Impact of mixed exposure to PAHs and metals on DNA methylation and DNA methyltransferase

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.