bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of laminin monoclonal antibodies on the development of cultured rat embryos
Authors: Rasmussen Max V. , Klein Norman W. , Abrahamson Dale R. , Chung Albert E.
Published: June 2005

Whole rat embryos (9.5 days of gestation) were exposed to six different monoclonal antibodies to laminin during 48 hr of culture. Four (LAM I, LAM V, 5A2, 9D2) of the six were teratogenic or lethal and two (LAM II, 5D3) were not toxic at comparable levels. Teratogenicity and lethality were not related to antibody level, subclass or affinity for whole laminin. Indirect immunofluorescence studies using mouse embryo sections revealed that the toxic antibodies bound in a diffuse manner, while the nontoxic antibodies showed distinct labeling of tissues. These observations suggest that previous varied responses seen in cultured rat embryos exposed to laminin antibodies obtained from humans, monkeys, and rats were the result of differences in the epitope specificity of those antibodies. © 1994 Wiley‐Liss, Inc.
Offspring of women infected with varicella during pregnancy: A prospective study
Authors: Jones Kenneth L. , Johnson Kathleen A. , Chambers Christina D.
Published: June 2005

Despite the well‐recognized association between maternal varicella infection and a specific pattern of malformation in the offspring referred to as fetal varicella syndrome, the full spectrum of this disorder as well as its frequency in the offspring of women infected with varicella during pregnancy is unknown. In order to resolve these issues, we have evaluated pregnancy outcome in 194 women who contacted us during pregnancy, soon after the onset of their infection: 132 (68%) during the 1st trimester and 171 (88%) prior to the onset of the 20th week, the most critical period relative to fetal susceptibility. Of those 171 women, there were 146 liveborn babies, 6 spontaneous abortions, 7 therapeutic abortions (one because of an anencephalic fetus), 2 stillborn infants, and nine pregnancies lost to follow‐up. Of the 146 liveborn births, there were 2 with features consistent with the fetal varicella syndrome: one a child with mild cutaneous scars on her face, arms, and legs, Horner syndrome involving her left eye and a scar on her retina, leading to blindness in that eye; and the other, a child with horizontal nystagmus who is otherwise normal at 1 year of age. An additional four liveborn infants had a single major malformation which included unilateral microtia, bowel obstruction secondary to an ileal band, bilateral double ureters, and a thyroglossal duct cyst. This study suggests that prenatal varicella infection is associated with a wider spectrum of severity than has been previously appreciated and indicates that maternal varicella infection prior to the 20th week of pregnancy is associated with only a small risk for the developing fetus. © 1994 Wiley‐Liss, Inc.
Cardiovascular birth defects and prenatal exposure to female sex hormones: A reevaluation of data reanalysis from a large prospective study
Authors: Hook Ernest B.
Published: June 2005

In data of the U.S. Collaborative Perinatal Study (CPS), the Drug Epidemiology Unit (DEU) reported a relative risk of about 2.3 between maternal female sex hormone exposure during months 1 to 4 of pregnancy and cardiovascular malformation in infants (Heinonen et al., '77a N. Engl. J. Med., 296:67–70). Wiseman and Dodds‐Smith ('84, Teratology, 30:359–370) reexamined the original CPS data and found the DEU had made some errors in classification of exposure and disease. Also they challenged the classification of cases as “exposed” in those born to mothers who received the compounds outside the day 19 to 50 window of cardiovascular embryogenesis. Wiseman and Dodds‐Smith stated that their reanalysis “clearly showed that there was [in the data used by the DEU] no statistically significant association between exposure in the critical organogenic period of pregnancy and cardiac malformation in offspring.” They did not undertake any statistical analysis, but their reanalysis resulted in a widespread nonacceptance of the association reported by the DEU. The study reported here reclassified the cases of the original DEU study in accord with the implications of the Wiseman and Dodds‐Smith reanalysis of exposure and disease. After this reclassification, an effect magnitude measure of association, the relative risk rose from 2.33 to 2.48 and remained nominally significant statistically at the .05 level. Thus, if anything, the quantitative consequences of the Wiseman and Dodds‐Smith review of the data, when applied in an unbiased manner, result in an, increase in the measure of effect. The increase is consistent with the theoretical epidemiological expectation that correction of random errors in a database and of other non‐differential misclassification, will tend to raise the estimate of an underlying association in the population studied. While these results reestablish the reported association, they do not, of course, prove that the positive association represents causal induction of defects in conceptuses by female sex hormones. © 1994 Wiley‐Liss, Inc.
Analysis of lower birth weight in infants with congenital limb deficiency
Authors: Czeizel Andrew E. , Elek Csaba , Ivicsics Kate
Published: June 2005

A case‐control study on different groups of isolated congenital limb deficiency was performed using a population‐based and validated Hungarian data set of 537 cases. All groups showed a significantly lower birth weight. The adjusted odds ratio indicated a significantly lower mean birth weight in infants with terminal transverse deficiencies and a significantly higher rate of preterm birth in those with amniogenic defects (part of the early amnion rupture sequence). The different analyses showed that the lower birth weight in the terminal transverse group was caused mainly by intrauterine growth retardation. Lack of limb parts appears to be of secondary importance, especially in the upper limb. © 1994 Wiley‐Liss, Inc.
Maternal age and oral cleft malformations: Data from a population‐based series of 576,815 consecutive livebirths
Authors: Baird P. A. , Sadovnick A. D. , Yee I. M. L.
Published: June 2005

