Development, Validation, and Application of a Human Reproductive Toxicity Prediction Model Based on Adverse Outcome Pathway,Environmental Science & Technology

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Development, Validation, and Application of a Human Reproductive Toxicity Prediction Model Based on Adverse Outcome Pathway
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2022-08-12 , DOI: 10.1021/acs.est.2c02242
Haoyue Tan _{1,

2} , Jinqiu Wu _{1,

2} , Rong Zhang _{1,

2} , Chi Zhang _{1,

2} , Wei Li _{1,

2} , Qinchang Chen _{1,

2} , Xiaowei Zhang _{1,

2} , Hongxia Yu _{1,

2} , Wei Shi _{1,

2}

Affiliation

A growing number of environmental contaminants have been proved to have reproductive toxicity to males and females. However, the unclear toxicological mechanism of reproductive toxicants limits the development of virtual screening methods. By consolidating androgen (AR)-/estrogen receptors (ERs)-mediated adverse outcome pathways (AOPs) with more than 8000 chemical substances, we uncovered relationships between chemical features, a series of pathway-related effects, and reproductive apical outcomes─changes in sex organ weights. An AOP-based computational model named RepTox was developed and evaluated to predict and characterize chemicals’ reproductive toxicity for males and females. Results showed that RepTox has three outstanding advantages. (I) Compared with the traditional models (37 and 81% accuracy, respectively), AOP significantly improved the predictive robustness of RepTox (96.3% accuracy). (II) Compared with the application domain (AD) of models based on small in vivo datasets, AOP expanded the ADs of RepTox by 1.65-fold for male and 3.77-fold for female, respectively. (III) RepTox implied that hydrophobicity, cyclopentanol substructure, and several topological indices (e.g., hydrogen-bond acceptors) were important, unbiased features associated with reproductive toxicants. Finally, RepTox was applied to the inventory of existing chemical substances of China and identified 2100 and 7281 potential toxicants to the male and female reproductive systems, respectively.

中文翻译：

基于不良结果通路的人类生殖毒性预测模型的开发、验证和应用

越来越多的环境污染物已被证明对雄性和雌性具有生殖毒性。然而，生殖毒物的毒理机制不明确，限制了虚拟筛选方法的发展。通过将雄激素 (AR)-/雌激素受体 (ER) 介导的不良后果通路 (AOPs) 与 8000 多种化学物质相结合，我们揭示了化学特征、一系列通路相关效应和生殖顶端结果之间的关系——性器官重量。开发并评估了一个名为 RepTox 的基于 AOP 的计算模型，以预测和表征化学品对男性和女性的生殖毒性。结果表明，RepTox具有三个突出的优势。(I) 与传统模型相比（分别为 37% 和 81% 的准确率），AOP 显着提高了 RepTox 的预测稳健性（96.3% 准确度）。（二）与基于小模型的应用领域（AD）比较在体内数据集中，AOP 分别将男性的 RepTox 的 AD 扩展了 1.65 倍和女性的 3.77 倍。(III) RepTox 暗示疏水性、环戊醇子结构和几个拓扑指标（例如，氢键受体）是与生殖毒物相关的重要、公正的特征。最后，将RepTox应用于中国现有化学物质清单，分别鉴定出2100种和7281种对男性和女性生殖系统的潜在毒物。

更新日期：2022-08-12

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