McLachlan J A, Newbold R R, Li S, Negishi M
Tulane/Xavier Center for Bioenvironmental Research, Tulane University, New Orleans, LA 70112-2699, USA.
APMIS. 1998 Jan;106(1):240-2; discussion 243-4. doi: 10.1111/j.1699-0463.1998.tb01342.x.
Many chemicals in the environment mimic the female sex hormone, estrogen. Exposure to environmental estrogens during early fetal development was proposed by Sharpe & Skakkebaek as a potential risk factor for subsequent testicular disease, including neoplasia and poor semen quality. To understand the mechanisms of action of estrogenic chemicals during differentiation of the male genital tract, we have studied developmental exposure to the synthetic estrogen, diethylstilboestrol (DES). While DES is a much more potent estrogen than most environmental chemicals examined, several of these compounds share some of the same properties as DES, such as a relative lack of binding to serum estrogen carrying proteins. Prenatal exposure to DES is associated with poor semen quality, prostatic disease, cryptorchidism and testicular neoplasia in mice. A rare form of testicular cancer, rete testis carcinoma, was observed in five percent of male mice treated in utero with DES. We also demonstrated altered regulation of an estrogen responsive gene, lactotransferrin (LTF) in the seminal vesicles of treated mice, but not the controls. Likewise, LTF was irreversibly altered in the uteri of developmentally treated females; at the molecular level altered methylation of the gene appears to be involved, thus, providing a potential marker for hormonal effects during development. The induction of permanent or "imprinted" responses during the development of a relatively estrogen-free reproductive tract cell suggests that undifferentiated targets for estrogen action may be sites for subsequent growth and differentiation defects associated with neoplasia.
环境中的许多化学物质会模拟女性性激素雌激素。夏普和斯卡克贝克提出，在胎儿早期发育过程中接触环境雌激素是后续睾丸疾病（包括肿瘤形成和精液质量不佳）的一个潜在风险因素。为了了解雌激素类化学物质在男性生殖道分化过程中的作用机制，我们研究了合成雌激素己烯雌酚（DES）的发育暴露情况。虽然DES比大多数检测的环境化学物质具有更强的雌激素活性，但其中一些化合物与DES具有一些相同的特性，比如相对缺乏与血清雌激素携带蛋白的结合。产前接触DES与小鼠精液质量不佳、前列腺疾病、隐睾症和睾丸肿瘤有关。在子宫内接受DES治疗的雄性小鼠中，有5%出现了一种罕见的睾丸癌——睾丸网癌。我们还证明，在接受治疗的小鼠精囊中，雌激素反应基因乳铁蛋白（LTF）的调节发生了改变，而对照组则没有。同样，在发育过程中接受治疗的雌性小鼠子宫中，LTF也发生了不可逆的改变；在分子水平上，基因甲基化的改变似乎与之有关，因此，这为发育过程中的激素效应提供了一个潜在的标志物。在相对无雌激素的生殖道细胞发育过程中诱导出永久性或“印记”反应，这表明雌激素作用的未分化靶点可能是随后与肿瘤形成相关的生长和分化缺陷的位点。