It has been suggested that older mothers are more likely to have a child with isolated cleft palate (CP) or cleft lip ± cleft palate (CL ± CP), but most of these studies have been based on fairly small sample sizes. Data from a population‐based registry with multiple sources of case ascertainment were used to examine any association of maternal age with the incidence of these defects in infants without other congenital anomalies. The study group consisted of all cases with CP or CL ± CP without other congenital anomalies from a series of over half a million consecutive livebirths during the period 1966 to 1981 inclusive in British Columbia. During the study period, the overall incidences of isolated CP and isolated CL ± CP per 10,000 livebirths were 3.9 and 8.2, respectively. No association with maternal age was found when either isolated CP or isolated CL ± CP was analyzed as a group. When analyzed by sex, and by CP or CL ± CP, no significant maternal‐age effect was observed for males and females with CP or CL ± CP. Our population‐based data, therefore, do not show that older mothers are more likely to have a child with cleft palate, or cleft lip ± cleft palate. © 1994 Wiley‐Liss, Inc.
Volume and glucose concentration of rat amniotic fluid: Effects on embryo nutrition and axis rotation
Authors: Park Hyoung W. , Shepard Thomas H.
Published: June 2005

In order to pursue our previous studies of the changes in neural tube microvilli produced by glucose, we developed a micro method of measuring glucose concentration in the very small volumes of amniotic fluid during neurulation. The volume of amniotic fluid was found to increase nearly 10‐fold during major neurulation (day 10 to day 11 in the rat). This increase in volume and our repeated observations that physical removal of the restraining amnion initiates embryonic rotation leads us to propose that the growth of the amniotic cavity is essential for conversion from the ventral‐to dorsi‐flexion of the embryonic axis. Amniotic fluid volume continues to increase until day 18 but dropped by day 20.

A method for glucose determination was developed using the color reaction on glucose oxidase indicator paper. The intensity of the color was analyzed with a color scanner. Amniotic glucose was 27.1 ± 1.6 mg/dl on day 10 and continued in this range with some fluctuation until day 20 when it decreased. We isolated days 10, 11, and 16 embryonic sites from their decidua and incubated them at 0°C and 38°C while measuring glucose concentration. The glucose concentration did not show significant decrease at 0°C on day 10 or 11 or on day 16 at 38°C. At 38°C the day 10 embryo amniotic fluid glucose disappeared after 22 minutes and the day 11 amniotic fluid glucose was gone in 34 minutes. These depletion times were statistically different. The magnitude of glucose depletion on day 10 was shown by calculation to be approximately 323 μmoles/gm protein per hour which is a substantial portion of the glucose utilized by the embryo as determined in previous experiments (731 μmoles/gm protein per hour). This model may serve as a way to study glucose utilization by embryos after their exposure to various teratogens. © 1994 Wiley‐Liss, Inc.
Increased risk of craniosynostosis with maternal cigarette smoking during pregnancy
Authors: Alderman Beth W. , Bradley Cynthia M. , Greene Carol , Fernbach Sandra K. , Barón Anna E.
Published: June 2005

We analyzed data from a population‐based case control study to determine whether maternal prenatal smoking or alcohol drinking might increase the risk of craniosynostosis. Between 1986 and 1989, the Colorado Craniosynostosis Registry ascertained 233 children whose diagnoses were confirmed by an independent radiologist. Of the 212 (91%) cases who participated, 86 had lambdoid, 69 had sagittal, 25 had coronal, 18 had metopic, and 14 had multiple suture synostosis. Random sampling of birth certificate records yielded 367 eligible controls, of whom 291 (79%) participated. Study staff interviewed case and control mothers between 1989 and 1991 for prenatal smoking and alcohol drinking. We used Mantel‐Haenszel and polychotomous logistic regression techniques to estimate the relative odds of craniosynostosis for smoking and drinking in all cases and in relevant case subgroups. Smoking was associated with c relative odds of craniosynostosis of 1. 7 (95% confidence interval, 1.2–2.6). For smoking of more than one pack per day, the relative odds were 3.5 (1.5–8.4) for all types of synostosis. No strong or significant association was noted for drinking. Maternal prenatal smoking may increase the risk craniosynostosis in this population. © 1994 Wiley‐Liss, Inc.
Prevention of fluvastatin‐induced toxicity, mortality, and cardiac myopathy in pregnant rats by mevalonic acid supplementation
Authors: Hrab Roman V. , Hartman Howard A. , Cox Raymond H.
Published: June 2005

Mevalonic acid is a product of the enzyme HMG‐CoA reductase which is essential for cholesterol biosynthesis. Fluvastatin (Sandoz compound XU 62‐320) is a potent inhibitor of this enzyme and, hence, mevalonic acid production. In three separate studies, oral administration of fluvastatin at 12 and 24 mg/kg/day to mated rats from day 15 of gestation through weaning resulted in unanticipated maternal mortality at the time of parturition and during lactation. Microscopic evaluations performed in two studies revealed significant cardiac myopathy in the dying animals. Drug‐related clinical signs, significant maternal body weight loss, and an increase in stillborn pups and neonatal mortality were also noted at one or both dose levels. Supplementation of fluvastatin administration with 500 mg/kg b.i.d. of me valonic acid completely blocked and/or ameliorated the mortality, cardiac myopathy, and other adverse effects. These studies indicate that the adverse maternal effects observed with fluvastatin before or following parturition resulted from exaggerated pharmacologic activity at the dose levels administered, i.e., inhibition of the enzyme HMG‐CoA reductase, its immediate product mevalonic acid, and cholesterol biosynthesis. © 1994 Wiley‐Liss, Inc.
The effects of natural and synthetic retinoids on the differentiation of RCJ C5.18 chondrogenic cells
Authors: Von Schroeder Herbert P. , Hashimoto Yuichi , Heersche Johan N. M.
Published: June 2005

