DNA methylation signature of oxidative stress and its mediating role in response to metal exposure

Metal exposure could induce oxidative stress, yet the underlying epigenetic mechanisms remain unclear. Herein, we aimed to investigate the DNA methylation signatures associated with oxidative stress biomarkers, including 8-hydroxyguanine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α), and evaluate their mediating role in metal-induced oxidative stress. A genome-wide DNA methylation association study was conducted in discovery panel (Shiyan, N = 155) with validation in an independent replication panel (Wuhan-Zhuhai, N = 50). We identified 24 differentially methylated positions (DMPs) associated with 8-OHdG (P < 1 × 10⁻⁵), 17 of which were replicated (P < 0.05), along with one validated DMP associated with 8-iso-PGF2α. Two-sample Mendelian randomization analyses supported the causal role of cg15457217 (WDFY1) for 8-OHdG and cg16689883 (LOC284930) for 8-iso-PGF2α. Among the 18 replicated DMPs, five were significantly associated with the expression levels of their annotated genes (KIDINS220, SBF2, DENND1A, PIWIL4, KAT6B). Urinary levels of individual metals (e.g., arsenic, cadmium, molybdenum, strontium) and metal mixtures (assessed by weighted quantile sum regression) were positively associated with both oxidative stress biomarkers. Mediation analyses revealed that 14 replicated DMPs mediated 12.54–33.44 % of the associations for 8-OHdG and 12.60–13.83 % for 8-iso-PGF2α. Notably, cg06197624 (SMIM20) and cg09953898 (KIDINS220) exhibited a significant inverse association with 8-OHdG (FDR < 0.05) and mediated up to 33.44 % of the effect of metal exposure on oxidative DNA damage. These findings demonstrated the mediating role of DNA methylation in metal-induced oxidative stress, highlighting the epigenetic loci involved in redox-related biological responses. Further studies with larger sample sizes and longitudinal assessments are warranted to validate our findings.