Probing the Mechanism of Hepatotoxicity of Hexabromocyclododecanes through Toxicological Network Analysis

Abstract

The prediction and mechanism analysis of hepatotoxicity of contaminants, because of their various phenotypes and complex mechanisms, is still a key problem in environmental research. We applied a toxicological network analysis method to predict the hepatotoxicity of three hexabromocyclododecane (HBCD) diastereoisomers (alpha-HBCD, beta-HBCD, and gamma-HBCD) and explore their potential mechanisms. First, we collected the hepatotoxicity related genes and found that those genes were significantly localized in the human interactome. Therefore, these genes form a disease module of hepatotoxicity. We also collected targets of alpha-, beta-, and gamma-HBCD and found that their targets overlap with the hepatotoxicity disease module. Then, we trained a model to predict hepatotoxicity of three HBCD diastereoisomers based on the relationship between the hepatotoxicity disease module and targets of compounds. We found that 593 genes were significantly located in the hepatotoxicity disease module (Z = 11.9, p < 0.001) involved in oxidative stress, cellular immunity, and proliferation, and the accuracy of hepatotoxicity prediction of HBCD was 0.7095 +/- 0.0193 and the recall score was 0.8355 +/- 0.0352. HBCD mainly affects the core disease module genes to mediate the adenosine monophosphate-activated kinase, p38MAPK, PI3K/Akt, and TNF alpha pathways to regulate the immune reaction and inflammation. HBCD also induces the secretion of IL6 and STAT3 to lead hepatotoxicity by regulating NR3C1. This approach is transferable to other toxicity research studies of environmental pollutants.