摘要:

AbstractThe data of the Collaborative Behavioral Teratology Study (CBTS) were analyzed. Population‐effect sizes were estimated, in terms of confidence intervals, by meta‐analysis. A treatment effect of methylmercury was clearly observed and a dose‐response effect was also observed. On the other hand, no clear treatment effect was observed in the d‐amphetamine study. The effect of auditory startle habituation was very large, although it was limited to the high‐dose group in the methylmercury study. The effects observed for physical landmarks were, as a whole, somewhat larger than those for behavioral measures. There is no clear evidence for sex‐related differences except for activity measures. A curious treatment effect that was not referred to in the CBTS report was observed: eye‐opening day and incisor‐eruption day were hastened by the treatment of methylmercury. Power analysis results showed that obtaining a statistically significant effect for these compounds is very difficult, suggesting that even though published papers reported the significant effect of these compounds there might have been many unpublished experiments that obtained nonsignificant effects. If one uses these compounds as positive controls, a very large sample size will be needed. No highly sensitive test that is reproducible across compounds or dose‐levels was observed among tests emp

ISSN:0040-3709    

DOI:10.1002/tera.1420400202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractDuring the period from 1969 to 1985, 107 pairs of twins, of which at least one in each pair had congenital hydrocephalus, were ascertained in Japan. The rate of concordance for hydrocephalus among these twins was 15%, with a slightly higher rate in like‐sex male twins (28%) than in like‐sex female twins (14%). The rates were 21% in like‐sex and 0% in unlike‐sex pairs. Two twin pairs had one anencephalic twin and one hydrocephal

ISSN:0040-3709    

DOI:10.1002/tera.1420400203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractDFMO (α‐difluoromethylornithine) is a specific irreversible inhibitor of ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines, which in turn control macromolecule synthesis during cell proliferation. The current study was designed to investigate the effects of inhibition of ODC during discrete prenatal periods on renal growth and function. We administered 5 doses of 500 mg/kg DFMO or saline s.c. to timed pregnant Sprague‐Dawley rats at 12 hr intervals beginning on gestation days (GD) 11, 14, or 17. Half the dams were killed on GD 20 for fetal morphological analyses and half were allowed to go to term. Renal function was assessed on postnatal days (PD) 3, 6, 10, and 14 by tests of basal renal clearance and urinary concentrating ability, and on PD 42–44 we measured serum chemistries. All three gestational treatment regimens resulted in postnatal deficits in general growth. Only in the GD 11–13 treatment group was there evidence of embryotoxicity and neonatal renal pathophysiology. Fetal weights and urogenital morphology were altered following GD 14–16 treatment and there were persistent deficits of renal growth. GD 17–19 treatment was associated only with transient postnatal deficits of renal growth. Thus, inhibition of ODC during critical prenatal periods induced distinct developmental effects. However, there were no associations between impaired renal growth and function. These data indicate that general tissue growth is not always a predictor of physiological development and support the necessity of multifaceted approaches to the understanding of adverse developme

ISSN:0040-3709    

DOI:10.1002/tera.1420400204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractNeonatal rats were exposed to 6.6 g/kg of alcohol each day between postnatal days 4 and 10 while artificial‐rearing procedures were used, in a manner which produced high peak and low trough blood alcohol concentrations each day. Gastrostomy controls were reared artificially with maltose/dextrin isocalorically substituted for alcohol in the milk formula, and suckle controls were reared normally by dams. The pups were sacrificed on day 10 and tissue sections (2 μm thick) were obtained in the sagittal plane through the cerebellum and in the horizontal plane through the hippocampal formation. Overall area measures were obtained for the hippocampus proper, area dentata, and cerebellum, along with areas of the cell layers of these regions. In the hippocampal formation, cell counts were made of the pyramidal cells of the hippocampus proper, the multiple cell types of the hilus, and the granule cells of the area dentata. In the cerebellum, cell counts of Purkinje cells, granule cells of the granular layer, granule cells of the external granular layer, and mitotic cells of the external granular layer were obtained from lobules I, V, VII, VIII, and IX. Alcohol selectively reduced areas and neuronal numbers in the cerebellum but had no significant effects on neuronal numbers in the hippocampal formation. Purkinje cells exhibited the greatest percent reductions, and cerebellar granule cells were significantly reduced in the granular layer but not in the external granular layer. All lobules showed these effects, but lobule I was significantly more affected than the other four lobules that were analyzed. The results demonstrate the differential vulnerability of selected neuronal populations to the developmental toxicity of alcohol exposure during the brain growth spu

