title: Global and MGMT promoter hypomethylation independently associated with genomic instability of lymphocytes in subjects exposed to high-dose polycyclic aromatic hydrocarbon.
abstract: Global hypomethylation, gene-specific methylation, and genome instability are common events in tumorigenesis. To date, few studies have examined the aberrant DNA methylation patterns in coke oven workers, who are highly at risk of lung cancer by occupational exposure to polycyclic aromatic hydrocarbons (PAHs). We recruited 82 PAH-exposed workers and 62 unexposed controls, assessed exposure levels by urinary 1-hydroxypyrene, and measured genetic damages by comet assay, bleomycin sensitivity, and micronucleus assay. The PAHs in coke oven emissions (COE) were estimated based on toxic equivalency factors. We used bisulfite-PCR pyrosequencing to quantitate DNA methylation in long interspersed nuclear element-1 (LINE-1) and O(6)-methylguanine-DNA methyltransferase (MGMT). Further, the methylation alteration was also investigated in COE-treated human bronchial epithelial (16HBE) cells. We found there are higher levels of PAHs in COE. Among PAH-exposed workers, LINE-1 and MGMT methylation levels (with CpG site specificity) were significantly lowered. LINE-1, MGMT, and its hot CpG site-specific methylation were negatively correlated with urinary 1-hydroxypyrene levels (r = -0.329, p < 0.001; r = -0.164, p = 0.049 and r = -0.176, p = 0.034, respectively). In addition, LINE-1 methylation was inversely associated with comet tail moment and micronucleus frequency, and a significant increase of micronucleus in low MGMT methylation group. In vitro study revealed that treatment of COE in 16HBE cells resulted in higher production of BPDE-DNA adducts, LINE-1 hypomethylation, hypomethylation, and suppression of MGMT expression. These findings suggest hypomethylation of LINE-1 and MGMT promoter could be used as markers for PAHs exposure and merit further investigation.
authors.affiliation: Key Laboratory of Chemical Safety and Health, National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nanwei Road, Beijing, 100050, People's Republic of China.
authors.forename: Huawei
authors.initials: H
authors.lastname: Duan
authors.affiliation: Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Zhini
authors.initials: Z
authors.lastname: He
authors.affiliation: Key Laboratory of Chemical Safety and Health, National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nanwei Road, Beijing, 100050, People's Republic of China.
authors.forename: Junxiang
authors.initials: J
authors.lastname: Ma
authors.affiliation: Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, People's Republic of China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Sheng
authors.affiliation: Key Laboratory of Chemical Safety and Health, National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nanwei Road, Beijing, 100050, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Bin
authors.affiliation: Key Laboratory of Chemical Safety and Health, National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nanwei Road, Beijing, 100050, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Chemical Safety and Health, National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nanwei Road, Beijing, 100050, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Niu
authors.affiliation: Key Laboratory of Chemical Safety and Health, National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nanwei Road, Beijing, 100050, People's Republic of China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Dong
authors.affiliation: Institute of Industrial Health, Anshan Steel Industrial Corporation, Anshan, 114044, People's Republic of China.
authors.forename: Han
authors.initials: H
authors.lastname: Lin
authors.affiliation: Key Laboratory of Chemical Safety and Health, National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nanwei Road, Beijing, 100050, People's Republic of China.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, People's Republic of China.
authors.forename: Benzhan
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.affiliation: Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Chemical Safety and Health, National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nanwei Road, Beijing, 100050, People's Republic of China. yxzheng@163bj.com.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000328:Adult; D015415:Biomarkers; D015153:Blotting, Western; D002478:Cells, Cultured; D002681:China; D043171:Chromosomal Instability / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D019175:DNA Methylation; D042822:Genomic Instability / Q000187:drug effects*; D006801:Humans; D008214:Lymphocytes / Q000502:physiology*; D008297:Male; D008669:Metallurgy; D008745:Methylation; D009153:Mutagens / Q000633:toxicity; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D016273:Occupational Exposure; D011083:Polycyclic Compounds / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011721:Pyrenes / Q000652:urine; D013232:Steel; D013447:Sulfites / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D009153:Mutagens; D011083:Polycyclic Compounds; D011721:Pyrenes; D013447:Sulfites; D013232:Steel; D019853:O(6)-Methylguanine-DNA Methyltransferase; C033146:1-hydroxypyrene; C042345:hydrogen sulfite