Cellular Response to Halobenzoquinone Disinfection Byproducts Mediated by Aryl Hydrocarbon Receptor: Integrated Metabolomic and Transcriptomic Analysis

Halobenzoquinones (HBQs) are a class of emerging disinfection byproducts (DBPs) linked to potential cancer risks. In this study, we explored the cellular mechanism of HBQ toxicity and carcinogenicity from the perspectives of metabolomic and transcriptomic responses in human hepatoma (HepG2) cells. HBQs triggered xenobiotics biodegradation and metabolism and subsequently dysregulated amino acid metabolism and nucleotide metabolism. The RAS signaling pathway and PI3K-AKT signaling pathway, which were highly related to pathways of cancer, were significantly impacted. The enrichment of these pathways coincidently suggested the activation of the aryl hydrocarbon receptor (AhR) as a pivotal molecular initiating event (MIE), supported by the high binding affinities of HBQs to AhR observed in both molecular docking and fluorescence spectroscopy experiments. Six metabolites among these disturbed pathways including oxidized glutathione (GSSG), uridine diphosphate glucuronic acid (UDP-GlcUA), threonine, phenylalanine, deoxyuridine, and adenosine triphosphate (ATP) were linearly correlated to cell viability. These metabolites might serve as candidates for further evaluation as biomarkers for HBQ exposure. Nucleophilic reactivity and the numbers of methyl groups of HBQs were pinpointed to be key molecular descriptors determining cellular metabolic interference. The results of this study offered promising insight into the potential carcinogenic mechanism of HBQs with the assistance of cellular metabolomics and transcriptomics.