ISSN:0040-3709    

DOI:10.1002/tera.1420400205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractThe teratogenicity of phenytoin may result from its enzymatic bioactivation to a reactive intermediate, which, if not detoxified, can interact with embryonic tissues and alter development. Glutathione (GSH) is an important cofactor/substrate for many physiological processes and for the detoxification of xenobiotic reactive intermediates. This study examined the effects of the GSH depletor diethyl maleate (DEM) and the GSH synthesis inhibitor L‐buthionine‐(S,R)‐sulfoximine (BSO) on phenytoin embryopathy. Phenytoin, 55 mg/kg, was administered intraperitoneally (ip) to pregnant CD‐1 mice at 0900 hr on gestational days 12 and 13. Pretreatment with DEM, 150 or 300 mg/kg ip, enhanced the incidence of phenytoin‐induced cleft palates by 3.3‐fold and 2.3‐fold, respectively (P<0.05), without affecting the incidence of resorptions, postpartum death, or mean fetal weight. BSO, 1,800 mg/kg ip, given 0.5 hr prior to phenytoin, resulted in a 2.4‐fold increase in postpartum lethality and a 5‐fold increase in fetal weight loss (P<0.05), without altering the incidence of resorptions or cleft palates. In two subsequent studies, BSO, 680–1,018 mg/kg/day, was given in the drinking water on gestational days 9 to 13 in the first study and on days 10 to 14 in the second study. Phenytoin, 55 mg/kg ip, was given on days 11 and 12 and on days 11 to 13 in the respective studies. In the first drinking water study, BSO enhanced the incidence of phenytion‐induced fetal resorptions 3.8‐fold and cleft palates 3.3‐fold (P<0.05) but did not affect postpartum death. In the second study, BSO enhanced the incidence of resorptions, cleft palates, and postpartum death by 2‐fold, 2.6‐fold, and 1.7‐fold, respectively (P<0.05). In both of the latter two studies, phenytoin‐induced fetal weight loss was altered by BSO treatment (P<0.05). BSO alone had no embryopathic effects. These results suggest that GSH may be involved in the detoxification of a reactive intermediate of phenyti

ISSN:0040-3709    

DOI:10.1002/tera.1420400206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractRhodamines 123 and 6G (Rh 123 and Rh 6G) are cationic fluorescent dyes that inhibit oxidative phosphorylation following their selective accumulation within mitochondria. Neutral rhodamines (e.g., Rh 116 and Rh B) do not share these properties. To determine if cationic and neutral rhodamines differ in their effect on mammalian development, pregnant CD‐1 mice were injected i.p. with Rh 123, Rh B, or Rh 116 at doses of 15 mg/kg/day. The rhodamines were given alone or in combination with 500 mg/kg/day 2‐deoxy‐D‐glucose (2‐DOG), an inhibitor of glycolysis, daily on gestation days 7–10 (copulation plug = day 1). Additional pregnant mice were similarly treated with Rh 6G at a dose of 0.5 mg/kg/day. Controls were given saline equimolar to the dose of 2‐DOG. Treatment with Rh 6G, alone or in combination with 2‐DOG, significantly increased the incidences of prenatal mortality (17% and 35%, respectively) when compared with the control incidence (6%). Treatment with Rh 123 or Rh 6G, alone or with 2‐DOG, inhibited fetal growth. Treatment with the neutral rhodamines had little effect on prenatal survival or growth. Exposure to Rh 6G, with or without 2‐DOG, was associated with high incidences of gross malformations (41% and 61%, respectively). Rh 116 or Rh B, with or without 2‐DOG, and Rh 123 alone were not associated with statistically significant teratogenic effects, but results of the latter treatment were suggestive of such an effect (9.1% grossly malformed fetuses vs. 0% for controls). The incidences of skeletal malformations were significantly increased in the test groups given Rh 6G + 2‐DOG, Rh 123 + 2‐DOG, or Rh 6G alone. These results suggest a relationship between the charge on the rhodamine molecule and effects on the conceptus, and these effects may have been mediated at least in part by interference with

