinal changes were due to the fact that the retina continued to grow despite the lack of expansion of the eye as a whole.
Prenatal ethanol weakens the efficacy of reinforcers for adult mice
Authors: Gentry G. David , Middaugh Lawrence D.
Published: June 2005

Pregnant C57BL/6cr mice were fed a liquid diet containing 20% of the total calories from either ethanol (E) or sucrose (S) for gestation days 5–17. Adult male and female (six of each from both prenatal‐treatment groups) offspring were tested under various schedules of food reinforcement. The first phase was a test of fixed‐ratio (FR) acquisition in which the required number of responses per unit of reinforcement was increased from 1 to 20 to 100. Prenatal ethanol exposure interacted with other factors to produce an acquisition deficit. The second phase involved responding under extinction (Ext). Under standard Ext procedures there were no prenatal‐ethanol effects; however, when a conditioned reinforcer was superimposed on an FR 5, the E males did not increase their rates as much as the S males. Finally, under a multiple FR 5 DRO 15‐sec (differential‐reinforcement‐of‐other‐behavior) arrangement, prenatal‐ethanol effects were found in each component. For the FR 5 component, prenatal ethanol eliminated the sex differences found in the S subjects. For the DRO 15‐sec component, prenatal ethanol elevated response rates. The results indicate a general decreased efficacy of positive reinforcement in adult mice following prenatal ethanol exposure.
Heritable pulmonary lobation anomaly in the rat
Authors: Aoyama Hiroaki , Teramoto Shoji , Shirasu Yasuhiko
Published: June 2005

A new mutant gene which caused fusion of lung lobes was found in the Wistar rat. The genetic analysis revealed an autosomal recessive inheritance and the mutant gene was named fused pulmonary lobes (gene symbol: fpl). The right lung of the fpl/fpl homozygotes had fused lobes of varying degrees. The fpl/fpl homozygotes were semilethal at the neonatal stage and had externally visible associated malformations such as malocclusion of incisors, eyelid anomalies, and digit abnormalities in the fore‐ and hindlimbs with different incidences. These traits were considered to be caused by the pleiotropic effects of the fpl gene.
Behavioural and developmental abnormalities in mouse trisomy 19: An animal model of mental retardation induced by chromosome imbalance
Authors: Buselmaier W. , Bacchus C. , Grohé G. , Winking H.
Published: June 2005

Murine trisomy 19 (Ts19) can be regarded as a general model of human trisomies. It is the only autosomal trisomy in the mouse that survives the perinatal period. Therefore, it is the only animal model available for postnatal investigations of trisomy‐specific mental retardation. To evaluate the extent of developmental retardation during the late‐embryonic and fetal period of gestation, total body weight development was documented for 60 Ts19‐fetuses and compared with that of 219 euploid in utero‐mates. In addition, a postnatal study on body‐weight development of 77 Ts19‐neonates and 74 euploid littermates was performed starting on day 1 postpartum and continuing until spontaneous death or until day 22. Forty‐seven Ts19‐individuals were further tested in nine behavioural test systems in order to determine their neurophysiological developmental profile. Findings were compared with agedependent morphologic and physiologic parameters. The data obtained in the present study show a significant retardation of organ‐ and body‐weight development in Ts19‐mice starting on day 14 of gestation. Retardation of physiological parameters is progressive and persists throughout the perinatal and postnatal periods. Furthermore, the trisomic individuals showed specific behavioural abnormalities.
Use of the correlation of liability in twins and siblings in the study of birth defects
Authors: Newman Thomas B. , Browner Warren S.
Published: June 2005

The epidemiologic approach to determining the etiology of disease involves identification of potential risk factors and then comparison of disease incidence among people with varying levels of exposure to the potential risk factors. This paper defines risk factors which correspond to different levels of genetic and environmental proximity to index cases of birth defects. Genetic proximity is estimated by the coefficient of relationship (R): 0.5 for siblings and dizygotic twins and 1.0 for monozygotic twins. Environmental proximity is measured by a combination of two variables: one variable for those potentially preventable risk factors common to siblings (S) and another for those common only to twins (T). Discordance in identical twins is attributed to a third type of environmental factors (U) that are unshared by twins and include random (stochastic) factors. The association between these risk factors and birth defects is estimated by using a linear model of the correlation of liability for different relatives. The coefficients derived from the model reflect the relative importance of genetic and different types of environmental risk factors as causes for the defects and can be used to identify birth defects most likely to be caused by measurable and possibly preventable risk factors. These defects could then be assigned high priority for future studies and preventive efforts.
Common hierarchies of susceptibility to the induction of neural tube defects in mouse embryos by valproic acid and its 4‐propyl‐4‐pentenoic acid metabolite
Authors: Finnell Richard H. , Bennett Gregory D. , Karras Steven B. , Mohl Virginia K.
Published: June 2005

