Histone modifications in benzo[a]pyrene carcinogenicity and toxicity: mechanisms, implications, and prospects

Benzo[a]pyrene (B[a]P), a widespread environmental carcinogen, exerts multifaceted toxicity beyond direct DNA damage. Recent studies highlight the profound capacity of B[a]P to disrupt epigenetic landscapes, particular histone modifications, across diverse biological systems. This review synthesizes both in vitro and in vivo experimental findings to elucidate the mechanisms and consequences of B[a]P-induced histone modifications. In vitro studies demonstrate that B[a]P and its ultimate metabolite, BPDE, significantly alter key histone marks, including phosphorylation (γH2AX), acetylation (H3K9/14/18/27ac, H4K5/12/16ac), methylation (H3K4/9/27/36/79 me), lactylation (H4K12la), and ubiquitination (uH2A), in epithelial and connective cells. These changes are driven through multiple interconnected pathways: (1) Direct interference, where BPDE-dG adducts physically widen the DNA minor groove, entrapping histone tails and sterically blocking modifying enzymes; (2) Regulation of epigenetic enzymes, via modulating the expression/activity of HDACs, HATs, HMTs, and ubiquitin ligases; and (3) Oxidative stress and receptor signaling, primarily through AhR activation and ROS generation, altering metabolite pools and downstream kinase cascades. In vivo evidence from animal models and occupational human exposure confirms these alterations, linking specific histone code disruptions (e.g. decreased H3K36me3, H3K79me2; increased H3K9me2) to functional outcomes such as genomic instability, impaired DNA repair, aberrant gene expression, stemness promotion, and ultimately carcinogenicity in lung, liver, and reproductive tissues. Notably, B[a]P toxicity exhibits tissue, cell-type, and species specificity, and can be transgenerational. Emerging as potential biomarkers and therapeutic targets, these B[a]P-driven epigenetic alterations represent a critical, non-mutational axis of its toxicity. This mechanistic understanding bridges genetic and epigenetic carcinogenesis, offering novel insights for its risk assessment and intervention strategies.