Objective To investigate the association of mixed exposure to polycyclic aromatic hydrocarbons (PAHs) and metals with the changes in DNA methylation markers.

Methods Across-sectional design was performed to conduct a marker study among 768 subjects. Urinary 1-hydroxypyrene (1-OHP) levels were detected by UPLC-MS to evaluate the internal exposure level of PAHs, and urinary metal concentrations were detected by ICP-MS. Enzyme linked immunosorbent assay(ELISA) was used for the quantification of global DNA methylation (%5mC) of leucocyte, and real-time fluorescence quantitative PCR was used to measure the expression changes of DNA methylation transferases (DNMTs). The association of metals with %5mC and DNMTs was explored through the multiple linear regression analysis model and the mediation analysis model. Furthermore, the relationship between mixed exposure and %5mC was explored by the quantile g-computation regression model and the Bayesian kernel machine regression(BKMR) model.

Results The linear regression analysis showed that the level of %5mC was reduced by 6.79% and 2.95% with each IQR increase in urinary 1-OHP and urinary nickel (1.06 μmol/mol creatinine, 27.75 μmol/mol creatinine), respectively. The expression level of DNMT1 was increased by 11.04% with each IQR increase in urinary nickel (27.75 μmol/mol creatinine). The expression levels of DNMT3B were reduced by 22.48%, 19.64%, and 24.59% with each IQR increase in urinary 1-OHP, urinary manganese, and urinary iron (1.06 μmol/mol creatinine, 32.04 μmol/mol creatinine, 2 402.76 μmol/mol creatinine), respectively. The mixed exposure model showed that mixed exposure to PAHs and metals could lead to decreased expression levels in global DNA methylation (%5mC) and DNMT3B, and PAHs was the main component associated with the change of global DNA methylation (%5mC). The mediating effect analysis showed that DNMT1 expression had a smediating role in the relationship between nickel exposure and global DNA methylation (%5mC).

Conclusion Mixed exposure to PAHs and metals may lead to genomic DNA hypomethylation, and the metal nickel may affect the level of global DNA methylation (%5mC) by affecting DNMT1 expression.