Villeneuve Daniel L, Knoebl Iris, Kahl Michael D, Jensen Kathleen M, Hammermeister Dean E, Greene Katie J, Blake Lindsey S, Ankley Gerald T
US Environmental Protection Agency, Mid-Continent Ecology Division, Duluth, MN, USA.
Aquat Toxicol. 2006 Mar 10;76(3-4):353-68. doi: 10.1016/j.aquatox.2005.10.016. Epub 2005 Dec 2.
There is growing evidence that some chemicals present in the environment have the capacity to inhibit, or potentially induce, aromatase activity. This study compared aromatase activities and isoform-specific mRNA expression in brain and ovary tissue from non-exposed fathead minnows representing three different ages and stages of reproductive activity, and from fathead minnows exposed to the aromatase inhibitor fadrozole for 7d. The goal was to determine whether measures of a single aromatase endpoint in either brain or ovary tissue would be sufficient to understand and predict system-wide effects of endocrine disrupting chemicals on aromatase activity and transcript levels. Aromatase activity in the ovary, but not brain, varied significantly with age/reproductive category, with adults held in non-reproductive conditions showing significantly lower activity than juveniles and reproductively-active adults. Significant correlations between isoform-specific transcript levels and aromatase activity were observed for ovary tissue, but those relationships were not robust for all age/reproductive categories, nor were they sustained in fadrozole-treated fish. In vitro, fadrozole inhibited the aromatase activity of brain and ovary post-mitochondrial supernatants with similar potency (IC50s = 8.82 +/- 1.58 and 6.93 +/- 0.80 microM for brain and ovary, respectively), despite large differences in the magnitude of activity. In vivo, fadrozole altered aromatase activity and isoform-specific transcript levels in both brain and ovary tissue, but concentration-response relationships were different for each tissue. Aromatase activity and P450aromB mRNA expression in brain showed a dose-dependent decrease at concentrations greater than 5.55 microg/L. In contrast, ovary activity showed an inverted U-shaped concentration-response consistent with the interplay between increased P450aromA transcript levels in ovary and competitive inhibition of the aromatase enzyme. As a whole, results of this study did not reveal any robust correlations between brain and ovary aromatase activity and/or isoform-specific mRNA expression. However, they were consistent with the current body of evidence related to teleost aromatase regulation, suggesting that increased understanding of the biology of aromatase may facilitate system-wide understanding of effects on aromatase based on relatively few measured endpoints.
越来越多的证据表明，环境中存在的某些化学物质具有抑制或潜在诱导芳香化酶活性的能力。本研究比较了来自代表三种不同年龄和生殖活动阶段的未暴露黑头软口鲦鱼，以及暴露于芳香化酶抑制剂法倔唑7天的黑头软口鲦鱼的脑和卵巢组织中的芳香化酶活性及同工型特异性mRNA表达。目的是确定在脑或卵巢组织中单一芳香化酶终点指标是否足以理解和预测内分泌干扰化学物质对芳香化酶活性和转录水平的全系统影响。卵巢中的芳香化酶活性（而非脑）随年龄/生殖类别有显著变化，处于非生殖状态的成年鱼的活性显著低于幼鱼和具有生殖活性的成年鱼。在卵巢组织中观察到同工型特异性转录水平与芳香化酶活性之间存在显著相关性，但这些关系并非在所有年龄/生殖类别中都稳固，在经法倔唑处理的鱼中也未持续存在。在体外，尽管活性大小存在很大差异，但法倔唑以相似的效力抑制脑和卵巢线粒体后上清液的芳香化酶活性（脑和卵巢的IC50分别为8.82±1.58和6.93±0.80 microM）。在体内，法倔唑改变了脑和卵巢组织中的芳香化酶活性及同工型特异性转录水平，但每种组织的浓度-反应关系不同。当浓度大于5.55微克/升时，脑中的芳香化酶活性和P450aromB mRNA表达呈剂量依赖性下降。相反，卵巢活性呈现倒U形浓度-反应，这与卵巢中P450aromA转录水平增加与芳香化酶的竞争性抑制之间的相互作用一致。总体而言，本研究结果未揭示脑和卵巢芳香化酶活性及/或同工型特异性mRNA表达之间存在任何稳固的相关性。然而，它们与目前关于硬骨鱼芳香化酶调节的证据一致，表明对芳香化酶生物学的更多了解可能有助于基于相对较少的测量终点对芳香化酶的影响进行全系统理解。
