Reproductive abnormalities in female mice exposed neonatally to various doses of coumestrol

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Abstract
Female C57BL/Crgl mice were neonatally exposed to various doses of coumestrol to determine the threshold doses required for the occurrence of reproductive tract abnormalities. Newborn mice received daily subcutaneous injections of 10−3, 10−2, 8 × 10−2, 10−1, 1, 5, 25, 50, and 100 μg coumestrol in 0.005 ml dimethyl sulfoxide (DMSO) or DMSO alone, or received no treatment for the first 5 d of life. Some of the animals were ovariectomized at 40 d of age. Mice were killed at 20–22 mo of age. All neonatal doses of coumestrol advanced vaginal opening before that of controls. At 2 and 20–22 mo of age, doses ≥25 μg consistently resulted in ovary‐independent persistent vaginal cornification as judged by vaginal smears. Intact untreated and DMSO‐treated control mice exhibited aging changes in the genital tract, some cervical adenosis and early cervicovaginal pegs and downgrowths, uterine cystic glandular hyperplasia, corpora lutea, and scattered areas of ovarian ceroid deposition. Intact mice receiving neonatal coumestrol exhibited cervicovaginal pegs and downgrowths (at all doses with the exception of 25 and 50 μg), cervical adenosis (at doses ≥ 8 × 10−2 μg), uterine squamous metaplasia (significant at doses ≥50 μg), and a decrease in uterine cystic glandular hyperplasia (significant at doses ≥25 μg). The levels of 10−1, 5, and 100 μg neonatal coumestrol daily resulted in hemorrhagic follicles. An increase in ovarian ceroid deposition (significant at doses ≥5 μg) was observed. At 40 d and 20–22 mo of age, corpora lutea were consistently absent from the 100‐μg‐treated animals. Most of the ovariectomized untreated and DMSO‐treated control animals showed typical castrate‐like morphology of the genital tract, with the majority of the control mice exhibiting uterine cystic glandular hyperplasia. Ovariectomized mice receiving coumestrol neonatally exhibited various degrees of cervicovaginal alterations: pegs and downgrowths (significant at all doses with the exception of 10−1 μg), endometrial collagen deposition (significant at ≥25 μg), and reduced or absent uterine glands (significant at 10−3, and 10−11, and at all doses ≥5 μg).