The teratogenic effects of valproic acid and its 4‐propyl‐4‐pentenoic acid (4‐en) metabolite were investigated in three inbred mouse strains that were known to possess differing sensitivity to heat‐induced neural tube defects. In the heat‐resistant DBA/2J strain, administration of either valproic acid or the metabolite during the critical period of neural tube development failed to produce any abnormal offspring. Similar treatment in the moderately heat‐sensitive LM/Bc strain resulted in up to 19.8% exencephalic fetuses. The highly heat‐sensitive SWV strain was also very susceptible to the induction of neural tube defects by either valproic acid or its 4‐en metabolite. When administered on gestational day 8 plus 12 hours, the parent compound produced 35% exencephalic fetuses, while the metabolite had a response frequency of 32.4%. Thus, the hierarchy of susceptibility for the induction of neural tube defects in these inbred mouse strains was exactly the same whether the teratogen was a physical agent such as hyperthermia or a chemical compound such as valproic acid. If such diverse agents as these should interact to produce malformations, then it is possible that a wide variety of other agents might interact in a similar manner to produce neural tube defects.
Retinoic acid induction of featherlike structures from reticulate scales
Authors: Fisher Cynthia J. , Knapp Loren W. , Sawyer Roger H.
Published: June 2005

Retinoic acid‐induced transformation of reticulate scales to feather‐like structures (Dhouailly and Hardy, '78) provides a useful model to study biochemical differentiation in avian skin. In this study, immunofluorescent analysis of reticulate scale‐feathers (RSFs) indicates that they contain β keratin in feather barbs and, thus, are true feathers, biochemically. Epidermal cells that would otherwise produce only α keratin in reticulate scales are induced to reorganize and differentiate into barb ridge cells that accumulate feather β keratins. The mechanism for these dramatic morphological and biosynthetic responses to retinoic acid is unknown.
Embryonic catch‐up growth after exposure to the ketone body D,L,‐beta‐hydroxybutyrate in vitro
Authors: Shum L. , Sadler T. W.
Published: June 2005

The capability of rodent embryos to recover in growth and development subsequent to exposure to an insult was investigated employing whole embryo culture. Early somite stage mouse embryos were exposed to 32mM D,L,‐beta‐hydroxybutyrate (D,L,‐βOHB) for 24 hr (Period I), and were then transferred and maintained in control medium for an additional 36 hr maximum (Period II). Growth of this recovery group (Group B) was monitored at various time points of Period II and the results were compared with an unexposed control group (Group A) and another continuously‐exposed reference group (Group C). At the end of Period I, 100% of D,L,‐βOHB‐exposed embryos exhibited neural tube closure defects and were growth retarded. At 36 hr of Period II, cranial and caudal neural tube defects of Group B embryos were reduced to 3–7% and 0%, respectively. These embryos also demonstrated an excess in growth velocity during recovery so that at the end of Period II, total protein content was comparable to control values. In contrast, Group C embryos remained growth retarded and showed a significant increase in cranial and caudal neural tube defects (20 and 75%, respectively). Thus, neurulating mouse embryos were capable of catch‐up growth following an embryotoxic exposure to D,L,‐βOHB. The progression of development of total protein values and morphological features such as elimination of neural tube defects was intimately related to the amount of time allowed for recovery. Moreover, an elevation of growth rate over normality, which is characteristic of catch‐up growth, was observed.
Studies of embryotoxic mechanisms of niridazole: Evidence that oxygen depletion plays a role in dysmorphogenicity
Authors: Fantel A. G. , Juchau M. R. , Burroughs C. J. , Person R. E.
Published: June 2005

Previous study has shown that niridazole (NDZ) is dysmorphogenic to rat embryos between days 10 and 11 under culture conditions including 5% oxygen. Other studies have found that reductive embryonic biotransformation is required but that covalent binding is not a major basis of this embryotoxicity. In research presented here, NDZ exposure of homogenates prepared from day 10 rat embryos resulted in stimulation of oxygen uptake from incubation media. Further studies showed that a large percentage of this increased oxygen uptake was associated with the generation of superoxide anion radical and hydrogen peroxide. These findings led us to hypothesize that redox cycling forms the basis of the in vitro dysmorphogenicity of NDZ. The basic premise of this hypothesis is that as a result of redox cycling, oxygen is depleted from the sensitive tissues of embryos. In order to investigate it, we devised a technique for carefully controlling and monitoring oxygen tensions in embryo cultures. We found that when oxygen concentrations of 4% were established, a highly significant incidence of asymmetric defects resulted. These defects appeared analogous to those induced by NDZ exposure, consisting of asymmetric necrosis of mesenchymal tissue near the cephalic end of the neural tube and thinning of the neuroepithelium on the right. We concluded that the hypoxia induced by redox cycling of NDZ and related nitroheterocycles represents a major embryotoxic principle of action.
A mouse model for neural tube defects: The Curtailed (Tc) mutation produces spina bifida occulta in Tc/ + animals and spina bifida with meningomyelocele in Tc/t
Authors: Park Chong‐Hiyo T. , Pruitt Jeffrey H. , Bennett Dorothea
Published: June 2005

