ISSN:0040-3709    

DOI:10.1002/tera.1420520502

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

年代:1995

数据来源: WILEY

摘要:

AbstractNew Zealand White robbits were treated orally with 0 (controls), 50, 100, or 150 mg/kg phenytoin on days 14‐16 of pregnacy. Total and free plasma concentrations of phenytoin were determined in maternal plasma 2, 6, and 24 hr after the final dose in all aimals. In addition, after administration of 150 mg/kg maternal plasma concentrations were also determined after 12 and 48 hr, the concentrations in amniotic fluid after 6 hr and those in fetal tissue 6 and 24 hr after the final treatment. A high degree of plasma protein binding was observed in maternal blood. Treatment with 50 mg/kg resulted in free plasma concentrations of up to 5.0 μmol/1 during the 24 hr period following the final dose. Significantly higher free plasma concentrations were observed at the two higher dose levels; up to 9.7 μmol/1 at 100 mg/kg and 12.7 μmol/1 at 150 mg/kg. Digital hypoplasia was not seen in the control group or the animals treated with 50 mg/kg. However, treatment with 100 mg/kg resulted in hypoplasia in a single or a few digits in approximately 50% of the fetuses, and 150 mg/kg provoked hypoplasia in almost all digits in all fetuses. These results show that even though the doses which caused digital defects in rabbits are much higher than those used therapeutically, the resulting free concentrations of phenytoin are similar to those which are associated wth the some type of defects in humans. These data indicate that the pharmacologically induced fetal hypoxia/ischemia and vascular disruption preceding malformations of this type, which were observed in a previous study in rabbits, may be of human relevance. © 1995 Wiley‐Li

ISSN:0040-3709    

DOI:10.1002/tera.1420520503

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe serum levels of total and visceral yolk sac (VYS)‐reactive sheep IgG have been determined following injection of a teratogenic sheep anti‐VYS antiserum. After intravenous injection, levels of VYS‐reactive IgG fell rapidly, with 75% of the amount in the injection removed in the first 5 min, and 90% by 60 min. By contrast, 90% or more of the total sheep IgG was still present at these times. A similar difference in clearance was seen after intraperitoneal injection, although the serum levels also reflected the presence of a pool of antiserum in the peritoneum and the simultaneous influx and efflux of IgG into and from the circulation. The clearance pattern was similar in pregnant and nonpregnant rats; it is concluded that antibodies against VYS‐specific antigens comprise a very small fraction of VYS‐reactive antibodies in the antiserum. ELISA and Western blot analysis indicated extensive cross‐specificity with antigens present in rat tissues other than the VYS. Similar teratogenic effects were observed after intravenous or introperitoneal injection of the antiserum at 8.5 days of gestation; we conclude that the proximal effect likely begins within the period immediately after the injection. The results are also considered within the context of published reports that the VYS shows structural and functional damage for several days after intraperitoneal administration of antiserum at 8.5 days. © 1995 Wil

ISSN:0040-3709    

DOI:10.1002/tera.1420520504

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

年代:1995

数据来源: WILEY

摘要:

AbstractRecently developed statistical methodology is presented for analyzing correlated developmental toxicity data where multiple measures are obtained on individual units such as rat pups. Of particular interest is the assessment of the homogeneity of effects from chemical exposure across different outcomes such as malformation types or non‐ossification of forepaw digits. Such contrasts are referred to as within‐cluster effects, as they represent differences between observations within a cluster (e.g., pup). Between‐cluster effects correspond to comparison of observations from different clusters, e.g., pups exposed to varied doses of chemicals or carcinogens. Two classes of statistical models are available for estimation of these distinct types of effects: (1) cluster‐specific models in which regression adjustments are made for cluster effects, and hence all parameters are interpreted as within‐cluster effects; and (2) population‐averaged models in which no explicit adjustments are made for cluster, and thus all parameters are interpreted as group differences without regard to whether they represent between‐ or within‐cluster effects. Many models in the developmental toxicity literature are population‐averaged logistic regression models ignoring variation among clusters which may be significant under strong influences of genetic and environmental factors. Under such conditions, confidence interval‐based inference for effect homogeneity will depend upon the class of models. These issues are illustrated with data from two developmental toxicity studies: (1) a National Toxicology Program study of the effects of in utero exposure to di(2ethylhexyl)phthalate among three malformation outcomes in mouse pups; and (2) a study conducted by Hartsfield to investigate the effects of anticonvulsant phenytoin on the risk of non‐ossification among digits of the left and right forepaws in rat pups.

