Ankley Gerald T, Jensen Kathleen M, Durhan Elizabeth J, Makynen Elizabeth A, Butterworth Brian C, Kahl Michael D, Villeneuve Daniel L, Linnum Ann, Gray L Earl, Cardon Mary, Wilson Vickie S
U.S. Environmental Protection Agency, ORD, NHEERL, Mid-Continent Ecology Division, Duluth, Minnesota 55804, USA.
Toxicol Sci. 2005 Aug;86(2):300-8. doi: 10.1093/toxsci/kfi202. Epub 2005 May 18.
Many chemicals that adversely affect reproduction and/or development do so through multiple pathways within the reproductive tract and hypothalamic-pituitary-gonadal axis. Notable in this regard are fungicides, such as prochloraz or fenarimol, which in mammals have the potential to impact endocrine function through inhibition of CYP enzymes involved in steroid metabolism, as well as through antagonism of the androgen receptor(s). The objective of our studies was to assess the effects of prochloraz and fenarimol on reproductive endocrine function in a model small fish species, the fathead minnow (Pimephales promelas), using both in vitro and in vivo assays. The two fungicides inhibited in vitro CYP19 aromatase activity in brain and ovarian homogenates from the fish, with prochloraz exhibiting a greater potency than fenarimol. Prochloraz and fenarimol also bound competitively to the cloned fathead minnow androgen receptor expressed in COS-1 cells. The two fungicides significantly reduced fecundity of the fish in a 21-day reproduction assay at water concentrations of 0.1 (prochloraz) and 1.0 (fenarimol) mg/l. The in vivo effects of prochloraz on plasma steroid (17beta-estradiol, testosterone, 11-ketotestosterone) and vitellogenin (an estrogen-responsive protein) concentrations, as well as on gonadal histopathology, were consistent with inhibition of steroidogenesis. Fenarimol also affected several aspects of endocrine function in vivo; however, the suite of observed effects did not reflect either aromatase inhibition or androgen receptor antagonism. These studies contribute to a better mechanistic understanding of the extrapolation of effects of endocrine-disrupting chemicals across vertebrate classes.
许多对生殖和/或发育产生不利影响的化学物质是通过生殖道和下丘脑-垂体-性腺轴内的多种途径来实现的。在这方面值得注意的是杀菌剂，如咪鲜胺或氯苯嘧啶醇，在哺乳动物中，它们有可能通过抑制参与类固醇代谢的CYP酶以及拮抗雄激素受体来影响内分泌功能。我们研究的目的是使用体外和体内试验，评估咪鲜胺和氯苯嘧啶醇对一种小型鱼类——黑头软口鲦（Pimephales promelas）生殖内分泌功能的影响。这两种杀菌剂在体外抑制了该鱼类脑和卵巢匀浆中的CYP19芳香化酶活性，其中咪鲜胺的效力比氯苯嘧啶醇更强。咪鲜胺和氯苯嘧啶醇还与COS-1细胞中表达的克隆黑头软口鲦雄激素受体竞争性结合。在水浓度为0.1（咪鲜胺）和1.0（氯苯嘧啶醇）mg/l的21天繁殖试验中，这两种杀菌剂显著降低了鱼类的繁殖力。咪鲜胺对血浆类固醇（17β-雌二醇、睾酮、11-酮睾酮）和卵黄蛋白原（一种雌激素反应蛋白）浓度以及性腺组织病理学的体内影响与类固醇生成的抑制作用一致。氯苯嘧啶醇在体内也影响了内分泌功能的几个方面；然而，观察到的一系列影响既不反映芳香化酶抑制作用，也不反映雄激素受体拮抗作用。这些研究有助于更好地从机制上理解内分泌干扰化学物质对不同脊椎动物类群影响的外推情况。