Curtailed (Tc), a dominant mutation on mouse chromosome 17, causes a tailless phenotype and occasional hindlimb paralysis in heterozygotes. Histologically, Tc/ + embryos show a variety of abnormalities including budding and ventral duplication of the developing spinal cord, duplication and intermittent absence of the notochord, and partial or complete absence of bony vertebrae, all posterior to midliver level. When Tc is heterozygous with t‐haplotypes that contain the “tail interaction factor,” tct, the phenotype is more severe, and a dorsal blood blister exists in the lumbosacral area. Our microscopic observations reveal that Tc/tw5 mice have a lumbosacral spina bifida with meningomyelocele. This results from the absence of bony vertebrae, extensive thinning of the dermis dorsally, and the rupturing of the previously closed neural tube, probably by increased cerebrospinal fluid (CSF) pressure on the necrotic, attenuated roof plate. Thinning of the roof plate, which facilitates the rupturing of the spinal cord, is not observed in Tc/ +, which suggests that this phenomenon is associated with the interaction of Tc with the t‐allele. Later in the development of Tc/tw5 embryos, adjacent blood vessels are ruptured, resulting in hemorrhage into the CSF space to give the external appearance of a blood blister. Tc/ + mice also show an absence of bony vertebrae dorsally in the lumbosacral region, but they lack the dorsal blood blister, and the dermal layer overlying the bony defect retains its normal thickness; these observations describe a spina bifida occulta.
Teratologic potential of 2‐methoxyethanol and transplacental distribution of its metabolite, 2‐methoxyacetic acid, in non‐human primates
Authors: Scott W. J. , Fradkin R. , Wittfoht W. , Nau H.
Published: June 2005

The embryotoxic effects of 2‐methoxyethanol (2‐ME) were studied in non‐human primates to better assess the risk for women of child‐bearing age exposed to this agent. Macaca fascicularis females were treated daily throughout the organogenetic phase of pregnancy (days 20–45) by gavage and the fetuses collected at day 100 by Caesarean section. At the highest dose (0.47 mmole/kg), all eight pregnancies ended in death of the embryo. One of these dead embryos was abnormal, missing a digit on each forelimb. At the middle dose (0.32 mmole/kg), three of 10 pregnancies ended in embryonic death, presumably due to 2‐ME exposure and three of 13 pregnancies met a similar fate at the low dose (0.16 mmole/kg). In each of these two groups, an additional pregnancy was lost to abortion, but both were thought to be spontaneous, which usually occurs in 10–20% of untreated macaque pregnancies. These results indicate that 2‐ME is a potent toxin to the developing primate embryo and thereby furthers the concern about exposure of pregnant women to this agent, although maternal toxicity was evident in nearly all treated pregnancies and was especially severe in the high‐dosage animals. Distribution of the major metabolite of 2‐ME, 2‐methoxyacetic acid (2‐MAA), indicated a long half‐life (ca.20 h), resulting in accumulation of metabolite in maternal serum after repeated daily dosing. Transplacental studies revealed uniform distribution in the embryo and extraembryonic fluids at a concentration similar to that in maternal serum. The yolk sac, on the other hand, accumulated a very high concentration of 2‐MAA, but the embryotoxic significance of this observation is unknown.
Lectin teratogenesis II: Demonstration of increased binding of concanavalin a to limb buds of rabbit embryos during the teratogenically sensitive period
Authors: DeSesso John M. , Niewenhuis Robert J. , Goeringer Gerald C.
Published: June 2005

The plant lectin concanavalin A (con A) causes malformations of rabbit embryos when 160μg (in 40 μl) are injected into the exocoelom on gestational days 12–15 but does not cause malformations on days 10–11. The purpose of this study was to investigate the mechanism for increased susceptibility of day 12–15 embryos to con A teratogenicity. Light microscopy of day 11 embryos 15–20 hr after treatment with con A revealed no observable difference from controls. Day 13 embryos at similar times exhibited limb buds with large areas that were denuded of ectoderm. Concurrent addition of α‐methyl‐D‐mannoside (αMM), a specific inhibitor of con A, to the injection solution of day 13 embryos resulted in limb buds that appearded normal. The regions of con A binding to day 11 and day 13 embryos were visualized through epifluorescent microscopy of untreated embryos stained with fluorescein‐labelled con A. Day 11 embryos exhibited moderate fluorescence on the surface of limb buds and the pericardial region. Day 13 embryos exhibited strong fluorescence of limb bud surfaces; the pericardial region remained moderately fluorescent. Addition of αMM to the incubation medium resulted in no fluorescence above background. Visualization of con A receptors was accomplished by ultrastructural analysis of forelimb buds stained with ferritin‐labelled con A. Ferritin label was observed only on the surfaces of the ectoderm and was sparse over all regions of day 11 limb buds. In contrast, ferritin label was moderately heavy in all regions of the day 13 limb buds. No labelling occurred when the ferritin‐labelled con A was preincubated with αMM. These observations indicate that the number of exposed con A receptors on limb buds of teratogenically sensitive embryos (day 13) is increased, compared with the number of exposed receptors on limb buds of younger, insensitive (day 11) embryos. The increased number of exposed con A receptors on limb buds during the teratogenically sensitive period provides not only increased binding of the lectin to sensitive embryos but also a potential mechanism for the anomalous attachment of distal regions of the limb buds to the body wall.
Unique anomalies in cephalothoracopagus Janiceps conjoined twins with implications for multiple mechanisms in the abnormal embryogenesis
Authors: Baron Beverly W. , Shermeta Dennis W. , Ismail Mahmoud A. , Ben‐Ami Tamar , Yousefzadeh David , Carlson Nancy , Amarose Anthony P. , Esterly John R.
Published: June 2005

