Delbès Géraldine, Duquenne Clotilde, Szenker Jessica, Taccoen Julie, Habert René, Levacher Christine
Laboratory of Differentiation and Radiobiology of the Gonads, Université Paris 7-Denis Diderot and CEA, DSV/iRCM/SCSR/LDRG and INSERM, Unité 566, F-92265, Fontenay aux Roses, France.
Toxicol Sci. 2007 Sep;99(1):234-43. doi: 10.1093/toxsci/kfm160. Epub 2007 Jun 14.
There is now compelling evidence that inappropriate exposure to estrogen during fetal or neonatal life could affect adult reproductive functions because the testis is sensitive to estrogens during specific periods of its development. Therefore, we investigated the effects of exogenous estrogens on gametogenesis and steroidogenesis during fetal and neonatal testicular development in the rat. We used in vitro systems, organ cultures, and dispersed testicular cell cultures, which allow the development of fetal and neonatal germ cells (gonocytes) and Leydig cells. Exogenous estrogens inhibited testosterone production in dispersed testicular cell cultures throughout fetal life, but this inhibition was observed only in the early fetal stages in organ culture. By using an aromatase inhibitor (letrozole, Novartis Pharma AG), we showed that the inhibitory effect of exogenous estrogens on testosterone production is masked in the whole testis at later stages (20.5 days postconception) due essentially to local production of estrogens. In both systems, additions of high concentrations (10(-6) M) of 17beta-estradiol or diethylstilbestrol decreased the number of gonocytes during the first fetal proliferative period but not during the neonatal period. Letrozole was without effect, suggesting that the aging-related loss of responsiveness of gonocytes is not due to any aromatase activity in the gonocytes.
目前有确凿证据表明，在胎儿期或新生儿期不适当暴露于雌激素会影响成年后的生殖功能，因为睾丸在其发育的特定阶段对雌激素敏感。因此，我们研究了外源性雌激素对大鼠胎儿期和新生儿期睾丸发育过程中配子发生和类固醇生成的影响。我们使用了体外系统、器官培养和分散的睾丸细胞培养，这些方法可以使胎儿期和新生儿期的生殖细胞（生殖母细胞）和睾丸间质细胞发育。外源性雌激素在整个胎儿期均抑制分散的睾丸细胞培养物中睾酮的产生，但在器官培养中仅在胎儿早期观察到这种抑制作用。通过使用芳香化酶抑制剂（来曲唑，诺华制药公司），我们发现外源性雌激素对睾酮产生的抑制作用在后期（受孕后20.5天）的整个睾丸中被掩盖，这主要是由于雌激素的局部产生。在这两种系统中，添加高浓度（10^(-6) M）的17β-雌二醇或己烯雌酚会减少胎儿期第一个增殖期生殖母细胞的数量，但在新生儿期则不会。来曲唑没有效果，这表明生殖母细胞与年龄相关的反应性丧失并非由于生殖母细胞中的任何芳香化酶活性所致。
