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Exposure to persistent organic pollutants (POPs) has been associated with epigenetic changes such as DNA methylation, which can influence human health. However, the association between POPs and DNA methylation by sex was not shown in previous studies.We investigated the association between POPs and DNA methylation in men and women using a larger population.A cross-sectional study was conducted using the data of 444 Koreans (253 men and 191 women). Measurements for sixteen different POPs, including six organochlorine pesticides (OCPs) and ten polychlorinated biphenyls (PCBs) were taken in serum. DNA methylation via Alu and LINE-1 in peripheral leukocytes was measured by pyrosequencing. To evaluate the association between POPs and DNA methylation, the Pearson's correlation and multiple linear regression analyses were performed.Except for PCB52 and PCB101, we found significant inverse associations between p,p’-DDE, cis-Heptachlor epoxide, and PCBs and Alu assay in men after adjusting for age, BMI, smoking status, and alcohol consumption (β = −0.67 for p,p′-DDE; −0.28 for cis-Heptachlor epoxide; in the range from −0.43 to −1.60 for PCBs). In women, PCB153 and PCB180 showed statistically significant inverse association with Alu assay (β = −0.22 for PCB153; −0.22 for PCB180). Except for PCB101, p,p′-DDE and PCBs were positively associated with LINE-1 assay in women (β = 0.48 for p,p′-DDE; in the range from 0.40–0.89 for PCBs) while p,p′-DDE, PCB153, and PCB180 showed positive associations with LINE-1 assay in men (β = 0.55 for p,p′-DDE; 0.65 for PCB153; 1.02 for PCB180).We found that several POPs were associated with global DNA hypomethylation in the Alu assay for men and global DNA hypermethylation in the LINE-1 assay for women.Exposure to POPs has been associated with epigenetic changes such as DNA methylation.We investigated the association between POPs level and DNA methylation.Measurements for 6 OCPs and 10 PCBs were taken in serum.The sum of POPs level was associated to DNA hypomethylation in men.The sum of POPs level was associated to DNA hypermethylation in women.