Burroughs C D, Mills K T, Bern H A
Department of Integrative Biology, University of California, Berkeley.
J Toxicol Environ Health. 1990 Jun;30(2):105-22. doi: 10.1080/15287399009531415.
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 X 10(-2), 10(-1), 1, 5, 25, 50, and 100 micrograms 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 greater than or equal to 25 micrograms 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 micrograms), cervical adenosis (at doses greater than or equal to 8 X 10(-2) micrograms), uterine squamous metaplasia (significant at doses greater than or equal to 50 micrograms), and a decrease in uterine cystic glandular hyperplasia (significant at doses greater than or equal to 25 micrograms). The levels of 10(-1), 5, and 100 micrograms neonatal coumestrol daily resulted in hemorrhagic follicles. An increase in ovarian ceroid deposition (significant at doses greater than or equal to 5 micrograms) was observed. At 40 d and 20-22 mo of age, corpora lutea were consistently absent from the 100-micrograms-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) micrograms), endometrial collagen deposition (significant at greater than or equal to 25 micrograms), and reduced or absent uterine glands (significant at 10(-3), and 10(-11), and at all doses greater than or equal to 5 micrograms).
将新生雌性C57BL/Crgl小鼠暴露于不同剂量的香豆雌酚中，以确定出现生殖道异常所需的阈剂量。新生小鼠每天皮下注射含10(-3)、10(-2)、8×10(-2)、10(-1)、1、5、25、50和100微克香豆雌酚的0.005毫升二甲基亚砜（DMSO），或仅注射DMSO，或在出生后的前5天不进行处理。部分动物在40日龄时进行卵巢切除。小鼠在20 - 22月龄时处死。所有新生期香豆雌酚剂量均使阴道开口早于对照组。在2月龄以及20 - 22月龄时，剂量大于或等于25微克经阴道涂片判断始终导致不依赖卵巢的持续性阴道角化。未处理和经DMSO处理的完整对照小鼠生殖道出现衰老变化，一些宫颈腺病、早期宫颈阴道栓和向下生长、子宫囊性腺增生、黄体以及散在的卵巢类蜡质沉积区域。接受新生期香豆雌酚的完整小鼠出现宫颈阴道栓和向下生长（除25和50微克剂量外所有剂量均有）、宫颈腺病（剂量大于或等于8×10(-2)微克时出现）、子宫鳞状化生（剂量大于或等于50微克时显著）以及子宫囊性腺增生减少（剂量大于或等于25微克时显著）。每日10(-1)、5和100微克新生期香豆雌酚剂量导致出血性卵泡。观察到卵巢类蜡质沉积增加（剂量大于或等于5微克时显著）。在40日龄和20 - 22月龄时，接受100微克处理的动物始终没有黄体。大多数未处理和经DMSO处理的卵巢切除对照动物显示出典型的去势样生殖道形态，大多数对照小鼠出现子宫囊性腺增生。新生期接受香豆雌酚的卵巢切除小鼠表现出不同程度的宫颈阴道改变：栓和向下生长（除10(-1)微克剂量外所有剂量均显著）、子宫内膜胶原沉积（大于或等于25微克时显著）以及子宫腺体减少或缺失（10(-3)、10(-1)以及所有大于或等于5微克剂量时显著）。