The anatomic features of female conjoined twins with the Janiceps type of cephalothoracopagus are described. Abnormalities included bilateral clefts of the alveolar arches, shared rudimentary mandible, high, arched clavicles, multiple rib deformities, single shared foregut and small intestine, absent large intestines, omphalocele, multicystic kidneys, hypoplastic lungs, interconnected aortas and neck vessels, single ovary with elongated uterus in each twin, displaced labia, abnormal segmentation of the vertebrae, spinal dysraphism, diastasis of the symphysis pubis, malrotated lower extremity, bilateral posterior dislocation of the hips, and club feet. There were two hearts with internal anomalies. Both spinal cords had a myelocele in the lumbar region. The abnormalities noted in previous reports of conjoined twins of this type are reviewed and compared. We propose that factors associated with conjoining, dysgenetic (developmental) defects, and deformations resulting from crowding in utero all may have been important in the abnormal development in this case.
Amelia: Incidence and associated defects in a large population
Authors: Froster‐Iskenius Ursula G. , Baird Patricia A.
Published: June 2005

Amelia, or complete absence of a limb, is a very rare congenital anomaly. The incidence of amelia in a population of 1,213,913 consecutive livebirths in British Columbia during the period 1952–1984 was studied using the records of a population‐based registry with multiple sources of ascertainment. There were 18 cases of amelia, giving a minimal incidence rate of 0.15 per 10,000 livebirths for this birth defect. Amelia occurred equally frequently in upper and lower limbs, and 11 of 18 (61%) liveborn cases also had malformations of other organ systems. In the group with lower limb amelia a specific pattern of associated malformations, which included omphalocele and diaphragmmatic defects, was identified. There was no evidence for familial recurrence of amelia. Conditions to be considered in differential diagnosis are discussed.
Influence of maternal dietary zinc intake on in vitro tubulin polymerization in fetal rat brain
Authors: Oteiza Patricia I. , Cuellar Susana , Lönnerdal Bo , Hurley Lucille S. , Keen Carl L.
Published: June 2005

The hypothesis that one of the biochemical lesions underlying zinc deficiency‐induced teratogenicity is altered microtubule formation was tested. Day 19 fetuses from zinc‐deficient Sprague‐Dawley dams were characterized by low brain supernate zinc concentrations and slow brain tubulin polymerization rates compared to controls. Brain supernate tubulin and protein concentrations were similar in zinc‐deficient and control fetuses. In vitro brain tubulin polymerization rates were increased following addition of zinc to either control or zinc‐deficient brain supernates; however, the stimulatory effect of added zinc on polymerization was significantly higher in brain supernates obtained from zinc‐deficient fetuses compared to controls. These results support the idea that one effect of fetal zinc deficiency is a reduction in tubulin polymerization, which in turn may result in altered microtubule function.
Comparison of the incidence of 5‐azacytidine‐induced exencephaly between MT/HokIdr and Slc:ICR mice
Authors: Matsuda Motoko
Published: June 2005

The incidence of 5‐azacytidine‐induced exencephaly was compared between MT/HokIdr strain (MT) and Slc:ICR strain (ICR) mice. MT mice have a genetic predisposition for exencephaly, but ICR mice do not. Pregnant mice were given 5‐azacytidine (1 mg/kg to 100 μg/kg) injected intraperitoneally on Day 7.5 of gestation (vaginal plug day = Day 0.5), and fetuses were observed for external malformations on Day 18.5 of gestation. One hundred μg/kg 5‐azacytidine induced exencephaly in MT mice but not in ICR mice, and 1 mg/kg 5‐azacytidine resulted in resorptions in MT mice but caused exencephaly in ICR mice. These results indicated that MT mice had 10‐fold more sensitivity to 5‐azacytidine than ICR mice. It seems likely that less than effective doses of teratogens for animals without genetic predispositions are still effective in inducing malformations in animals with a genetic predisposition for malformations. When 4‐somite‐stage embryos of both MT and ICR mice were cultured in rat serum supplemented with 5‐azacytidine, 0.02 μg/ml 5‐azacytidine induced the failure of closure of cephalic neural tube in MT embryos but not in ICR embryos, and 0.2 μg/ml 5‐azacytidine induced severe growth retardation in MT embryos but in ICR embryos it only induced embryos with smaller heads and fewer somites than in control. These results indicated that MT mouse embryos in culture also had a 10‐fold‐increased sensitivity to 5‐azacytidine compared with ICR mouse embryos, suggesting maternal effects play no significant role in their increased sensitivity to 5‐azacytidine.
Correlation between the birth prevalence of isolated hypospadias and parental subfertility
Authors: Czeizel A. , Tóth J.
Published: June 2005

