Comparative toxicity analysis of benzo[a]pyrene and PAH4 on HepG2 cells using transcriptomics and metabolomics

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants posing potential health risks. PAH4 (sum of benzo[a]pyrene (BaP), chrysene, benz[a]anthracene and benzo[b]fluoranthene) has been proposed as a marker to evaluate the occurrence of total PAHs. However, toxicity effects of exposure to PAH4 mixture and its toxicity differences with single PAH are little-known. Here, we systematically investigated the hepatotoxicity mechanisms of PAH4 and compare its toxicity with BaP using HepG2 cell model. Our results showed that BaP and PAH4 exposure induced cytotoxicity and oxidative stress. Furthermore, both BaP and PAH4 activated P53 signaling pathway, leading to cell apoptosis, and disrupted peroxisome proliferator-activated receptor (PPAR) signaling and induced lipid metabolism disorder. Integrated analysis of transcriptomics and metabolomics indicated that BaP and PAH4 shared similar toxicity mechanisms, commonly affecting the metabolic pathways including glycerolipid and glycerophospholipid metabolism. Moreover, the integrated biomarker response (IBR) analysis demonstrated that BaP and PAH4 exhibited similar global toxicity on HepG2 cells. We further found that the toxicity effects of PAH4 could be partially alleviated by an aryl hydrocarbon receptor (AHR) antagonist, indicating a potential role of AHR signaling in PAH4-induced hepatotoxicity. Overall, these findings provided insights into the toxicological mechanisms and interaction effects of PAHs mixtures.