Abstract：
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;00:1-12. © 2024 SETAC.
摘要：
定量不良结果途径（qAOP）描述了反应-反应关系，该关系将化学相互作用与特定分子靶标的幅度和/或持续时间与所产生的具有监管相关性的顶端水平毒性的概率和/或严重程度联系起来。本研究开发了第一个针对潜在毒性的qAOP，表明早期生活暴露会对成年后的健康产生不利影响。具体来说,通过在现有qAOP的基础上，开发了一种qAOP，用于通过多环芳烃（PAHs）对鱼类的芳香烃受体2（AHR2）进行胚胎激活，从而导致成年期雌性繁殖力降低，以用于（1）激活AHR导致鸟类和鱼类的早期生命死亡，和（2）细胞色素P450芳香化酶活性的抑制导致鱼类繁殖力降低。使用斑马鱼（Daniorerio）作为模型物种，苯并[a]芘作为模型PAH，建立了三个相关的定量关系：（1）成年女性的血浆雌激素作为胚胎暴露的函数，（2）成年女性血浆卵黄蛋白原作为血浆雌激素的功能，（3）成年雌性的繁殖力是血浆卵黄蛋白原的函数。在标准化的体外AHR反式激活测定法中，针对早期死亡率开发了第四个定量关系，该关系是对AHR2激活敏感性的函数，以整合毒性等效性计算，从而可以预测暴露于未经测试的PAHs的影响。使用斑马鱼作为胚胎暴露于另一种PAH的实验数据评估了所得qAOP预测的准确性，苯并[k]荧蒽。本研究中开发的qAOP证明了AOP框架在定量生态风险评估和监管决策中能够考虑潜在毒性的潜力。环境毒物化学2024；00：1-12。©2024SETAC。