Factors associated with the occurrence of isolated hypospadias have been studied. We previously reported a secular trend association between hypospadias occurrence and progestagen use by the Hungarian population. Further study does not support that secular trend association. The use of progestagens for the treatment of reproductive problems is a very complex issue, and there are other factors relating to male and female fertility that differentiate the hypospadias families from the controls. It appears that families with problems of subfertility are at increased risk for the occurrence of hypospadias. Our data support more recent studies, which do not demonstrate an association between the occurrence of hypospadias and the administration of progestagens in humans.
Relationship of DNA damage and embryotoxicity induced by 4‐hydroperoxydechlorocyclophosphamide in postimplantation rat embryos
Authors: Little Sally A. , Mirkes Philip E.
Published: June 2005

4‐Hydroperoxydechlorocyclophosphamide (4‐OOHdeCl‐CP) is a preactivated analogue of cyclophosphamide (CP) that undergoes an elimination reaction to yield acrolein and the nonalkylating derivative of phosphoramide mustard (PM), i.e., dechlorophosphoramide mustard. We used this analogue to assess the role of acrolein in CP‐induced embryotoxicity. Embryotoxicity was assessed using day 10 rat embryos cultured in vitro. 4‐OOHdeCl‐CP was embryotoxic over a concentration range of approximately 75–150 μM and produced complete embryolethality at concentrations of 175 μM and above. This analogue induced abnormal development characterized by tail defects at low drug concentrations and microcephaly or prosencephalic hypoplasia at high concentrations. Using the technique of alkaline elution, we also assessed DNA damage induced by embryotoxic concentrations of drug. When embryos were cultured in serum‐containing medium during drug exposure, no DNA damage was detected, even at embryolethal drug concentrations. However, if cellular glutathione (GSH) was depleted with buthionine sulfoximine (BSO) before drug exposure and embryos were cultured in serum‐free medium during drug exposure, DNA damage, primarily DNA single‐strand breaks, was detected, but only at embryolethal concentrations. Using radiolabeled CP, we showed that acrolein does reach the embryo; however, more acrolein is incorporated into the yolk sac. Binding studies revealed that acrolein binds preferentially to cellular protein, whereas PM binds preferentially to DNA. These results suggest that, unlike the case with PM, the embryotoxic target for acrolein is protein and not DNA. Furthermore, our results indicate that acrolein may mediate its effects on the embryo via the yolk sac.
Prevention of unnecessary pregnancy terminations by counselling women on drug, chemical, and radiation exposure during the first trimester
Authors: Koren Gideon , Pastuszak Anne
Published: June 2005

As part of a new approach to counselling pregnant women concerned about antenatal exposure to drugs, chemicals, or radiation, we measured their tendency to terminate their pregnancy by using a visual analogue scale (VAS). Analysis of 78 cases where women had less than 50% tendency to continue pregnancy before they were advised by us reveals that 61 decided to continue their pregnancy after the consultation (57 normal, healthy infants, four miscarriages) and 17 terminated. Women who continued their pregnancy significantly changed their tendency after we discussed relevant information with them (from 34.3 ± 2.5% to 84.5 ± 3.3%, P<0.00001), whereas most of those who eventually terminated pregnancy did not change their tendency to continue pregnancy beyond the 50% mark (from 24.8 ± 5.4% to 45.1 ± 9.8%) (P>0.1). Only two of the women who terminated their pregnancy were exposed to teratogenic drugs; however, in most other cases, other obvious reasons, unrelated to the exposure in question, were identified by the women as leading reasons for termination.

An appropriate intervention in early pregnancy can prevent unnecessary pregnancy terminations by correcting misinformation and thereby decreasing the unrealistically high perception of risk by women exposed to nonteratogens.
Teratogenicity of the 13‐cis and all‐trans‐isomers of the aromatic retinoid etretin: Correlation to transplacental pharmacokinetics in mice during organogenesis after a single oral dose
Authors: Löfberg Boel , Chahoud Ibrahim , Bochert Gerd , Nau Heinz
Published: June 2005

NMRI mice were treated on day 11 (day 0 = plug day) of gestation with a single oral dose of 100 mg/kg of either all‐trans‐etretin (acitretin) or 13‐cis‐etretin. For teratology studies mice were sacrificed on day 18 of gestation, and the fetuses were examined for malformations. For pharmacokinetic studies, groups of 5 mice were sacrificed after 5, 10, and 30 min and 1, 2, 4, and 8 h. The concentrations of retinoids in maternal plasma and in embryos were determined by a newly developed HPLC gradient method. All‐transetretin induced malformations in 94% of the fetuses, mainly in fore and hind limbs and cleft palate. 13‐cis‐etretin did not show any teratogenic or embryolethal effects at the dose level used. These findings could be explained by a transplacental pharmacokinetic study. The maximum peak level and also the AUC (area under the concentration‐time curve) values of all‐trans‐etretin in the embryos was 7–8 times higher than corresponding values for 13‐cis‐etretin, probably due to extensive transport of the trans‐isomer and limited transport of the cis‐isomer from maternal plasma to the embryos. The concentration quotient between embryo and the maternal plasma was between 0.43 and 1.10 for all‐trans‐etretin, and only 0.16–0.31 for 13‐cis‐etretin over the time period studied. An in vivo isomerization of the compounds was also observed which was more extensive for 13‐cis‐etretin than for all‐trans‐etretin. Our results indicate that the low teratogenic potency of 13‐cis‐etretin is due to a limited placental transfer of this compound; on the other hand, the potent teratogen all‐transetretin is rapidly and extensively transferred to the embryo.
Neural tube defects and first trimester operations
Authors: Källén Bengt , Mazze Richard I.
Published: June 2005