RCJ C5. 18 (C5. 18) is a chondrogenic clonal cell line which, under standard culture conditions, develops chondroblastic features including the production of a cartilaginous matrix. Retinoic acid (RA) is known to inhibit the chondrogenic differentiation of C 5. 18 cells and this may parallel the teratogenic effects of retinoids in vivo; however, the question as to which of the 3 retinoic acid receptors (RAR α, β, γ) or the 3 retinoid X receptors (RXR α, β, γ) mediate this RA‐induced inhibition remains unanswered. We tested several retinoids with different receptor binding characteristics. Cartilage formation in C 5. 18 cultures was evaluated by counting the number of cartilage nodules formed, and by quantitating the glycosaminoglycan content of the cultures using alcian blue staining. All of the retinoids prevented cartilage formation in a dose‐dependent manner. Treatment with the retinoids did not affect cell number, thereby ruling out any toxic effects. RA, which binds to all 3 RARs with similar affinity, produced a 50% inhibition (IC50) of cartilage formation at 4 × 10−10M. We also tested Ch55, which also binds to all 3 RARs, but with higher affinity than RA. This compound was approximately 10 times more potent than RA (IC50 2 × 10−11M). 9‐cis RA, which binds to the 3 RARs with affinities similar to RA and also binds to the RXRs, was less active (IC508 × 10−9M), suggesting that RXR binding interferes with the inhibitory effect of ligand‐activated RARs. 9‐cis retinal, for which the binding characteristics are unknown, had the same effect as 9‐cis RA. The synthetic retinoids Am80 (IC50 6 × 10−11M) and Am580 (IC50 4 × 10−11M) were more potent than RA in inhibiting cartilage formation. Since these compounds bind only to RARα and β, and with higher affinity than RA, the observed inhibition of cartilage formation suggests that interaction of the ligand with RARα and/or β is sufficient to induce the effects on cartilage development. If reports suggesting than Am580 binds exclusively to RARα are correct, these finding could imply that RARγ alone is sufficient to mediate the inhibitory effect of the retinoids. Surprisingly, Re80, which binds to RARα and β with a binding affinity similar to RA (and does not bind significantly to RARγ or the RXRs), was the most potent retinoid in our system (7 × 10−13 M). This finding supports mediation of the retinoid effect through α and β receptors. Our results suggest that the retinoids act via RARα and/ or β to inhibit chondroblast differentiation. © 1994 Wiley‐Liss, Inc.
Prevalence of neural tube defects in Cape Town, South Africa
Authors: Buccimazza Sandro S. , Molteno Christopher D. , Dunne Timothy T. , Viljoen Denis L.
Published: June 2005

The aim of the study was to document the frequency of neural tube defects (NTD) over a 20‐year period in Cape Town and to determine the effects of race, gender, maternal age, parity, and season of conception on the prevalence. Multiple sources of ascertainment were used, including all maternity hospital records, neurosurgical and spinal defects clinic data, as well as those from the Human Genetics Department and Fetal Abnormality Group. The prevalence rates for NTD fluctuated between 1.74 and 0.63 per 1,000 births, but showed no significant trends over the 20‐year period. Prevalence rates were highest for the white population group at 2.56 per 1,000 births compared to 0.95 per 1,000 for blacks and 1.05 per 1,000 for those of mixed ancestry. The higher rates in the whites, who are of British and European extraction and belong to the more affluent section of the community, would suggest that the possible effects of nutrition and infection are overshadowed by genetic factors. There was a female preponderance for both spina bifida (M: F ratio 0. 89) and anencephaly (M: F ratio 0. 67). The highest NTD rates were found at both ends of the maternal age range (<20 years and >35 years of age). The prevalence was highest at the extremes of birth order (1.65 and 1.58 for birth order 1and > 7, respectively, and 0.56 and 0.45 for birth order 5 and 6, respectively). A seasonal variation occurred which differed from that reported for the Northern Hemisphere and may reflect local climatic conditions. © 1994 Wiley‐Liss, Inc.
Acardia: Predictive risk factors for the co‐twin's survival
Authors: Healey Martin G.
Published: June 2005

This study aimed to find factors in acardiac pregnancies that could be used to predict survival rates of the pump fetus. Five cases of acardia at Monash Medical Centre were found, and all case reports available in the literature from 1960 to 1991 (184 cases) were collected and analyzed. Acardia is more common in nulliparous women and in monoamniotic monochorionic pregnancy. The acardiac fetus usually has a two‐vessel umbilical cord and is most likely to develop structures supplied by the lower aortic branches. Delivery is more often preterm (mean gestation = 31.1 weeks) than normal twins. The overall perinatal mortality for the pump fetus is 35% in twins and 45% in triplets. Factors associated with a statistically significant increase in perinatal mortality for the pump fetus include delivery before 32 weeks gestation, acardiacus anceps form of acardia, and the presence of arms, ears, larynx, trachea, pancreas, kidney, or small intestine in the acardiac fetus. Active intervention in these pregnancies is reasonable. © 1994 WiIey‐Liss, Inc.
Effects of static and time‐varying (50‐Hz) magnetic fields on reproduction and fetal development in rats
Authors: Mevissen Meike , Buntenkötter Siegfried , Löscher Wolfgang
Published: June 2005

