Probing the Mechanism of Hepatotoxicity of Hexabromocyclododecanes through Toxicological Network Analysis

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
(α-HBCD, β-HBCD, and γ-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 α-, β-, and γ-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 TNFα 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.