Predictive approaches to assessing the toxicity of contaminant mixtures have been largely limited to chemicals that exert effects through the same biological molecular initiating event. However, by understanding specific pathways through which chemicals exert effects, it may be possible to identify shared "downstream" nodes as the basis for forecasting interactive effects of chemicals with different molecular initiating events. Adverse outcome pathway (AOP) networks conceptually support this type of analysis. We assessed the utility of a simple AOP network for predicting the effects of mixtures of an aromatase inhibitor (fadrozole) and an androgen receptor agonist (17β-trenbolone) on aspects of reproductive endocrine function in female fathead minnows. The fish were exposed to multiple concentrations of fadrozole and 17β-trenbolone individually or in combination for 48 or 96 h. Effects on 2 shared nodes in the AOP network, plasma 17β-estradiol (E2) concentration and vitellogenin (VTG) production (measured as hepatic vtg transcripts) responded as anticipated to fadrozole alone but were minimally impacted by 17β-trenbolone alone. Overall, there were indications that 17β-trenbolone enhanced decreases in E2 and vtg in fadrozole-exposed fish, as anticipated, but the results often were not statistically significant. Failure to consistently observe hypothesized interactions between fadrozole and 17β-trenbolone could be due to several factors, including lack of impact of 17β-trenbolone, inherent biological variability in the endpoints assessed, and/or an incomplete understanding of interactions (including feedback) between different pathways within the hypothalamic-pituitary-gonadal axis. Environ Toxicol Chem 2020;00:1-10. © 2020 SETAC.

中文翻译：

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基于不良结果通路网络的雄激素受体激动剂和芳香酶抑制剂对鱼类内分泌功能相互作用的评估。

评估污染物混合物毒性的预测方法在很大程度上仅限于通过相同的生物分子引发事件产生影响的化学品。然而，通过了解化学品发挥作用的特定途径，有可能确定共享的“下游”节点作为预测化学品与不同分子引发事件的相互作用效应的基础。不良结果通路 (AOP) 网络在概念上支持这种类型的分析。我们评估了一个简单的 AOP 网络在预测芳香酶抑制剂（fadrozole）和雄激素受体激动剂（17β-群勃龙）的混合物对雌性黑头鲦鱼生殖内分泌功能方面的影响的效用。将鱼单独或组合暴露于多种浓度的法屈唑和 17β-群勃龙 48 或 96 小时。对 AOP 网络中 2 个共享节点的影响、血浆 17β-雌二醇 (E2) 浓度和卵黄蛋白 (VTG) 产生（以肝 vtg 转录物测量）对单独的法屈唑有预期的反应，但单独受到 17β-群勃龙的影响最小。总体而言，有迹象表明，如预期的那样，17β-群勃龙增强了暴露于法屈唑的鱼中 E2 和 vtg 的降低，但结果通常没有统计学意义。未能始终如一地观察法屈唑和 17β-群勃龙之间假设的相互作用可能是由于几个因素，包括 17β-群勃龙缺乏影响、评估的终点的固有生物学变异性、和/或对下丘脑-垂体-性腺轴内不同途径之间的相互作用（包括反馈）的理解不完整。环境毒物化学 2020；00:1-10。© 2020 SETAC。