Mated Wistar rats were chronically exposed to a static magnetic field (MF) from day 1 to day 20 of pregnancy. Flux density of the MF was 30 mTesla (mT), i.e., within the range of exposures of operators of magnetic resonance imaging (MRI) devices. For comparison with effects of this static field, a time‐varying (50‐Hz) MF of the same flux density was used. In both experiments, i.e., static or 50‐Hz MF exposure, sham‐exposed groups of dams served as controls. On day 20, the dams were sacrificed for reproductive and teratological assessment. The litters were evaluated for numbers of implantations, fetal deaths and resorptions, gross external, visceral, and skeletal malformations, and fetal weights. No adverse effects were seen in the dams during MF exposure. The mean number of living fetuses per litter was significantly decreased in the group with static MF exposure, but not the group with 50‐Hz MF exposure. Further differences between the two types of field exposure were observed with respect to minor (skeletal) fetal anomalies which were increased in the 50‐Hz but not the static MF group. No serious malformations were seen in any group. In both MF exposed groups, increased skeletal ossification was found, possibly indicating an accelerated prenatal development. In a second experiment with static MF (30 mT) in which dams were exposed for the whole period of pregnancy, and postnatal growth and development of offspring were studied, the postnatal growth was significantly enhanced in offspring following their prenatal MF exposure. In the offspring of this experiment, no behavioral disturbances were determined by severa I standardized test procedures of behaviora I teratology, indicating normal development of brain functions. In summary, the data of the present study indicate that the effects of static and alternating MF on reproduction and fetal development differ. The increased fetal loss during static MF exposure suggests that static MF of such high flux density may induce embryotoxic effects, while 50‐Hz MF exposure does not seem to be associated with any severe reproductive risks. © 1994 Wiley‐Liss, Inc.
Interactive developmental toxicity of radiofrequency radiation and 2‐methoxyethanol in rats
Authors: Nelson B. K. , Conover David L. , Shaw Peter B. , Werren Dwight M. , Edwards Richard M. , Hoberman Alan M.
Published: June 2005

Concurrent exposures to chemical and physical agents occur in the workplace; exposed workers include those involved with the microelectronics industry, plastic sealers, and electrosurgical units. Previous animal research indicates that hyperthermia induced by an elevation in ambient temperature can potentiate the toxicity and teratogenicity of some chemical agents. We previously demonstrated that combined exposure to radiofrequency (RF; 10 MHz) radiation, which also induces hyperthermia and is teratogenic to exposed animals, and the industrial solvent, 2‐methoxyethanol (2ME), produces enhanced teratogenicity in rats. The present study replicates and extends the previous research investigating the enhanced teratogenicity of combined RF radiation and 2ME exposures. The interactive dose‐related teratogenicity of RF radiation (sham exposure or maintaining colonic temperatures at 42.0oC for 0, 10, 20, or 30 min) and 2ME (0, 75, 100, 125, or 150mg/kg) was investigated by administering various combinations of RF radiation and 2ME to groups of rats on gestation days 9 or 13; gestation‐day 20 fetuses were examined for external, skeletal, and visceral malformations. The results are consistent with and extend our previous research findings. Synergism was observed between RF radiation and 2ME for some treatment combinations, but not for others. The study also clarified which gestational periods, RF radiation exposure durations, and 2ME doses would be most informative in future interaction studies to determine the lowest interactive effect level. Day 9 exposures generally evidenced little effect by 2ME, either by itself or in combination with RF radiation. In contrast, day 13 exposures resulted in highly significant effects from 2ME and RF radiation. The structures showing strong evidence of effects from both 2ME and RF radiation after exposure on gestation day 13 were the forepaw digits, forepaw phalanges, hindpaw digits, hindpaw phalanges, hind limbs, metacarpals, and metatarsals. Statistical analyses did not show a global synergistic effect, but did show evidence for a synergistic effect at intermediate levels of the dose ranges. Future research will address potential interactions at lower doses. © Wiley‐Liss, Inc.
Oxidative metabolism of aflatoxin B1 by lipoxygenase purified from human term placenta and intrauterine conceptal tissues
Authors: Datta Kaushik , Kulkarni Arun P.
Published: June 2005

Aflatoxin B1(AFB1) is a teratogen in rodents and may be a human transplacental carcinogen. Although the presence of DNA adducts of AFB1 in the human placentas has been noted, the enzymes(s) responsible for the bioactivation was not identified. In this investigation, the linoleic acid (LA)‐dependent cooxidation of AFB1 catalyzed
by lipoxygenase (LO) purified by Con A affinity chromatography from the term placentas of nonsmokers was studied. HPLC chromatograms detected the presence of 5‐ and 15‐HETE as the major metabolites and 12‐HETE as a minor metabolite upon incubation of arachidonic acid (AA) with affinity purified human term placental LO. These results suggest that a mixture of LO isozymes is present in the affinity‐purified enzyme preparations of term placentas. The optimal assay conditions to observe maximum rate of epoxidation included in cubation of 250 μM AFB1 with 80 μg LO and 3.5 mM LA at pH 7.2 AFB1‐8, 9‐tris‐diol produced in the reaction was estimated spectrofluorimetrically. AVmax of 432 ± 26 pmol of AFB1‐8, 9‐tris diol produced/min/mg protein and a Km of 77 μM for AFB1 were observed. The AFB1‐8,9‐tris‐diol formation was dependent on the incubation time, concentration of enzyme protein, AFB1, and LA. LO catalyzed epoxidation of AFB1 was inhibited by NDGA, BHT, BHA. ETI, and gossypol. The evidence presented here clearly demonstrates that placental LO is capable of epoxidation of AFB1. Similar results were observed with LO preparations of human intrauterine conceptal tissue at 8–10 weeks of gestation. © Wiley‐Liss, Inc.
International study of sex ratio and twinning of neural tube defects
Authors: Källén Bengt , Cocchi Guido , Knudsen Lisbeth B. , Castilla Eduardo E. , Robert Elisabeth , Daltveit Anne Kjersti , Lancaster Paul L. , Mastroiacovo Pierpaolo
Published: June 2005

The goal of this study based, on information collected from eight congenital malformation registry programs around the world, was to analyze sex and twinning of affected infants and fetuses, according to type of neural tube defect (NTD) and other variables The type of defect and its location, whether it occurred in isolated form or was associated with other malformations, population from which data were retrieved, vital status of the infant, and gestational age of the fetus/infant were considered.

