title: Associations between DNA methylation in DNA damage response-related genes and cytokinesis-block micronucleus cytome index in diesel engine exhaust-exposed workers.
abstract: Recently, diesel engine exhaust (DEE) was reclassified as a known carcinogen to humans. DNA methylation alterations in DNA damage response (DDR)-related genes have the potential to affect DEE exposure-related cancer risk. However, the evidence regarding the association between DEE exposure and methylation alterations in DDR-related genes is limited. In 117 DEE-exposed workers and 112 non-DEE-exposed workers, we measured urinary concentrations of six mono-hydroxylated polycyclic aromatic hydrocarbons (OH-PAHs). We also determined the methylation levels of three DDR-related genes (p16, RASSF1A, and MGMT) and LINE-1 by bisulfite-pyrosequencing assay. We found that DEE-exposed workers exhibited significantly lower mean promoter methylation levels of p16, RASSF1A, and MGMT than non-DEE-exposed workers (all p < 0.001). In all study subjects and non-smoking workers, increasing quartiles of urinary summed OH-PAHs was associated with hypomethylation of p16, RASSF1A, and MGMT (all p < 0.05). In non-smoking workers, methylation in p16, RASSF1A, and MGMT decreased by 0.36 % [95 % confidential interval (CI): -0.60, -0.11 %], 0.46 % (95 % CI: -0.79, -0.14 %), and 0.55 % (95 % CI: -0.95, -0.15 %), respectively, in association with highest versus lowest quartile of urinary summed OH-PAHs. In addition, p16, RASSF1A, MGMT, and LINE-1 methylation levels showed negative correlations with cytokinesis-block micronucleus cytome index which was previously measured in the same workers (all p < 0.05). In conclusion, our results clearly indicated that DEE exposure and increased genetic damage were associated with hypomethylation of p16, RASSF1A, and MGMT. Future studies with larger sample size are needed to confirm these associations.
authors.affiliation: Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nanwei Rd, Beijing, 100050, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, 74 Zhongshan Rd 2, Guangzhou, 510080, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, 74 Zhongshan Rd 2, Guangzhou, 510080, China.
authors.forename: Zhini
authors.initials: Z
authors.lastname: He
authors.affiliation: Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nanwei Rd, Beijing, 100050, China.
authors.forename: Huawei
authors.initials: H
authors.lastname: Duan
authors.affiliation: Department of Environmental Toxicology, The Institute of Environmental and Human Health, Texas Tech University, 1207 Gilbert Drive, Lubbock, TX, 79416, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Gao
authors.affiliation: Luoyang Center for Disease Control and Prevention, 9 Zhenghe Rd, Luoyang, 471000, China.
authors.forename: Haisheng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Henan Institute of Occupational Medicine, Kangfuxi Street, Zhengzhou, 450052, China.
authors.forename: Shanfa
authors.initials: S
authors.lastname: Yu
authors.affiliation: Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, 74 Zhongshan Rd 2, Guangzhou, 510080, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.affiliation: Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nanwei Rd, Beijing, 100050, China. zhengyx@chinacdc.cn.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D002681:China; D015331:Cohort Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D048749:Cytokinesis / Q000187:drug effects* / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D006801:Humans; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D015162:Micronucleus Tests; D016273:Occupational Exposure / Q000009:adverse effects* / Q000032:analysis; D011084:Polycyclic Aromatic Hydrocarbons / Q000652:urine; D025521:Tumor Suppressor Proteins / Q000235:genetics; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D011084:Polycyclic Aromatic Hydrocarbons; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D001335:Vehicle Emissions; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes
keywords: DNA damage response-related genes; DNA methylation; Diesel engine exhaust; Hypomethylation