ISSN:0040-3709    

DOI:10.1002/tera.1420520505

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

年代:1995

数据来源: WILEY

摘要:

AbstractValproic acid (VPA) is an anticonvulsant drug known to cause spina bifida in humans. Administration of the vitamin, folic acid has been reported to decrease the frequency of VPA‐induced exencephaly in mice treated with the drug in vivo. A protective effect by folinic acid has not been observed in vitro. The purpose of this investigation was to reexamine the ability of folinic acid to decrease the incidence of VPA‐induced neural tube defects in vivo. We also examined the effect of increased intake of folic acid on zinc levels in various maternal and embryonic tissues. Folinic acid, whether administered by intraperitoneal injection or in osmotic mini‐pumps, did not decrease the number of mouse fetuses with VPA‐induced exencephaly. Dietary supplementation with 10–20 times the daily required intake of folic acid in rodents also failed to decrease the embryotoxicity of VPA. Such dietary supplementation had no effect on zinc levels in maternal liver, brain, or kidney, nor in embryonic tissues. These results indicate that folic acid is not able to reverse the embryotoxicity induced by the anticonvulsant, that there is no apparent effect of high dietary folate intake on maternal or embryonic zinc levels and suggest that folate is probably not involved in the mechanism of VPA‐induced embryotoxicity. © 1995 Wil

ISSN:0040-3709    

DOI:10.1002/tera.1420520506

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

年代:1995

数据来源: WILEY

摘要:

AbstractIn chick embrayos, the anterior greater portion of the neural tube develops by the folding, apposition, and fusion of the neuroectoderm. The smaller caudal portion that forms the secondary neural tube (lumbosacral and coccygeal regions) is derived from the tail bud, an aggregate of mesenchymal cells located at the caudal limit of the body. Tail bud mesenchyme, arranged in a solid cord, undergoes mesenchymal‐ epithelial transformation to form the secondary neural tube. Previous evidence suggests that this transformation is accompanied by modulation of cell surface glycoconjugates in the differentiating tissues. In this study, we show by lectin histochemistry and lectin blotting of proteins isolated by SDS‐PAGE, thatDatura stramoniumagglutinin (DSA) binds preferentially to differentiating tail bud cells. This lectin is specific for β1‐4‐linkedN‐acetylglucosamine oligomers, such as the oligosaccharides of the poly‐N‐acetyllactosamine series that have been previously implicated in cell differentiation. Ultrastructural lectin cytochemistry indicates that at least some of the proteins binding DSA are localized extracellularly. The use of DSA as a teratogen resulted in embryos showing a variety of neural tube and notochord defects. We have also examined the binding of DSA to embryos that were treated with teratogenic doses of retinoic acid by sub‐blastodermal injection, and find that the DSA‐ binding patterns are perturbed. Analysis of DSA‐ treated embryos using the TUNEL technique indicated that cell death was not a factor in DSA teratogenesis. This strongly suggests that the glycoconjugates of the cell surface have a role in the normal differentiation of tail bud mesenchyme into the neuroepithelium of the secondary neural tube. Perturbations of glycoconjugate activity results in defects of the secondary neural tube and associated tail bud derivatives. ©

ISSN:0040-3709    

DOI:10.1002/tera.1420520507

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

年代:1995

数据来源: WILEY

摘要:

AbstractCigarette smoking during pregnancy exposes the fetus to both nicotine and hypoxia/ischemia; postnatal exposure to second‐hand smoke also involves substances that cause hypoxia (CO, HCN). Although developing cardiac cells are more resistant to hypoxia‐induced damage than are mature cells, we examined whether nicotine affects this resistance, either when exposure is concurrent with hypoxia, or when animals are exposed to nicotine prenatally and receive subsequent hypoxic exposure. One, 8‐, or 15‐day‐old rats exposed to 7% O2for 2 hr all showed inhibition of cardiac DNA synthesis. By contrast, administration of nicotine at either low (0.3 mg/kg) or high (3 mg/kg) doses failed to alter DNA synthesis. To examine effects on cells that were not undergoing mitosis, we examined ornithine decarboxylase (ODC), an enzymatic marker for cell damage. One day old rats showed inhibition of ODC by hypoxia, a response that represents preservation of cell integrity; by 8 days of age, ODC was increased by hypoxia, evidence of cell damage. The high dose of nicotine evoked an increase in ODC at all ages and the low dose exacerbated the effects of hypoxia at 8 days of age. Prenatal nicotine exposure caused a transient inhibition of cardiac DNA synthesis but did not produce evidence of cell damage (ODC, protein synthesis markers) by itself, nor did it alter the effect of a subsequent postnatal exposure to hypoxia. These results suggest that cardiac cell damage could emerge as a consequence of concurrent, repeated exposures to nicotine and hypoxia. Such effects could contribute to the elevated incidence of perinatal morbidity/mortality and Sudden Infant Death Syndrome associated with smoking. © 1995 Wiley

ISSN:0040-3709    

DOI:10.1002/tera.1420520508

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe 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

ISSN:0040-3709    

DOI:10.1002/tera.1420520509

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

年代:1995

数据来源: WILEY

ISSN:0040-3709    

DOI:10.1002/tera.1420520510

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

年代:1995

数据来源: WILEY

ISSN:0040-3709    

DOI:10.1002/tera.1420520501

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

年代:1995

数据来源: WILEY