ISSN:0040-3709    

DOI:10.1002/tera.1420400207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractThe relationship between Bendectin exposure during the first trimester of pregnancy and the occurrence of congenital malformations was prospectively studied in 31,564 newborns registered in the Northern California Kaiser Permanente Birth Defects Study. The odds ratio for any major malformation and Bendectin use was 1.0 (95% confidence interval 0.8–1.4). There were 58 categories of congenital malformations; three of them were statistically associated with Bendectin exposure (microcephaly—odds ratio = 5.3, 95% confidence interval = 1.8–15.6; congenital cataract—odds ratio = 5.3, 95% confidence interval = 1.2–24.3; lung malformations (ICD‐8 codes 484.4–484.8)—odds ratio = 4.6, 95% confidence interval = 1.9–10.9). This is exactly the number of associations that would be expected by chance. An independent study (the Collaborative Perinatal Project) was used to determine whether vomiting during pregnancy in the absence of Bendectin use was associated with these three malformations. Two of the three (microcephaly and cataract) had strong positive associations with vomiting in the absence of Bendectin use. We conclude that there is no increase in the overall rate of major malformations after exposure to Bendectin and that the three associations found between Bendectin and individual malformations are unli

ISSN:0040-3709    

DOI:10.1002/tera.1420400208

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractWe evaluated the causality of the association between intrauterine exposure to phenytoin and postnatal neuroblastoma using an in vitro lymphocyte toxicity assay for phenytoin‐induced reactions in an unusual sibship. In addition, we investigated intrauterine phenytoin exposure in a case series of infants and children with neuroblastoma diagnosed over 17 years at our center. The response of lymphocytes from our index case with neuroblastoma exposed in utero to phenytoin was within the normal range, whereas the mother and a sibling with fetal hydantoin syndrome (FHS) exhibited an intermediate toxicity. None of the 188 case of childhood neuroblastoma diagnosed between 1969 and 1988 had been exposed in utero to phenytoin, indicating that, statistically, the drug cannot be associated with neuroblastoma in more than two cases with this malignancy in our cohort, or in 1.5% of all cases of neuroblastoma. Although our data do not suggest an association between phenytoin in pregnancy and postnatal neuroblastoma, it is still possible that there is an increased risk for neuroblastoma in children with FH

ISSN:0040-3709    

DOI:10.1002/tera.1420400209

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractPregnant C57B1/6J mice were treated with 100 mg/kg body weight of all‐trans retinoic acid in sesame oil on day 11.0 of gestation. Among the live fetuses harvested on day 18 of gestation, 100% had mesomelic defects of the limbs as determined by gross examination and skeletal staining. Control fetuses treated with sesame oil had no observable limb malformations. Some treated and control embryos were harvested 12 hr after treatment and examined for patterns of cell death by using the supravital stain Nile blue sulphate and methylene‐blue‐ and acid‐fuchsin‐stained histological sections. Retinoic‐acid‐induced cell death in the core of the limb was always associated with the zones of programmed cell death as seen in control embryos of comparable stages. This, in concet with previous studies demonstrating excessive cell death in regions of programmed cell death that correlated with subsequent malformations, leads us to conclude that the pathogenesis of mesomelic malformations has a primary association with the phenomenon of programm

ISSN:0040-3709    

DOI:10.1002/tera.1420400210

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractThe contribution made by mesenchymal cells during the later stages of palatal development was examined in control and hydrocorti‐sone‐treated hamster embryos. Cross‐sectional area of the palatal shelf was measured, and the numbers of both epithelial and mesenchymal cell were counted. DNA synthesis was measured by3H‐thymidine incorporation and was usd as an index of growth by cell proliferation. The observations in controls indicated that, unlike development during the initial 24 hr, the later period of vertical palate development, followed by reorientation of shelves and their closure, was characterized by a steady level of mesenchymal cell number and palatal shelf area. An absence of corresponding growth in the epithelial cell number suggests that the cells may accommodate the growth either by increasing their size and/or by stretching along the basal lamina. Hydrocortisone treatment did not alter the growth pattern of cell numbers or shelf area. However, it prevented the fusion between the opposing shelves, perhaps by affecting the cytodifferentiation of the palatal tissues. Although a continuous increase in the number of mesenchymal cells during the latter half of vertical shelf development, i.e., between days 11:00 and 12:00 of gestation, is not required for reorientation and fusion of the shelves, it is not clear from the data from the present study whether a critical number of cells and/or cell density is essential for reorientation and fusion of the palate. It was suggested that, for normal palatal development, information on cell cycle and positioning of mesenchymal cells within the shelf during the vertical development may be crucial for further understanding of subsequent events of palato

ISSN:0040-3709    

DOI:10.1002/tera.1420400211

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY