Associations between environmental metal mixture exposure and urinary DNA adduct biomarkers of oxidative and alkylative damage in adults

초록

Environmental exposure to heavy metals commonly occurs as complex mixtures, yet their combined effects on early molecular markers of DNA damage remain insufficiently understood. This study, using advanced mixture modeling approaches, investigated associations between urinary metal exposure and multiple urinary DNA adducts reflecting oxidative and alkylative DNA damage. We conducted a cross-sectional analysis of 1153 community-dwelling adults participating in the Forensic Research via Omics Markers study in Korea. Urinary concentrations of seven metals (mercury, cadmium, lead, chromium, manganese, nickel, and arsenic) were measured, and six urinary DNA adducts (N3-methyladenine, N6-methyl-2 '-deoxyadenosine, O6-methylguanine, N7-methylguanine, 8-hydroxy-2 '-deoxyguanosine, and 8-hydroxyguanosine) were simultaneously quantified using a validated liquid chromatography-tandem mass spectrometry method. Associations were assessed using multivariable linear regression, quantile g-computation, and Bayesian kernel machine regression (BKMR), adjusting for demographic, lifestyle, and health-related covariates. In single-metal models, higher urinary nickel and chromium concentrations were significantly associated with increased levels of N3-methyladenine (nickel: beta = 0.203, 95% confidence interval [CI]: 0.120-0.295; chromium: beta = 0.183, 95% CI: 0.100-0.267). Mixture analyses revealed significant positive overall effects of metal co-exposure on most DNA adducts, strongest with O6-methylguanine (psi = 0.446, 95% CI: 0.234-0.658) per one-quartile joint increase in all metals. BKMR results supported these findings and identified nickel, chromium, lead, and arsenic as key contributors to alkylationrelated DNA damage. These results suggest that both individual metals and their combined exposure contribute to early DNA damage, highlighting urinary DNA adducts as sensitive biomarkers for assessing health risks associated with environmental metal mixture exposure.

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