ISSN:0040-3709    

DOI:10.1002/tera.1420390402

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

年代:1989

数据来源: WILEY

摘要:

AbstractTwo measures of postnatal development are described in this paper: the PAC50 and AD50. These measures proved to be more sensitive than the use of means in the evaluation of three radiation studies involving postnatal developmental evaluation. PAC50 is the percent of achievement of a goal by litters or offspring in an experimental group at the age when 50% of the control litters or offspring in each group attain that goal. AD50 is the age (acquisition day) at which 50% of the litters or offspring in each group attain a specified developmental goal. This methodology is a useful technique for analyzing selected behavioral data following in utero X‐irradiation and may prove to be a sensitive means of determining postnatal alteration due to prenatal exposure to a variety of suspect agent

ISSN:0040-3709    

DOI:10.1002/tera.1420390403

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

年代:1989

数据来源: WILEY

摘要:

AbstractA 20‐year study of 1,124 spontaneously aborted embryos and fetuses found 214 (19.0%) to have a localized defect or identifiable syndrome. No clear trend of change over time was noted. The rate is compared with other studies of spontaneously aborted specimens and is approximately ten times higher than in newborns. Forty (3.6%) had neural tube defects and 30 (2.7%) had a clinically recognized chromosomal phenotype. Fifteen had Turner's phenotype, four trisomy 18, and 11 triploidy. Amniotic bands occurred in eight. Two had bilateral renal agenesis. Thirty had some form of facial clef

ISSN:0040-3709    

DOI:10.1002/tera.1420390404

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

年代:1989

数据来源: WILEY

摘要:

AbstractGroups of 12 Charles River CD virgin female rats were either supplemented with 25,000 IU/kg of vitamin A palmitate or not during the first 8 days of pregnancy and in the first experiment given a single dose of either 5 or 10 mg/kg of all‐trans‐retinoic acid (RA) on day 9 of pregnancy. In a second experiment, similar groups were given either 4 or 8 mg/kg RA daily from day 6 through day 15 so that each treatment with RA was given to vitamin A supplemented rats or nonsupplemented rats. The high systemic background of vitamin A increased the teratogenicity of the 10 mg/kg dose of RA given on day 9 by 50%, but reduced the teratogenicity of the 8 mg/kg dose given on days 6–15. The reasons for this paradox are discussed and related to the human propensity to self‐medicate with megadoses of v

ISSN:0040-3709    

DOI:10.1002/tera.1420390405

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

年代:1989

数据来源: WILEY

摘要:

AbstractRetinoic acid is a natural vitamin A derivative that undergoes oxidative metabolism in the body to yield several metabolites, which apparently represent the products of a detoxification pathway. To assess if such metabolic conversions diminished teratogenic potency, one of the major metabolites (4‐oxo‐all‐trans‐retinoic acid) was tested for its teratogenic activity in pregnant ICR mice and further investigated for its pharmacokinetic features to determine if it accumulated in the embryo in concentrations sufficient to elicit a teratogenic response. Administration of single oral doses (10, 25, 50, or 100 mg/kg) of the compound to ICR mice on day 11 of gestation. (plug day = day 0) produced dose‐dependent frequencies of serious fetal anomalies of the type usually associated with the use of retinoic acid and other retinoids. The metabolite was equivalent in teratogenic potency to retinoic acid, and, in the instance of cleft palate frequency, it was even more active. Concentrations of 4‐oxo‐all‐trans‐retinoic acid and its 13‐cisisomer were measured in the maternal plasma and whole embryos at 30 min to 10 hr after administration of the lowest (10 mg/kg) and the highest (100 mg/kg) teratogenic dose of 4‐oxo‐all‐trans‐retinoic acid by means of high‐performance liquid chromatography methodology. Distribution of the compound in the maternal system and transfer to the embryo occurred rapidly with either dose. Peak concentration in the maternal plasma and the embryo persisted for 3–4 hr after the higher dose but not with the lower dose; however, elimination kinetics for the two dose levels were similar. Irrespective of the dose, the half‐life of the compound was longer in the embryo than in the maternal plasma. The values for the area under the concentration vs. time curve in the embryo, 3.5 μg.hr/g after the lower dose and 13.6 μg.hr/g after the higher dose, provided a preliminary estimate of teratologically effective retinoid levels since the two dose levels elicited a minimal (25%) and a maximal (100%) teratogenic response, respectively. From these results we conclude that 1) 4‐oxo‐trans‐RA is a potent teratogen, 2) it may contribute substantially to the teratogenic activity of all‐trans‐RA, and 3) AUC values, as reported here, may serve as a basis for comparison of teratogenic potencies of other re

