Landscape of environmental pollutant-driven alterations of nucleic acid modifications in hepatoma cells

Growing evidence shows that environmental pollutants pose widespread risks to human health. These pollutants have been detected in multiple human organs, raising concerns about their potential toxic effects. Beyond conventional toxicity pathways, many pollutants disrupt biological systems by perturbing epigenetic machinery. Nucleic acid modifications play crucial roles in gene regulation, and exploring the landscape of environmental pollutant-driven alterations in nucleic acid modifications can yield new insights into their toxicology and health impacts. In this study, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify two DNA modifications (5mC and 5hmC) and fifteen RNA modifications. We then systematically evaluated changes of these modifications after exposure to eighteen pollutants spanning five categories: bisphenols (BPs), per- and polyfluoroalkyl substances (PFASs), phthalate esters (PAEs), heavy metals (metals), and organophosphate esters (OPEs). The results demonstrate that pollutant exposure significantly remodels the nucleic acid modification landscape, with pollutant- and dose-specific patterns. Notably, correlation-network analyses reveal that environmental pollutant exposure reshapes the interactions between DNA and RNA modifications, suggesting that crosstalk between these epigenetic marks represents a novel mechanism underlying the epigenetic toxicity of environmental pollutants. These findings underscore the necessity of evaluating both DNA and RNA epigenetic marks to fully understand the toxicology of environmental pollutants from a nucleic acid epigenetics perspective. Collectively, these data support that environmental pollutants selectively perturb DNA and RNA epigenetic marks, offering potential signatures for exposure assessment.