Systematic Identification of Molecular Targets and Pathways Related to Human Organ Level Toxicity.

Abstract

The mechanisms leading to organ level toxicities are poorly understood. In this study, we applied an integrated approach to deduce the molecular targets and biological pathways involved in chemically induced toxicity for eight common human organ level toxicity end points (carcinogenicity, cardiotoxicity, developmental toxicity, hepatotoxicity, nephrotoxicity, neurotoxicity, reproductive toxicity, and skin toxicity). Integrated analysis of in vitro assay data, molecular targets and pathway annotations from the literature, and toxicity-molecular target associations derived from text mining, combined with machine learning techniques, were used to generate molecular targets for each of the organ level toxicity end points. A total of 1516 toxicity-related genes were identified and subsequently analyzed for biological pathway coverage, resulting in 206 significant pathways (p-value <0.05), ranging from 3 (e.g., developmental toxicity) to 101 (e.g., skin toxicity) for each toxicity end point. This study presents a systematic and comprehensive analysis of molecular targets and pathways related to various in vivo toxicity end points. These molecular targets and pathways could aid in understanding the biological mechanisms of toxicity and serve as a guide for the design of suitable in vitro assays for more efficient toxicity testing. In addition, these results are complementary to the existing adverse outcome pathway (AOP) framework and can be used to aid in the development of novel AOPs. Our results provide abundant testable hypotheses for further experimental validation.