Villeneuve Daniel L, Blake Lindsey S, Brodin Jeffrey D, Greene Katie J, Knoebl Iris, Miracle Ann L, Martinovic Dalma, Ankley Gerald T
U.S. Environmental Protection Agency, ORD, NHEERL, Mid-Continent Ecology Division, Duluth, Minnesota 55804, USA.
Toxicol Sci. 2007 Aug;98(2):395-407. doi: 10.1093/toxsci/kfm124. Epub 2007 May 21.
This study evaluated changes in the expression of steroidogenesis-related genes in male fathead minnows exposed to ketoconazole (KTC) or vinclozolin (VZ) for 21 days. The aim was to evaluate links between molecular changes and higher level outcomes after exposure to endocrine-active chemicals (EACs) with different modes of action. To aid our analysis and interpretation of EAC-related effects, we first examined variation in the relative abundance of steroidogenesis-related gene transcripts in the gonads of male and female fathead minnows as a function of age, gonad development, and spawning status, independent of EAC exposure. Gonadal expression of several genes varied with age and/or gonadal somatic index in either males or females. However, with the exception of aromatase, steroidogenesis-related gene expression did not vary with spawning status. Following the baseline experiments, expression of the selected genes in male fathead minnows exposed to KTC or VZ was evaluated in the context of effects observed at higher levels of organization. Exposure to KTC elicited changes in gene transcription that were consistent with an apparent compensatory response to the chemical's anticipated direct inhibition of steroidogenic enzyme activity. Exposure to VZ, an antiandrogen expected to indirectly impact steroidogenesis, increased pituitary expression of follicle-stimulating hormone beta-subunit as well as testis expression of 20beta-hydroxysteroid dehydrogenase and luteinizing hormone receptor transcripts. Results of this study contribute to ongoing research aimed at understanding responses of the teleost hypothalamic-pituitary-gonadal axis to different types of EACs and how changes in molecular endpoints translate into apical outcomes reflective of either adverse effect or compensation.
本研究评估了暴露于酮康唑（KTC）或乙烯菌核利（VZ）21天的雄性黑头呆鱼中类固醇生成相关基因的表达变化。目的是评估暴露于具有不同作用模式的内分泌活性化学物质（EACs）后分子变化与更高水平结果之间的联系。为了辅助我们对EAC相关效应的分析和解释，我们首先研究了雄性和雌性黑头呆鱼性腺中类固醇生成相关基因转录本的相对丰度随年龄、性腺发育和产卵状态的变化，而不考虑EAC暴露情况。雄性或雌性中，几个基因的性腺表达随年龄和/或性腺体细胞指数而变化。然而，除芳香化酶外，类固醇生成相关基因的表达不随产卵状态而变化。在基线实验之后，在更高组织水平观察到的效应背景下，评估了暴露于KTC或VZ的雄性黑头呆鱼中所选基因的表达。暴露于KTC引起基因转录变化，这与对该化学物质预期直接抑制类固醇生成酶活性的明显补偿反应一致。暴露于VZ，一种预期间接影响类固醇生成的抗雄激素，增加了垂体中促卵泡激素β亚基的表达以及睾丸中20β-羟基类固醇脱氢酶和促黄体激素受体转录本的表达。本研究结果有助于正在进行的研究，旨在了解硬骨鱼下丘脑-垂体-性腺轴对不同类型EACs的反应，以及分子终点的变化如何转化为反映不良反应或补偿的顶端结果。