Swedish health care registries were used to identify women who had surgery during pregnancy and their offspring. Among the 2,252 infants born to women who had first trimester operations during 1973–1981, six had definite diagnoses of neural tube defects (expected number, 2.5). Scrutiny of the records showed that 572 operations occurred during gestational weeks 4–5, the period of neural tube formation, and that the mothers of five of the six infants with neural tube defects had an operation during that period (expected number of neural tube defects, 0.6) although one of the offspring probably had Meckel's syndrome. The relationship between neural tube defects and operation during pregnancy is discussed including the possibility that the association may be random.
Developmental toxicity of soman in rats and rabbits
Authors: Bates Hudson K. , LaBorde James B. , Dacre Jack C. , Young John F.
Published: June 2005

Soman (GD; phosphonofluoridic acid, methyl‐,1,2,2‐trimethylpropyl ester) is an organophosphate compound with potent anticholinesterase activity. To determine developmental toxicity, soman was administered orally to CD rats on days 6 through 15 of gestation at dose levels of 0, 37.5, 75, 150, or 165 μg/kg/day and to New Zealand White (NZW) rabbits on days 6 through 19 of gestation at dose levels of 0, 2.5, 5, 10, or 15 μg/kg/day. At sacrifice, gravid uteri were weighed and examined for number and status of implants. Individual fetal body weights and external, visceral, and skeletal malformations were recorded. Mean maternal weight changes, fetal implantation status/litter, fetal weight, and fetal malformations/litter were compared between dose groups. Monitors for maternal toxicity were net body weight change, treatment weight change, mortality, and clinical signs of toxicity such as lethargy, ataxia, and tremors. Maternal rats and rabbits in the high‐dose groups exhibited statistically significant increases in toxicity and mortality when compared to controls. There were no significant dose‐related effects among dose groups in the prevalence of postimplantation loss, malformations, or in average body weight of live fetuses per litter. There was no evidence of increased prenatal mortality or fetal toxicity in the CD rat or NZW rabbit following exposure to soman, even at a dose that produced significant maternal toxicity.
Teratogenic potential of two neurotropic drugs, haloperidol and dextromoramide, tested on mouse embryos
Authors: Jurand A. , Martin L. V. H.
Published: June 2005

Potential teratogenic activity of two neurotropic drugs, haloperidol and dextromoramide tartrate, was tested by using the mouse embryo experimental model. Like numerous other drugs of this class these two are also embryotoxic. After treatment 1 hour into the 9th gestation day they induce the neurotropic syndrome of malformations comprising exencephaly, craniorachischisis, kinking of the spinal cord, brachyury, and dilation of the fourth brain ventricle. In addition, dextromoramide tartrate was found to induce one more, so far unknown, neural tube defect, namely the ectopia of the neural tube. Delay of treatment by 1 or 2 hours tends to displace the location of the neural tube defects along the length of the neural axis towards the anterior and posterior directions. Even after accumulating these results at relatively high doses, it is difficult to estimate human reproductive risks from this animal data for human therapeutic doses.
Variability in the developmental toxicity of bropirimine with the day of administration
Authors: Marks Thomas A. , Black Daniel L. , Terry Roger D. , Branstetter Daniel G. , Kirton Kenneth T.
Published: June 2005

The aim of this study was to determine the mechanism by which bropirimine exerts its developmental toxicity. This drug is an immunomodulator and interferon inducer with antiviral and antitumor activities in experimental models. Timed‐pregnant Upj:TUC(SD)spf (Sprague‐Dawley) rats were given a single oral (gastric intubation) dose of bropirimine at 200 or 400 mg/kg (doses as high as 100 mg/kg/day have been employed in human cancer trials) on days 5, 6, 7, 8, 9, 10, 11, or 12 of gestation and in a second experiment on day 12, 13, 14, 15, 16, 17, 18, or 19 of gestation. The dams were killed 24 hours after dosing and their uterine contents examined. In a third experiment, bropirimine (400 mg/kg) was administered on day 4 of gestation and the uteri of different groups were examined on day 8, 9, 10, 11, or 12 of gestation. Serum progesterone levels were measured at sacrifice. In the first two experiments a battery of hematologic/clinical chemistry assays also were performed. In all three experiments, bropirimine‐related maternal toxicity was observed; such toxicity was characterized by significant decreases in weight gain, relative to the concurrent vehicle controls, as well as significant differences in several blood parameters including platelets, white blood cells, alanine aminotransferase, and aspartate transaminase. In the first experiment, bropirimine treatment on day 11, but not day 12, resulted in significant decreases in the number of live embryos per litter. In the second experiment, significant decreases in the number of live fetuses per litter occurred 24 hours after dosing on day 18 (200 and 400 mg/kg groups) or day 19 (400 mg/kg group). Decreases in serum progesterone appeared to correlate well with the embryolethal effects seen after treatment between days 6 and 11 of gestation, but not with the fetal lethality seen when treatment was given on day 17 or 18. The decreases in serum progesterone levels found most likely were the result of a luteolytic effect, although it is unknown if bropirimine has a direct or indirect effect on the corpora lutea. In the third experiment, bropirimine treatment on day 4 of gestation resulted in only slight preimplantational losses, but significant decreases were found in mean number of live embryos per litter after day 9. Uterine decidual necrosis has been observed in the first experiment where bropirimine was given on day 11; however, treatment on day 4 resulted in an apparent decrease in decidual development but not necrosis.
External genitalia abnormalities in male rats exposed in utero to finasteride, a 5α‐reductase inhibitor
Authors: Clark Robert L. , Antonello Joseph M. , Grossman Scott J. , Wise L. David , Anderson Charles , Bagdon Walter J. , Prahalada Srinivasa , MacDonald James S. , Robertson Richard T.
Published: June 2005

