Ankley Gerald T, LaLone Carlie A, Gray L Earl, Villeneuve Daniel L, Hornung Michael W
Mid-Continent Ecology Division, US Environmental Protection Agency, Duluth, Minnesota.
Toxicity Assessment Division, US Environmental Protection Agency, Research Triangle Park, North Carolina.
Environ Toxicol Chem. 2016 Nov;35(11):2806-2816. doi: 10.1002/etc.3456. Epub 2016 Jun 28.
The US Environmental Protection Agency has responsibility for assessing endocrine activity of more than 10 000 chemicals, a task that cannot reasonably be achieved solely through use of available mammalian and nonmammalian in vivo screening assays. Hence, it has been proposed that chemicals be prioritized for in vivo testing using data from in vitro high-throughput assays for specific endocrine system targets. Recent efforts focused on potential estrogenic chemicals-specifically those that activate estrogen receptor-alpha (ERα)-have broadly demonstrated feasibility of the approach. However, a major uncertainty is whether prioritization based on mammalian (primarily human) high-throughput assays accurately reflects potential chemical-ERα interactions in nonmammalian species. The authors conducted a comprehensive analysis of cross-species comparability of chemical-ERα interactions based on information concerning structural attributes of estrogen receptors, in vitro binding and transactivation data for ERα, and the effects of a range of chemicals on estrogen-signaling pathways in vivo. Overall, this integrated analysis suggests that chemicals with moderate to high estrogenic potency in mammalian systems also should be priority chemicals in nonmammalian vertebrates. However, the degree to which the prioritization approach might be applicable to invertebrates is uncertain because of a lack of knowledge of the biological role(s) of possible ERα orthologs found in phyla such as annelids. Further, comparative analysis of in vitro data for fish and reptiles suggests that mammalian-based assays may not effectively capture ERα interactions for low-affinity chemicals in all vertebrate classes. Environ Toxicol Chem 2016;35:2806-2816. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America.
美国环境保护局负责评估一万多种化学物质的内分泌活性，仅通过现有的哺乳动物和非哺乳动物体内筛选试验，无法合理地完成这项任务。因此，有人提议利用针对特定内分泌系统靶点的体外高通量试验数据，对用于体内试验的化学物质进行优先排序。最近针对潜在雌激素化学物质（特别是那些激活雌激素受体α（ERα）的物质）的研究广泛证明了该方法的可行性。然而，一个主要的不确定性在于，基于哺乳动物（主要是人类）高通量试验的优先排序是否能准确反映非哺乳动物物种中潜在的化学物质与ERα的相互作用。作者基于雌激素受体的结构属性信息、ERα的体外结合和反式激活数据，以及一系列化学物质对体内雌激素信号通路的影响，对化学物质与ERα相互作用的跨物种可比性进行了全面分析。总体而言，这项综合分析表明，在哺乳动物系统中具有中度至高雌激素活性的化学物质，在非哺乳动物脊椎动物中也应作为优先化学物质。然而，由于对环节动物等门中发现的可能的ERα直系同源物的生物学作用缺乏了解，优先排序方法对无脊椎动物的适用程度尚不确定。此外，对鱼类和爬行动物的体外数据进行的比较分析表明，基于哺乳动物的试验可能无法有效捕捉所有脊椎动物类别中低亲和力化学物质的ERα相互作用。《环境毒理学与化学》2016年；35：2806 - 2816。2016年由威利期刊公司代表SETAC出版。本文是美国政府的作品，因此在美国属于公共领域。