The material included 3,416 infants and 168 selectively aborted fetuses with anencephaly, 4,830 infants and 76 fetuses with spina bifida, and 1,022 infants and 19 fetuses with encephalocele. Less than 20% of infants with anencephaly or spina bifida and more than one‐third of infants with encephalocele had associated malformations.

A female excess was found among all infants with NTD but a male excess in fetuses delivered spontaneously before week 20, indicating selective male late fetal deaths. Sex ratio varied by type of NTD, vital status at birth, presence of associated malformations, and year of birth, with an increasing sex ratio for anencephaly during the 1960s and 1970s. Twinning was positively associated with NTD but the extent of this association varied with NTD type and program, while the distribution by sex type of pair of twin appeared to be similar to that of all births. Twins concordant for anencephaly or encephalocele were mainly found when the defect occurred as part of a syndrome, and only in like‐sexed pairs. Twins concordant for spina bifida had the isolated from of the defect and 5 of 6 pairs were like‐sexed. Thoracic spina bifida has a sex ratio more like anencephaly than lumbosacral spina bifida has, but twinning rate is more similar in anencephaly and lumbosacral than in thoracic spina bifida. © 1994 Wiley‐Liss, Inc.
Elevated midtrimester serum methylmalonic acid levels as a risk factor for neural tube defects
Authors: Adams M. J. , Khoury Muin J. , Scanlon Kelley S. , Stevenson Roger E. , Knight George J. , Haddow James E. , Sylvester Gregg C. , Cheek James E. , Henry Judy P. , Stabler Sally P. , Allen Robert H.
Published: June 2005

The role of folic acid in the primary prevention of neural tube defects (NTDs) is well established. However, questions related to the protective mechanism remain unanswered. To help answer these questions, we designed a case‐control study to assess the role of folate‐and cobalamin‐related metabolites in the pathogenesis of NTDs. Concentrations of folate, cabalamin, and 14 other related metabolites were measured by gas chromatography/mass spectrometry in midtrimester serum specimens from 32 women with an NTD‐affected pregnancy and from 132 control women, and in serum specimens from 46 nonpregnant women who had a history of NTD‐affected pregnancy and from 43 nonpregnant control women. Log‐transformed means of metabolites were compared between case and control women for both the midtrimester and nonpregnant groups. In the pregnant group, serum methylmalonic acid (MMA) concentrations were higher among case women than among control women (130 vs 105 nM). There was a strong dose‐response relationship between midtrimester serum MMA level and the risk for an NTD‐affected pregnancy, with the relative risk increasing 13‐fold for women with MMA levels>90th percentile. In the nonpregnant group, there was no difference in serum MMA levels between case and control women (140 vs 140 nM). Thus, the serum MMA levels of women in the midtrimester of pregnancies unaffected by NTDs were significantly lower than the levels of nonpregnant women, whereas the levels of women whose pregnancies were affected by NTDs were similar to those of nonpregnant women. The finding of elevated MMA serum concentrations among women in the midtrimester of NTD‐affected pregnancies suggests that cobalamin may be involved in the etiology of NTDs. The possible role of cobalamin in relation to the protective effect of folic acid needs further evaluation. © 1995 Wiley‐Liss, Inc.

This article is a US Government work and, as such, is in the public domain in the United States of America

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Effects of prenatal alcohol exposure on the postnatal morphology of the rat oculomotor nucleus
Authors: Burrows R. C. , Shetty A. K. , Phillips D. E.
Published: June 2005

Morphological development of the rat oculomotor nucleus was investigated on postnatal day 15 following a prenatal ethanol exposure. Analysis of toluidine blue stained plastic sections showed that the prenatal alcohol exposure caused a decrease in the density of neurons and an increase in the density of astrocytes in the center of the nucleus. There was an alcohol–induced reduction in the overall size of the cross‐sectional region of the oculomotor nucleus, but no effect on the number of neurons per unit area of that total oculomotor region, indicating a delay or alteration of the migration of neurons to their normal clustered position in the center of the nucleus. The areas of the neuronal cell nucleus and nucleolus were not affected by the alcohol exposure. Analysis of Golgi‐Cox‐impregnated multipolar neurons showed that the alcohol exposure caused a reduction in area of the cell soma; a reduction in the number of dendritic branches; and a reduction in the complexity of the dendritic arbor relative to distance from the soma, based on concentric ring analysis. The results of this study demonstrate that gestational alcohol exposure can retard the maturation of the oculomotor nucleus.© 1995 Wiley‐Liss, Inc.
Teratogen update: Ergot and ergotamine
Authors: Raymond Gerald V.
Published: June 2005