A series of studies was conducted to determine the developmental toxicity of the 5α‐reductase inhibitor finasteride (MK‐0906) in rats. This compound was administered orally once daily to pregnant rats during various extended treatment periods during gestation. F1 offspring were evaluated on Day 20 of gestation as well as postnatally through mating to produce an F2 generation. MK‐0906 treatment induced dosage‐related incidences of hypospadias (penischisis) in male offspring with a threshold dosage level near 0.1 mg/kg/day and a 100% effect level of 100 mg/kg/day (with dosing through Day 20 of gestation). MK‐0906 also caused decreased anogenital distance in male offspring. The dosage response for this effect (ranging from a 4.2% decrease at 0.003 mg/kg/day to a 38% decrease at 100 mg/kg/day) was more shallow than that for hypospadias. The decreases in anogenital distance were at least partially reversible postnatally with essentially complete recovery at dosages up to 0.1 mg/kg/day. There was also a dosage‐related, temporary induction of nipples in F1 males. All of these effects were apparent following treatment on Days 6 through 17 of gestation but were more pronounced when dosing extended to Day 20 of gestation. Slight maternal toxicity consisting of minor decreases in body weight gain occurred only at dosages of 3 mg/kg/day and higher, indicating the selective nature of the developmental toxicity. The 5α‐reductase enzyme located in the rat fetal genital tubercle was studied in vitro and compared to that in the adult ventral prostate. The values for Km, Vmax, and IC50 for inhibition by MK‐0906 were similar in the two tissues, suggesting that the enzymatic proteins in the genital tubercle and ventral prostate may be similar.
Effect of gestational sex steroid exposure on limb development and endochondral ossification in the pregnant C57BI/6J mouse: I. Medroxyprogesterone acetate
Authors: Carbone J. P. , Figurska K. , Buck S. , Brent R. L.
Published: June 2005

Although data supporting the teratogenic potential of intrauterine progestin exposure is lacking, concern persists among some individuals within the scientific community that these drugs have the potential for nongenital teratogenesis, especially with regard to limb reduction defects. Our laboratory has been interested in the ontogeny of steroid receptors in the developing embryo and in the role of steroid‐receptor interactions in limb development, particularly the process of endochondral ossification. Since limb reduction defects can be produced from abnormal processes that are operative during organogenesis or during midgestation (vascular disruption) we have designed an animal study whereby embryos were exposed to sex steroids throughout organogenesis and fetal development. The present study assesses the effects of medroxyprogesterone acetate (MPA) on intrauterine endochrondral bone development specifically, as well as overall embryo‐fetal development. Primagravid C57B1/6J mice were treated via subdermal pellets which deliver MPA at dosages of 5.0, 50.0, and 500.0 mg/kg/day on gestational days 7 through 19. These doses were 25‐, 250‐, and 2,500‐fold higher on a mg/kg basis than the human dose equivalent (HDE). No increases in nongenital malformations were noted at any evaluated MPA dosage level. At 25 × the HDE, MPA did not influence endochondral bone development as evidenced by a lack of significant effects on assessed bone growth parameters. In the 250‐ and 2,500‐fold HDE dosage groups, MPA was shown to exert an embryotoxic effect inducing 48 and 100% resorptions respectively. Mean embryo weights/litter were significantly reduced by MPA exposure at 250 × the HDE. Intrauterine exposure to 250 × the MPA HDE induced reductions in humeral and femoral diaphyseal length in proportion to a reduction in overall growth. The data demonstrate that MPA, administered at dosages of up to several orders of magnitude in excess of the HDE and which permitted embryo survival, did not induce increases in the frequency of nongenital teratogenesis at any dose or gestational stage. Importantly, limb reduction defects were not noted even in instances where the dosage of MPA induced an inhibition of endochondral bone growth.
Effects of secondary bile acids on the intrauterine development in rats
Authors: Zimber Amazia , Zusman Igor
Published: June 2005

