In the early 1960's, at Professor Bern's laboratory, University of California, Berkeley) in the US, Takasugi discovered ovary-independent, persistent vaginal changes in mice exposed neonatally to estrogen, which resulted in vaginal cancer later in life. Reproductive abnormalities in rodents were reported as a result of perinatal exposure to various estrogenic chemicals. Ten years later, vaginal cancers were reported in young women exposed in utero to the synthetic estrogen diethylstilbestrol (DES) and this has been called the “DES syndrome”. The developing organism is particularly sensitive to developmental exposure to estrogens inducing long-term changes in various organs including the reproductive organs. The molecular mechanism underlying the persistent vaginal changes induced by perinatal estrogen exposure was partly demonstrated. Persistent phosphorylation and sustained expression of EGF-like growth factors, lead to estrogen receptor α (ESR1) activation, and then persistent vaginal epithelial cell proliferation. Agents which are weakly estrogenic by postnatal criteria may have major developmental effects, especially during a critical perinatal period. The present review outlines various studies conducted by four generations of investigators all under the influence of Prof. Bern. The studies include reports of persistent changes induced by neonatal androgen exposure, analyses of estrogen responsive genes, factors determining epithelial differentiation in the Müllerian duct, ESR and growth factor signaling, and polyovular follicles in mammals. This review is then expanded to the studies on the effects of environmental estrogens on wildlife and endocrine disruption in Daphnids.

1960 年代初期，在美国加州大学伯克利分校伯尔尼教授的实验室中，高杉在新生儿暴露于雌激素的小鼠中发现了独立于卵巢的持续性阴道变化，这导致了以后的阴道癌。据报道，由于围产期暴露于各种雌激素化学物质，啮齿动物的生殖异常。十年后，在子宫内暴露的年轻女性中报告了阴道癌合成雌激素己烯雌酚（DES），这被称为“DES综合征”。发育中的有机体对雌激素的发育暴露特别敏感，雌激素会导致包括生殖器官在内的各种器官发生长期变化。部分证明了围产期雌激素暴露引起持续阴道变化的分子机制。EGF 样生长因子的持续磷酸化和持续表达，导致雌激素受体 α (ESR1) 激活，然后持续阴道上皮细胞增殖。根据出生后标准，雌激素较弱的药物可能会对发育产生重大影响，尤其是在关键的围产期。本综述概述了四代研究人员在伯尔尼教授的影响下进行的各种研究。这些研究包括由新生儿雄激素暴露引起的持续变化的报告、雌激素反应基因的分析、决定苗勒管上皮分化的因素、ESR 和生长因子信号传导以及哺乳动物的多卵泡。这篇综述随后扩展到环境雌激素对野生动物和水蚤内分泌干扰的影响的研究。