ISSN:0040-3709    

DOI:10.1002/tera.1420390406

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

年代:1989

数据来源: WILEY

摘要:

AbstractSeveral forms of vitamin A were tested in the in vitro hydra assay for their developmental toxicity hazard potential and site of action on progressive ontogenesis. Retinol, retinyl acetate, retinaldehyde,all transretinoic acid, and 13cisretinoic acid were tested fully, and each was established clearly as being able to perturb development of artificial hydra ‘embryos’ at, or near, adult toxic treatment levels. All forms of vitamin A tested interfered with differentiation, but, although the alcohol, acetate, and aldehyde forms (group I) prevented the initial stages of differentiation from occurring, the acid forms (group II) allowed the initial stages of differentiation to occur but not the final differentiation of tentacle buds. Group I compounds produced the developmental toxicity endpoint after as little as 24 h of transient exposure on the first day of development, but had no permanent effect on development at their minimal affective developmental concentration (D‐MAC) when exposure began after the first day of development. In contrast, transient 24‐h exposure to group II forms did not interfere with development. At, or even above, a concentration greater than the D‐MAC, more continuous exposure to them was required to interfere with differentiation. Consistent with tests of other chemicals, the concentrations needed to produce effects in hydra bore no relation to those needed to produce effects i

ISSN:0040-3709    

DOI:10.1002/tera.1420390407

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe 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 fascicularisfemales 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

ISSN:0040-3709    

DOI:10.1002/tera.1420390408

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

年代:1989

数据来源: WILEY

摘要:

AbstractRat embryos (9.5‐day‐old) were cultured for 48 hours in serum from diet‐induced folic‐acid‐deficient rats. Resultant embryos were frequently abnormal; many were growth retarded and exhibited a defect in the turning mechanism that inverts the embryo from ventrally to dorsally convex. Affected embryos displayed abnormal twisting or kinking of the neural tube. Gross anaemia was also frequently observed, and the protein content of the embryos was markedly less than that of embryos grown in normal rat serum. Supplementation of the deficient serum with folic acid improved growth and greatly reduced the occurrence of deformities. It virtually eliminated the incidence of gross anaemia but only partially restored the protein content of the embryos to the level observed in those grown in normal rat serum. The effects of the folate deficiency could be eliminated by supplementation with normal rat serum. The data indicate that embryos have a requirement for adequate folate in order for normal growth and differentiation to take place; they also suggest that some of the embryopathic effects of maternal folate deficiency are mediated by secondary effects on maternal metabolism. This may take the form of a disturbance in the production of maternally synthesised growth factors necessary for normal embryonic de

ISSN:0040-3709    

DOI:10.1002/tera.1420390409

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe effect of 6‐mercaptopurine (6‐MP) on the distribution of gavaged65Zn in maternal and embryonic tissues of Sprague‐Dawley rats was examined 24 hr after injection of the drug on day 13 of pregnancy. 6‐MP injection resulted in a significantly higher retention of counts of65Zn in maternal liver and lower counts in maternal plasma, uterus, placenta, and embryo than in controls. Compared to controls, gel chromatography of maternal liver from 6‐MP injected dams showed higher counts associated with a protein peak of molecular weight 6,000–8,000, the approximate molecular weight of the zinc‐binding protein metallothionein. These results support the idea that the zinc deficiency, which is observed in day 21 fetuses from dams injected with 6‐MP during midgestation, may be the result of a drug‐induced sequestering of zinc into maternal liver followed by a decrease in maternal plasma zinc and subsequent reduction in fetal zinc uptake. We suggest that this 6‐MP‐associated redistribution of zinc into maternal liver may be due to induction of maternal metallothionein

ISSN:0040-3709    

DOI:10.1002/tera.1420390410

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe 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 l

ISSN:0040-3709    

DOI:10.1002/tera.1420390411

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

年代:1989

数据来源: WILEY