The effects of secondary bile acids (lithocholic—LCA, and deoxycholic—DCA) on the in vivo development of rat embryos and fetuses were studied. Daily intraperitoneal injections of 2 ml of 1 mM LCA and of 5 mM DCA during days 6 till 15 of pregnancy resulted in an increase of resorptions among 20 day‐old fetuses to 22.8% and 9.9%, respectively, vs. 6.2% in controls. Similar injections on days 12 to 19 resulted in an increase of resorptions to 10.3% after treatment with LCA and to 36% after treatment with DCA. Percent of retarded embryos was similar for both bile acids: 7.7 and 8.7% after injections on days 6–15 and 12.3–12.5% after injections on days 12–19 of gestation. This was accompanied by a significant increase in the wet weight of the placenta of living embryos. Intraamniotic injections of 2 μl of 1 mM LCA into 10 day‐old embryos resulted in 18.5% resorptions (vs. 7.5% in controls), 9.2% malformations, and 3.1% growth retardations observed on day 12 of pregnancy. The rate of resorptions following this treatment increased on day 20 of pregnancy to 71% vs. 16% in controls. No differences were found in the wet weight of 20 day‐old living fetuses or their livers and placentas between experimental and control groups following i.p. or intraamniotic injections. In addition, single intrauterine instillation of 0.2 ml of 1 mM LCA 10–14 days before mating with normal isogeneic males resulted in 9% of malformations among 12 day‐old embryos while malformations were absent in the saline‐injected controls. The deleterious effects of secondary bile acids to the embryos were accompanied by damage to the visceral yolk sac. These findings may be significant in relation to the complications previously associated with cholestasis of pregnancy in humans.
Developmental toxicity of temafloxacin hydrochloride in the long‐tailed macaque (Macaca fascicularis)
Authors: Tarantal A. F. , Lehrer S. B. , Lasley B. L. , Hendrickx A. G.
Published: June 2005

The potential developmental toxicity of temafloxacin hydrochloride was studied in the long‐tailed macaque (Macaca fascicularis). Ten animals in each of the three drug‐treated groups (25, 50, and 100 mg/kg) were administered temafloxacin via nasogastric intubation during gestational days (GD) 20–50. A control group of ten animals received vehicle only. The dams were monitored daily for adverse physical signs and maternal blood samples were collected for analyses of serum progesterone (P), 17β‐estradiol (E2), and chorionic gonadotropin (CG). In addition, the conceptus was monitored periodically by ultrasound during gestation to confirm growth and viability. Increased maternal toxicity (weight loss, anorexia, emesis) and embryolethality were observed at 100 mg/kg, and a no‐observable‐adverse‐effect‐level (NOAEL) of 50 mg/kg was established. The incidence of prenatal mortality was as follows: Control = 1/10 (10%); 25 mg/kg = 1/10 (10%); 50 mg/kg = 2/10 (20%); and 100 mg/kg = 5/10 (50%). Analysis of P, E2, and CG indicated no significant effect of treatment. In addition, no significant differences were observed in embryonic/fetal growth and development when compared to historical controls. No gross structural changes were observed in fetuses exposed to 50 or 100 mg/kg, although one fetus exposed to 25 mg/kg exhibited microphthalmia. This anomaly was considered spontaneous and, therefore, unrelated to treatment.
Developmental alterations in offspring of female rats orally intoxicated by aluminum lactate at different gestation periods
Authors: Muller Guy , Bernuzzi Viviane , Desor Didier , Hutin Marie‐France , Burnel Daniel , Lehr Paul R.
Published: June 2005

Pregnant rats were treated orally with aluminum lactate (400 mg Al/kg/day) during three periods of gestation to determine the treatment's influence on mortality, weight gain, neuromotor maturation, and learning abilities of their pups. No effect of treatment on litter size, mortality rate, and weight gain of pups was detected. In the negative geotaxis test, the scores of pups from females treated during the second and third weeks of gestation were diminished. In the locomotor coordination and the operant conditioning tests, significant differences in the comparison of controls vs. the three treated groups were found, indicating long‐term effects of early intoxication upon the central nervous system.
Descriptive epidemiology of selected malformations of the aorta, Atlanta, 1970–1983
Authors: Martin Mary Louise , Adams Melissa M. , Mortensen Mary L.
Published: June 2005

To augment available population‐based epidemiologic data for obstructive malformations of the aorta, we studied the descriptive epidemiology of coarctation, hypoplasia, and interruption of the aortic arch in Atlanta from 1970 through 1983. The study used data from the Metropolitan Atlanta Congenital Defects Program, a population‐based birth defects registry. One hundred seventy infants were identified as having either interruption of the aortic arch (18), coarctation (131), or hypoplasia (21) of the aorta. The prevalence per 10,000 live births was as follows: interruption of the aortic arch, 0.50; coarctation, 3.62; and hypoplasia of the aorta, 0.58. Despite the differences in rates, the descriptive epidemiology for the three malformations was similar. None of the malformations was associated with gender or maternal age. Birth prevalence for whites was higher than that for other races; the increase, however, was statistically significant only for coarctation. Birth prevalence of these malformations increased during the period of observation, with the greatest increase (threefold) seen with interruption of the aortic arch. The rates for all malformation groups also showed a strong inverse association with birthweight.