Evaluation of the model anti-androgen flutamide for assessing the mechanistic basis of responses to an androgen in the fathead minnow (Pimephales promelas)
Evaluation of the model anti-androgen flutamide for assessing the mechanistic basis of responses to an androgen in the fathead minnow (Pimephales promelas)
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DOI：
10.1021/es040022b
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发表时间：
2004-12-01
影响因子：
11.4
通讯作者：
Wilson, V
中科院分区：
文献类型：
--
作者：
Ankley, GT;Defoe, DL;Wilson, V
在这项研究中，我们的特点的影响flutamine，模型哺乳动物雄激素受体（AR）拮抗剂，内分泌功能的黑头呆鱼（Pimephales promelas），一种小的鱼类，被广泛用于测试内分泌干扰化学品（EDCs）。用克隆的黑头呆鱼AR瞬时转染的全细胞的结合试验表明，荧光素酶与受体竞争性结合。然而，与哺乳动物系统中的情况一样，氟替卡松的2-羟基化代谢产物以比母体化学品高得多的亲和力与AR结合。与氟啶虫胺和雄激素17 β-群勃龙的混合物实验表明，抗雄激素有效地阻止群勃龙诱导的雄性化（婚姻结节生产）的女性黑头呆鱼，表明在体内的AR受体介导的反应的拮抗作用。相反，在群勃龙暴露的女性卵黄蛋白原的减少没有被氟替卡松阻断，这表明卵黄蛋白原的反应是不直接介导的AR。这些研究的结果提供的数据证明了使用黑头呆鱼作为模型物种检测通过与AR相互作用产生毒性的内分泌干扰物的有效性。
In this study, we characterized the effects of flutamide, a model mammalian androgen receptor (AR) antagonist, on endocrine function in the fathead minnow (Pimephales promelas), a small fish species that is widely used for testing endocrine-disrupting chemicals (EDCs). Binding assays with whole cells transiently transfected with cloned fathead minnow AR indicated that flutamide binds competitively to the receptor. However, as is true in mammalian systems, a 2-hydroxylated metabolite of flutamide binds to the AR with a much higher affinity than the parent chemical. Mixture experiments with flutamide and the androgen 17beta-trenbolone demonstrated that the antiandrogen effectively blocked trenbolone-induced masculinization (nuptial tubercle production) of female fathead minnows, indicating antagonism of an AR receptor-mediated response in vivo. Conversely, reductions in vitellogenin in trenbolone-exposed females were not blocked by flutamide, suggesting that the vitellogenin response is not directly mediated through the AR. The results of these studies provide data demonstrating the validity of using the fathead minnow as a model species for detecting EDCs that exert toxicity through interactions with the AR.