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.

Air Pollution and Epigenetics: Recent Findings

“…1 Overview of mechanisms through which air pollutants may act on the epigenome and subsequent disease risk Agency for Research on Cancer (IARC) [21,22]. When metabolized, PAHs can form DNA adducts and induce global hypomethylation and hypermethylation of specific genes associated with increased risk of neural impairments, neoplasia, and carcinogenesis [18,20,23,24].…”

“…Such epigenetic alterations are increasingly recognized as potential important mediators of health effects in the context of environmental or occupational settings that have high levels of PAHs. Several occupational studies, including studies of coke oven workers and steel, oil refinery, and petrochemical complexes, have observed associations between high levels of PAH exposure and LINE-1 hypomethylation [21,22,27].…”

“…In a study of coke oven workers, PAH exposure was associated with hypomethylation in the promoters of O6-methylguanine-DNA methyltransferase (MGMT), p53, and interleukin-6 (IL-6) in workers of the largest steel, oil refinery, and petrochemical complex in southeastern Asia (Rayong, Thailand) [27]. These genes are involved in DNA repair, cell cycle arrest and cell death, and inflammation, respectively [21,22,27,28]. Glutathione S-transferase Mu 2 (GSTM2) is another important gene in detoxification of PAHs.…”

Polycyclic aromatic hydrocarbons are associated with insulin receptor substrate 2 methylation in adipose tissues of Korean women

“…Even though the causative mechanisms of PAH-related health effects on the molecular level are not yet completely understood, PAHs exposure induced hypo-and hypermethylation at multiple promoter regions, suggesting that epigenetic modulation of genes may be a key mechanism (AlegriaTorres et al, 2013;Duan et al, 2013;Hew et al, 2015;Pavanello et al, 2009;White et al, 2016;Yang et al, 2012). Therefore, in this study, we evaluated if concentrations of PAHs in visceral AT were related to the methylation status of 12 key genes involved in glucose and lipid metabolism by using methylation-specific PCR (MSP).…”

Polycyclic aromatic hydrocarbon (PAH)–DNA adducts and breast cancer: modification by gene promoter methylation in a population-based study

“…In contrast, increased methylation of tumor suppressor genes, typically indicative of the gene being ‘silenced,’ has been considered to be relevant to cancer incidence [13] and has been demonstrated to be associated with breast cancer clinical/pathological factors and mortality in this study population [14]. Previous research has found that exposure to PAH may be associated with changes in DNA methylation [15-17]. …”