Ergotamine is a purified ergot alkaloid that has been suspected of being teratogenicAnimal data have shown effects mainly at doses toxic to the mother. Clinical reports in humans have been anecdotal, but in many the malformations are consistent with vascular injury. However, epidemiologic studies have not shown any clear increase in malformations among exposed infants. This may reflect the limited exposure and toxicity when used episodically. Ergot toxicity which can result in severe vasospasm does not spare the fetus or mother and ergotamine should not be considered without risk. Ergotamine should be avoided in pregnancy, and the counselling of the woman with an exposed fetus should focus on possible toxic exposure. © 1995 WiIey‐Liss, Inc.
Teratogenicity of low doses of all‐trans retinoic acid in presomite mouse embryos
Authors: Sulik Kathleen K. , Dehart Deborah B. , Rogers John M. , Chernoff Neil
Published: June 2005

This study was designed to examine the developmental dose response for all‐trans retinoic acid (TRA) administered at presomite stages in mouse embryos. Previous studies using hamsters [Shenefelt (1972) Teratology5: 103‐118] have shown that developmental stages corresponding to those present early on gestational day (GD) 7 in mice are most sensitive to retinoid‐induced teratogenesis. Our preliminary studies showed that at this treatment time, gavage dosages of 7. 5 mg/kg maternal body weight administered to C57B1/6N mice, an inbred strain, resulted in severe craniofacial malformations representing the holoprosencephaly, aprosencephaly spectrum. Additionally, in an outbred mouse strain, CD‐1, exencephaly was induced by dosages of 2. 5 mg/kg TRA and above. Readily detectable abnormalities of the eyes, including anophthalmia and severe microphthalmia and iridial colobomata, were induced by even lower doses of TRA in the C57B1/6N strain. Incidences of micro/anophthalmia were 6. 7%, 8. 1%, 12. 9% and 32. 4% at 0, 0. 313, 0. 625, and 1. 25 mg/kg, respectively. The dosages required to induce significant incidences of exencephaly (2. 5 mg/kg) and severe ocular abnormalities (125 mg/kg) on GD 7 in mice are approximately 50‐100‐fold less than those that are commonly used to examine the teratogenicity of this compound at later developmental stages in this species. The trend toward an increase in the incidence of severe ocular malformations at the lowest dose examined and the fact that subtle ocular malformations were not taken into account for this study suggest that even lower dosages may be effective. Practical implications of this study include (1) the obvious need to conduct threshold dose determination studies at the most sensitive developmental stage in a sensitive strain/species, and (2) the need for careful surveillance of human populations for brain and ocular malformations (not necessarily those falling within the realm of retinoic acid embryopathy) following retinoid exposure during early stages of pregnancy. © 1995 Wiley‐Liss, Inc.
Teratogen update: Carcinogenesis and teratogenesis associated with exposure to diethylstilbestrol (DES) in utero
Authors: Mittendorf Robert
Published: June 2005

Exposure of the human of the fetus to physician‐prescribed diethylstilbestrol and other synthetic estrogens (collectively referred to as “DES”) led to an important iatrogenic epidemic In the United States alone, at least four million fetuses and their mother had a substantial exposed these estrogens now known to be mild carcinogens and potent teratogens. Mothers exposed to DES may have a somewhat higher risk of breast cancer than women who were not exposed. The sequelae of in utero exposure of daughters include clear cell adenocarcinoma of the vagina and cervix, various gross anomalies of the genital tract that are associated with adverse outcomes of pregnancy, vaginal adenosis and other vaginal epithelial changes, and other possible health effects that have not yet been fully evaluated. Among sons exposed in utero to DES, no increase in the incidence of any cancer has been reported, but several anomalies of the genital tract have been described, and it is possible that some social behaviors are modified Although the grandchildren of the DES‐exposed daughters and sons have not been shown to have any abnormalities, some of them have been the products of short gestations. Future research, being funded by the National Cancer Institute, will permit monitoring of the DES‐exposed population to dertermine whether any other abnormalities will become apparent in them. © 1995 Wiley‐Liss, Inc.
Genetically determined absence of an initiation site of cranial neural tube closure is causally related to exencephaly in SELH/Bc mouse embryos
Authors: Gunn T. M. , Juriloff D. M. , Harris M. J.
Published: June 2005

The SELH/Bc mouse strain (SELH) has a high frequency of the lethal neural tube closure defect, exencephaly, in newborns and embryos. Previous work has shown that all SELH mouse embryos have an abnormal mechanism of rostral neural tube closure. They lack initiation of contact and fusion of the cranial neural tube at the prosencephalon/mesencephalon boundary (Closure 2), and undergo closure by extension of a more rostral site of fusion. This process fails in 10‐20% of embryos, where the mesencephalic folds remain unelevated, resulting in exencephaly. Previous work has also shown that the cause of liability to exencephaly in SELH mice is multigenic, involving a small number of loci.

