Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Information and Navigation College, Air Force Engineering University, Xi'an 710077, China.
Toxicol Appl Pharmacol. 2021 Jan 15;411:115370. doi: 10.1016/j.taap.2020.115370. Epub 2020 Dec 15.
Inorganic arsenic (iAs) is a worldwide environmental pollutant which exerts complicated and various toxic effects in organisms. Increasingly epidemic studies have revealed the association between iAs exposure and adult male reproductive impairment. Consistent with the proposal for toxicity testing in the 21st century (TT21C), the adverse outcome pathway (AOP) framework may help unravel the iAs-caused molecular and functional changes leading to male reproductive impairment.
Combining CTD's phenotype-disease inference data, iAs-phenotypes were anchored to five male reproductive diseases induced by iAs, and local network topological algorithm was applied in prioritizing their interference significance. Through integrating analysis in AOP Wiki knowledge base, filtered phenotypes were linked to key events consisting of AOPs and assembled together based on evidentially upstream and downstream relationships.
A subset of 655 phenotypes were filtered from CTD as potential key events and showed a significant coherence in five reproductive diseases wherein 39 significant phenotypes showed a good clustering features involving cell cycle, ROS and mitochondria function. Two AOP subnetworks were enriched in AOP Wiki where testosterone reduction and apoptosis of sperm served as focus events respectively. Besides, a candidates list of molecular initialing events was provided of which glucocorticoid receptor activation was overall assessed as an example.
This study applied computational and bioinformatics methods in generating AOPs for arsenic reproductive toxicity, which identified the imperative roles of testosterone reduction, response to ROS, spermatogenesis and provided a global view about their internal association. Furthermore, this study helped address the existing knowledge gaps for future experimental verification.
无机砷（iAs）是一种全球性的环境污染物，在生物体中具有复杂多样的毒性作用。越来越多的流行性病学研究揭示了 iAs 暴露与成年男性生殖损伤之间的关联。与 21 世纪毒性测试（TT21C）的建议一致，不良结局途径（AOP）框架可以帮助揭示导致男性生殖损伤的 iAs 引起的分子和功能变化。
结合 CTD 的表型-疾病推断数据，将 iAs 表型锚定到由 iAs 引起的五种男性生殖疾病上，并应用局部网络拓扑算法对其干扰意义进行优先级排序。通过在 AOPWiki 知识库中的综合分析，过滤出的表型与由 AOP 组成的关键事件相关联，并根据明显的上下游关系组装在一起。
从 CTD 中筛选出 655 个表型作为潜在的关键事件，这些表型在五种生殖疾病中表现出显著的一致性，其中 39 个显著表型表现出涉及细胞周期、ROS 和线粒体功能的良好聚类特征。在 AOPWiki 中富集了两个 AOP 子网，其中睾丸酮减少和精子凋亡分别作为焦点事件。此外，还提供了一个分子起始事件的候选列表，其中整体评估了糖皮质激素受体激活作为一个例子。
本研究应用计算和生物信息学方法生成砷生殖毒性的 AOP，确定了睾丸酮减少、ROS 反应、精子发生的重要作用，并提供了它们内部关联的全局视图。此外，这项研究有助于解决未来实验验证的现有知识空白。
