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Most of the attention currently focused on endocrine-active chemicals is directed to their effects on the development of offspring exposed to them in utero or during the neonatal period. Pregnant Crj:CD(SD)IGS rats were given ethinyl estradiol (EE) orally in doses of 0.5-50 microg/kg/day from gestational day 7 to postnatal day 18, and their offspring were examined for its effects. Our previous study according to a similar protocol demonstrated the occurrence of cleft phallus in the female offspring exposed to 50 microg/kg of EE in utero and during the lactation period. The present study was designed to assess (1) the reproducibility of the induction of cleft phallus, (2) the fertility of female rats with cleft phallus, and (3) whether any delayed effects, possibly delayed anovulation, were induced. At 50 microg/kg cleft phallus was observed in almost all of the female offspring, and slight retardation of body weight gain was detected in both sexes. At 15-17 weeks of age the animals with cleft phallus could copulate and had fertility comparable to the control group. At 6 months of age, on the other hand, 6/8 of the female offspring at 50 microg/kg exhibited abnormal cyclicity, including persistent estrus, and histological examination revealed follicular cysts and absence of corpora lutea in the ovaries of the rats with persistent estrus. These findings are consistent with delayed anovulation syndrome. The results suggest that observation of cyclicity at 6 months old is able to detect possible delayed ovarian dysfunction induced by perinatal exposure to chemicals.

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Abstract:To investigate the endocrine-mediated effects of neonatal administration of the weak estrogenic compounds, bisphenol A, nonylphenol and genistein, were subcutaneously injected with these compounds at doses of 0.1, 1, and 10 µg/rat/day for 5 days starting on postnatal day 1. Rats were autopsied at 47-50 days. Positive control groups were given diethylstilbestrol (DES) at the same dose levels as the other chemicals. The ano-genital distance, age of vaginal opening and preputial separation, and estrus cyclicity for all living offspring were examined. No abnormalities by the injection of nonylphenol and genistein were detected in this study. In the BPA groups, ano-genital distance in the females in the 1 and 10 µg BPA groups was shorter than in the control group, and the ventral prostate weight was higher in the 10 µg BPA group than in the control group. On the other hand, in the DES groups, delayed preputial separation occurred later in the 0.1 and 1 µg groups than in the control group, and in the 10 µg groups, preputial separation was not completed.Also the estrous stage persisted in female of all DES groups. Underdevelopment of the seminal vesicle and prostate were observed in males of the 1 and 10 µg DES groups, and fewer ovarian corpus lutea, ovarian follicular cysts, and uterine glands, as well as increased uterine epithelial height and squamous metaplasia of the epithelium in the uterus were observed in females of all DES groups. We concluded that the findings observed in the weak estrogenic compound groups were not toxicologically relevant changes and that the present data provide valuable information for the neonatal exposure assay using weak estrogenic compounds. (J Toxicol Pathol 2005; 18: 203-207)

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