Generating adverse outcome pathway (AOP) of inorganic arsenic-induced adult male reproductive impairment via integration of phenotypic analysis in comparative toxicogenomics database (CTD) and AOP wiki

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.