US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Lab, Duluth, Minnesota, USA.
Environ Toxicol Chem. 2011 Sep;30(9):2094-102. doi: 10.1002/etc.593. Epub 2011 Jul 9.
Inhibition of enzymes involved in the synthesis of sex steroids can substantially impact developmental and reproductive processes controlled by the hypothalmic-pituitary-gonadal (HPG) axis. A key steroidogenic enzyme that has received little attention from a toxicological perspective is 3β-hydroxysteroid dehydrogenase (3β-HSD). In these studies, we exposed reproductively-active fathead minnows (Pimephales promelas) to the model 3β-HSD inhibitor trilostane at two test concentrations (300 and 1,500 µg/L) over a 16-d period that included both 8-d exposure and 8-d recovery phases. Plasma concentrations of 17β-estradiol (E2) in females were depressed within hours of exposure to the drug and remained decreased at the highest trilostane concentration throughout the 8-d exposure. Reductions in E2 were accompanied by decreases in plasma concentrations of the estrogen-responsive protein vitellogenin (VTG). During the recovery phase of the test, plasma E2 and VTG concentrations returned to levels comparable to those of controls, in the case of E2 within 1 d. Up-regulation of ovarian expression of gene products for follicle-stimulating hormone receptor (fshr) and aromatase (cyp19a1a) suggested active compensation in trilostane-exposed animals. Effects of trilostane on HPG-related endpoints in exposed males were less pronounced, although, as in females, up-regulation of gonadal fshr was seen. Data from these time-course studies provide insights as to direct impacts, compensatory responses, and recovery from effects associated with perturbation of a comparatively poorly characterized enzyme/pathway critical to sex steroid synthesis. This information is important to the design and interpretation of approaches for assessing the occurrence and effects of HPG-active chemicals in both the laboratory and the field.
抑制参与性激素合成的酶可以显著影响下丘脑-垂体-性腺（HPG）轴控制的发育和生殖过程。一种从毒理学角度很少受到关注的关键类固醇生成酶是 3β-羟甾脱氢酶（3β-HSD）。在这些研究中，我们将具有生殖活性的黑头呆鱼（Pimephales promelas）暴露于模型 3β-HSD 抑制剂三氯司坦在两个测试浓度（300 和 1500μg/L）下 16 天，包括 8 天暴露和 8 天恢复阶段。暴露于药物后数小时内，雌性鱼类的 17β-雌二醇（E2）血浆浓度下降，并且在最高三氯司坦浓度下整个 8 天暴露期间仍保持降低。E2 的减少伴随着雌激素反应蛋白卵黄蛋白原（VTG）的血浆浓度降低。在测试的恢复阶段，E2 和 VTG 的血浆浓度恢复到与对照组相当的水平，E2 在 1 天内恢复到对照组水平。卵巢中促卵泡激素受体（fshr）和芳香酶（cyp19a1a）的基因产物表达的上调表明在三氯司坦暴露的动物中存在积极的代偿作用。暴露于三氯司坦的雄性动物的 HPG 相关终点的影响不太明显，尽管与雌性动物一样，也观察到了性腺 fshr 的上调。这些时间过程研究的数据提供了有关直接影响、代偿反应以及与干扰相对较差特征的酶/途径相关的效应的恢复的见解，这些酶/途径对性激素合成至关重要。这些信息对于设计和解释评估实验室和现场中 HPG 活性化学物质的发生和影响的方法非常重要。
