Evaluation of the aromatase inhibitor fadrozole in a short-term reproduction assay with the fathead minnow (Pimephales promelas)
Evaluation of the aromatase inhibitor fadrozole in a short-term reproduction assay with the fathead minnow (Pimephales promelas)
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DOI：
10.1093/toxsci/67.1.121
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发表时间：
2002-05-01
影响因子：
3.8
通讯作者：
Leino, RL
中科院分区：
文献类型：
--
作者：
Ankley, GT;Kahl, MD;Leino, RL
细胞色素P450芳香化酶（CYP 19）是脊椎动物类固醇生成中的关键酶，催化C19雄激素转化为C18雌激素，如β-雌二醇（E2）。本研究的目的是评估CYP 19抑制剂法倔唑对黑头呆鱼（黑头呆鱼）生殖内分泌学和生理学的影响，在短期生殖试验中提出了识别特定类别的内分泌干扰化学品。在暴露于2至50 μ g/l法倔唑水浓度21天的鱼中观察到生殖力的浓度依赖性降低。与预期的作用机制一致，有一个显着的抑制脑芳香化酶活性在男性和女性黑头呆鱼暴露于法倔唑。在女性中，这种抑制伴随着血浆E2和卵黄蛋白原浓度的浓度依赖性降低;后一种观察结果与E2激活雌激素受体启动卵生脊椎动物肝脏卵黄蛋白原生产的事实一致。暴露于法倔唑的雌性动物卵巢的组织学评估表明成熟卵母细胞减少，排卵前闭锁卵泡增加。暴露的雄性黑头呆鱼法倔唑显着增加血浆中的雄激素睾酮（T）和11-酮睾酮（KT）的浓度，并导致在睾丸中的精子的显着积累。本研究的结果表明，拟议的黑头呆鱼试验应有效地确定测试化学品作为潜在的芳香化酶抑制剂，无论是在其生殖毒性和具体的作用机制。这些结果还应有助于评估CYP 19抑制剂的潜在生态风险，特别是在将内分泌功能亚细胞指标（类固醇、蛋白质变化）的改变与整个生物体的不良后果相关的背景下。
Cytochrome P450 aromatase (CYP19) is a key enzyme in vertebrate steroidogenesis, catalyzing the conversion of C19 androgens to C18 estrogens such as beta-estradiol (E2). The objective of this study was to assess effects of the CYP19 inhibitor fadrozole on fathead minnow (Pimephales promelas) reproductive endocrinology and physiology in a short-term reproduction assay proposed for identifying specific classes of endocrine-disrupting chemicals. A concentration-dependent reduction in fecundity was observed in fish exposed for 21 days to water concentrations of fadrozole ranging from 2 to 50 mug/l. Consistent with the expected mechanism of action, there was a significant inhibition of brain aromatase activity in both male and female fathead minnows exposed to fadrozole. In females, this inhibition was accompanied by a concentration-dependent decrease in plasma E2 and vitellogenin concentrations; the latter observation is consistent with the fact that activation of the estrogen receptor by E2 initiates hepatic vitellogenin production in oviparous vertebrates. Histological assessment of ovaries from females exposed to fadrozole indicated a decrease in mature oocytes and an increase in preovulatory atretic follicles. Exposure of male fathead minnows to fadrozole significantly increased plasma concentrations of the androgens testosterone (T) and 11-ketotestosterone (KT) and resulted in a marked accumulation of sperm in the testes. Results of this study indicate that the proposed fathead minnow assay should effectively identify test chemicals as potential aromatase inhibitors, both in the context of their reproductive toxicity and the specific mechanism of action. These results also should be of utility in assessing the potential ecological risk of CYP19 inhibitors, in particular in the context of relating alterations in subcellular indicators of endocrine function (changes in steroids, proteins) to adverse consequences in the whole organism.