The purpose of the present study was to test the hypothesis that the genes causing the lack of Closure 2 also cause the liability to exencephaly in SELH, by observation of their joint transmission from genetically segregating animals. A concurrent mapping study provided the necessary genetic material, a segregating F2 generation from a cross of SELH with the normal LM/Bc strain. The genetic liability to exencephaly transmitted by individual F2 sires had been measured by the frequencies of exencephalic day 14 embryos they produced in testcrosses with SELH females. A selected subset of 13 of these test‐crossed F2 sires was bred with a second set of SELH females, and the embryos were examined earlier, during the period of neural tube closure, on days 8 and 9 of gestation, to determine the presence of Closure 2. Six F2 sires were among the highest exencephaly producers (6‐11%), six were among the lowest (0%), and one was intermediate (5%). Among embryos at the appropriate stage for scoring, the presence of Closure 2 was observed to be inversely correlated with the later risk of exencephaly, being present in 93% (71/76) from the low‐risk sires and 35% (36/103) from the high‐risk sires. In each case, the remaining embryos had a closure mechanism like that of SELH embryos. Among the individual intermediate‐ and high‐risk sires, there was also a clear correlation between the frequency of exencephaly in older embryos and the frequency of lack of Closure 2 in early embryos (rs=0.88; P<0.05). this study demonstrates that high liability to exencephaly and absence of Closure 2 are genetically transmitted together. That is, the cause of the lack of Closure 2 in SELH mice is shown to be also the probable cause of the high liability to exencephaly. © 1995 Wiley‐Liss, Inc.
Developmental toxicity of mangafodipir trisodium and manganese chloride in Sprague‐Dawley rats
Authors: Treinen Kimberley A. , Gray Tim J. B. , Blazak William F.
Published: June 2005

Mangafodipir trisodium (MnDPDP) is a manganese chelate being developed as a contrast agent for magnetic resonance imaging of the hepatobiliary system. The intended clinical dose is 5 μmol/kg. The potential for MnDPDP to induce embryotoxicity and/or teratogenicity in Sprague‐Dawley rats was investigated. Twenty five inseminated rats/group were intravenously administered 0, 2, 5, or 20 μmol/kg MnDPDP form days 6‐17 of gestation. Maternal toxicity was not observed at any dose of MnDPDP. There were no treatment‐related effects on the numbers of fetuse, fetal viability, numbers of resorptions, implantations and corpora lutea, or the percent of pre‐ and post‐implantation losses. However, at 20 μmol/kg, fetal body weights were significantly decreased (3.3 g vs. 3.9 g for control) and increased skeletal malformations were observed (141/270 vs. 0/285 in control). The malformations were of a specific type, which included. angulated or irregularly shaped clavicle, femur, fibula, humerus, ilium, radius, scapula, tibia, and/or ulna. To better define the developmental stage that is most susceptible to the effects of MnDPDP, a segmented developmental study was conducted. Twelve inseminated rats were administered 0, 20, 40, or 80 μmol/kg MnDPDP on days 6‐8, 9‐11, 12‐14, or 15‐17 of gestation. Skeletal malformations, identical to those seen in the previous study, were increased in adose‐dependent manner with the highest incidence occurring in fetuses from females dosed from days 15‐17 of gestation. A third study, in which 15 rats/group were dosed intravenously with 0, 5, 20, or 40 μmol/kg MnCl2 on days 6‐17 of gestation, produced indentical skeletal malformations to those seen with MnDPDP, indicating that manganese is the active moiety responsible for these specific malformations. © 1995 Wiley‐Liss, Inc.
Pantothenic acid decreases valproic acid‐induced neural tube defects in mice (I)
Authors: Sato Masako , Shirota Mariko , Nagao Tetsuji
Published: June 2005

The effect of the administration of pantothenic acid (PTA) on valproic acid (VPA)‐induced teratogenesis was examined in ICR mice. VPA (300, 400, and 500 mg/kg, s.c.) or PTA (3 × 10,3 × 100, and 3 × 300 mg/kg, i.p.) was injected on day 8.5 of gestation (plug day = day 0.5). Exencephaly was induced dose dependently by single injections of VPA. three administrations of PTA alone at any dose levels showed neither embryocidal nor teratogenic effects. In combined treatment experiements, PTA (3 × 300 mg/kg) was injected 1 hr before, immediately before, and 1 hr after VPA administration. PTA significantly reduced VPA‐induced exencephaly, while none of the other external malformations such as open eyelid or skeletal malformations such as fused, absent, or bifurcated ribs and fused thoracic vertebrae and fused sternebrae were reduced. The results suggest that PTA reduces the incidence of neural tube defect induced by VPA in mice. © 1995 Wiley‐Liss, Inc.
Zinc deficiency causes apoptosis but not cell cycle alterations in organogenesis‐stage rat embryos: Effect of varying duration of deficiency
Authors: Rogers John M. , Taubeneck Marie Weldon , Daston George P. , Sulik Kathleen K. , Zucker Robert M. , Elstein Kenneth H. , Jankowski Margaret A. , Keen Carl L.
Published: June 2005

Zinc deficiency is teratogenic in all species in which it has been examined. Zinc is an essential component of enzymes involved in DNA synthesis and cell proliferation, and may play an as yet undetermined role in apoptosis. To further our understanding of the role of zinc in normal development, we examined cell death and cell cycle parameters in embryos of pregnant rats fed a zinc‐deficient diet for 2 to 10 days (0.5 μg zinc/g diet; zinc‐adequate diet was 25 μg zinc/g). To elucidate sensitive periods of development and susceptible cell populations, dams were fed the zincdeficient diet from gestation day 1, 3, 7, or 9 and killed on day 11. Embryos were examined for morphology and developmental stage. From each litter, 2–3 embryos were stained with Nile blue sulfate (NBS) to visualize cell death, 3 embryos were frozen for flow cytometric cell cycle analysis and cell counts, and selected embryos were preserved for histological examination. Dams fed the zinc‐deficient diet for more than 3 days reduced their food intake through gestation day 8 but increased food intake on day 9. Maternal plasma zinc dropped to 10–25% of control levels in the zinc‐deficient groups. Zinc deficiency from gestation day 1 or 3 resulted in two categories of affected litters on day 11. One category had embryos which were morphologically normal but displayed extensive NBS staining in the visceral arches, neural tube, and somites. The second category had developmentally retarded or maldeveloped embryos which showed little NBS staining. Zinc deficiency from gestation day 7 produced cell death in the posterior dorsal midline in the area of premigratory neural crest cells, which was confirmed by histological examination. Zinc deficiency from gestation day 9 did not affect morphology or NBS staining. Percentages of cells in the G0/G1, S, and G2M phases of the cell cycle on gestation day 11, determined by flow cytometry, were similar to controls in all groups. This study shows tht as few as 4 days of maternal zinc deficiency can produce excess embryonal cell death, and that neural crest cells may be particularly sensitive. © 1995 Wiley‐Liss, Inc.
Studies of mitochondria in oxidative embryotoxicity
Authors: Fantel Alan G. , Person Richard E. , Tumbic Ruslan W. , Nguyen Tien‐Dat , Mackler Bruce
Published: June 2005

