Department of Environmental Sciences, College of the Coast & Environment, Louisiana State University, Baton Rouge, Louisiana, USA.
Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada.
Environ Toxicol Chem. 2024 Oct;43(10):2145-2156. doi: 10.1002/etc.5964. Epub 2024 Aug 2.
Quantitative adverse outcome pathways (qAOPs) describe the response-response relationships that link the magnitude and/or duration of chemical interaction with a specific molecular target to the probability and/or severity of the resulting apical-level toxicity of regulatory relevance. The present study developed the first qAOP for latent toxicities showing that early life exposure adversely affects health at adulthood. Specifically, a qAOP for embryonic activation of the aryl hydrocarbon receptor 2 (AHR2) of fishes by polycyclic aromatic hydrocarbons (PAHs) leading to decreased fecundity of females at adulthood was developed by building on existing qAOPs for (1) activation of the AHR leading to early life mortality in birds and fishes, and (2) inhibition of cytochrome P450 aromatase activity leading to decreased fecundity in fishes. Using zebrafish (Danio rerio) as a model species and benzo[a]pyrene as a model PAH, three linked quantitative relationships were developed: (1) plasma estrogen in adult females as a function of embryonic exposure, (2) plasma vitellogenin in adult females as a function of plasma estrogen, and (3) fecundity of adult females as a function of plasma vitellogenin. A fourth quantitative relationship was developed for early life mortality as a function of sensitivity to activation of the AHR2 in a standardized in vitro AHR transactivation assay to integrate toxic equivalence calculations that would allow prediction of effects of exposure to untested PAHs. The accuracy of the predictions from the resulting qAOP were evaluated using experimental data from zebrafish exposed as embryos to another PAH, benzo[k]fluoranthene. The qAOP developed in the present study demonstrates the potential of the AOP framework in enabling consideration of latent toxicities in quantitative ecological risk assessments and regulatory decision-making. Environ Toxicol Chem 2024;43:2145-2156. © 2024 SETAC.
定量不良反应途径（qAOP）描述了将化学相互作用的幅度和/或持续时间与特定分子靶标与监管相关的顶端毒性的可能性和/或严重程度联系起来的反应-反应关系。本研究开发了第一个用于潜伏毒性的 qAOP，表明生命早期暴露会对成年后的健康产生不利影响。具体来说，通过构建现有的 qAOP 来开发鱼类多环芳烃（PAHs）对芳香烃受体 2（AHR2）的胚胎激活导致成年雌性繁殖力下降的 qAOP，这些 qAOP 用于（1）激活芳香烃受体导致鸟类和鱼类的生命早期死亡率，以及（2）抑制细胞色素 P450 芳香酶活性导致鱼类繁殖力下降。使用斑马鱼（Danio rerio）作为模型物种和苯并[a]芘作为模型 PAH，开发了三个链接的定量关系：（1）成年雌性的血浆雌激素作为胚胎暴露的函数，（2）成年雌性的血浆卵黄蛋白原作为血浆雌激素的函数，以及（3）成年雌性的繁殖力作为血浆卵黄蛋白原的函数。还开发了第四个定量关系，用于生命早期死亡率，作为标准化体外 AHR 反式激活测定中 AHR2 激活敏感性的函数，以整合毒性等效计算，从而能够预测暴露于未经测试的 PAHs 的影响。使用暴露于另一种 PAH 苯并[k]荧蒽的胚胎斑马鱼的实验数据评估了由此产生的 qAOP 的预测准确性。本研究开发的 qAOP 表明，AOP 框架在定量生态风险评估和监管决策中考虑潜伏毒性的潜力。Environ Toxicol Chem 2024;43:2145-2156。 © 2024 SETAC。