While the limb bud and brain of the rat develop abnormally in response to transient uteroplacental hypoperfusion during late gestation, the heart appears to be protected. These malformations have been associated with the generation of reactive oxygen species (ROS). Studies were designed to examine superoxide generation by mitochondrial electron transport particles (ETP) from adult and conceptal tissues and to investigate characteristics that could be responsible for heightened concentrations of ROS in sensitive tissues. Parameters investigated included NADH oxidase and cytochrome c oxidase activities, cytochrome content, and superoxide dismutase activity.

NADH oxidase activities were significantly lower in sensitive tissues that also developed the highest concentrations of superoxide. Because ETP from adult CNS also had low NADH oxidase activity but did not show increased concentrations of superoxide, inhibition of electron transport did not adequately account for increased ROS concentrations. The reduced NADH oxidase activity of sensitive tissues could not be caused by inhibition at the cytochrome c oxidase region since this latter activity equaled or exceeded the former in all instances. No significant differences were found in the cytochrome contents of different tissues. There was significantly less superoxide dismutase activity in homogenates prepared from either of the two sensitive conceptal tissues compared with those from insensitive conceptal or adult tissues.

These studies confirm the presence of heightened concentrations of superoxide anion radical in ETP from teratogenically sensitive tissues and suggest that these concentrations may result primarily from decreased activity of superoxide dismutase(s) in those tissues. Superoxide anion radical could therefore be available to participate in the generation of the more toxic oxidant species such as the hydroxyl radical. © 1995 Wiley‐Liss, Inc.
Arnold‐Chiari‐like malformation associated with a valproate model of spina bifida in the rat
Authors: Briner Wayne , Lieske Ryan
Published: June 2005

The brains of rat fetuses exposed to saline and valproic acid (VA: 600 mg/kg or 1,200 mg/kg) at 10 days of gestation were examined for structural changes similar to that seen for the Arnold‐Chiari malformation (ACM) in humans. Only fetuses exposed to the 1,200‐mg/kg level VA demonstrated spina bifida (SB) type widening of the vertebral arch when compared to saline treated animals. When compared to controls, both 600‐and 1,200‐mg/kg VA animals demonstrated microencephaly. The brains of treated animals demonstrated alterations in their angular morphology such that the cerebellum was displaced toward the foramen magnum in a manner akin to human ACM. These findings indicate that valproate‐induced SB in the rat more closely approximates SB in humans than was previously appreciated and provides a model for experimental study of both SB and ACM. © 1995 Wiley‐Liss, Inc.
Inhibitors of glycolytic metabolism affect neurulation‐staged mouse conceptuses in vitro
Authors: Hunter E. Sidney , Tugman J. A.
Published: June 2005

In order to evaluate the apparent discordance between altered glucose metabolism and embryonic energy production, the effects of inhibitors of glucose utilization on morphological development and biochemical changes in mouse embryos in culture were evaluated. Day 9 ICR mouse conceptuses having 3‐6 pairs of somites were prepared for culture as previously described. 2‐Deoxyglucose (2DG) produced a concentration‐dependent effect on development. A 25 μM 2DG concentration did not induce neural tube closure defects (NTDs) but 100 μM, 100% of embryos exhibited this defect. A 17% reduction in the rate of lactate production by the conceptus was produced by a 24‐hr exposure period to 100 μM 2DG. Iodoacetate, which inhibits glyceraldehyde‐3‐phosphate dehydrogenase in adult tissues, produced high rates of NTDs at concentrations ⩾2.5 μM. Following a 24 hour exposure to iodoacetate, lactate production was inhibited at 10 and 25 μM. The effects of 2DG on embryonic ATP content were assessed to test the hypothesis that effects on glucose utilization would effect embryonic ATP content. Despite using 2DG concentrations that alter development and inhibit glycolysis, there were no effects on whole embryo or visceral yolk sac (VYS) ATP content. However, when the embryo was divided into regions, there was a specific reduction in ATP content in the head following a 24‐hr exposure period. No effect of 2DG on head ATP content was produced after 12 hr of exposure. To determine if there were region specific differences in 2DG uptake and distribution that could account for the differential effects of 2DG on ATP content, 14C‐2DG accumulation in different regions of the embryo and VYS was determined over the 24‐hr culture period. The uptake of 2DG was dependent on the medium 2DG concentration and suggested a higher accumulation in regions with decreased ATP. However, when the uptake was monitored for a 1‐hr period after a 24‐hr exposure, there was no region specific differences in 2DG uptake. These studies further document the adverse developmental effects of inhibitors of glucose utilization during the early stage of neurulation. The biochemical mechanism for induction of these defects is unclear, but an effect on ATP content does not appear to be solely responsible for the dysmorphogenesis. © 1996 Wiley‐Liss, Inc.