Abstract
Sufficient epidemiologic evidence shows an etiologic link between polycyclic aromatic hydrocarbons (PAH) exposure and lung cancer risk. While the genetic modifications have been found in PAH-exposed population, it is unclear whether gene-specific methylation involves in the process of PAH-associated biologic consequence. Sixty-nine PAH-exposed workers and 59 control subjects were recruited. Using bisulfite sequencing, we examined the methylation status of p16(INK4α) promoter in peripheral blood lymphocytes (PBL) from PAH-exposed workers and in benzo(a)pyrene (BaP)-transformed human bronchial epithelial (HBE) cells. The relationships between p16(INK4α) methylation and the level of urinary 1-hydroxypyrene (1-OHP) or the frequency of cytokinesis block micronucleus (CBMN) were analyzed. Compared with the control group, PAH-exposed workers exhibited higher levels of urinary 1-OHP (10.62 vs. 2.52 μg/L), p16(INK4α) methylation (7.95% vs. 1.14% for 22 "hot" CpG sites), and CBMN (7.28% vs. 2.92%) in PBLs. p16(INK4α) hypermethylation in PAH-exposed workers exhibited CpG site specificity. Among the 35 CpG sites we analyzed, 22 were significantly hypermethylated. These 22 hypermethylated CpG sites were positively correlated to levels of urinary 1-OHP and CBMN in PBLs. Moreover, the hypermethylation and suppression of p16 expression was also found in BaP-transformed HBER cells. PAH exposure induced CpG site-specific hypermethylation of p16(INK4α) gene. The degree of p16(INK4α) methylation was associated with the levels of DNA damage and internal exposure. p16(INK4α) hypermethylation might be an essential biomarker for the exposure to PAHs and for early diagnosis of cancer.
Highlights
Cancer development involves the accumulation of multiple genetic mutations over time and epigenetic altera-Authors' Affiliations: 1Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou; 2Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing; and 3Department of Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, ChinaNote: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online.P
We found that occupational exposure to polycyclic aromatic hydrocarbons (PAH) induced higher frequency of micronucleus in peripheral blood lymphocytes (PBL; ref. 25) and resulted in defect in DNA repair capacity [26]
Epigenetic aberration is increasingly considered to play an important role in cellular response to environmental chemicals and induction of biologic consequences [36, 37]
Summary
While the genetic modifications have been found in PAH-exposed population, it is unclear whether gene-specific methylation involves in the process of PAH-. Methods: Sixty-nine PAH-exposed workers and 59 control subjects were recruited. We examined the methylation status of p16INK4a promoter in peripheral blood lymphocytes (PBL) from PAH-exposed workers and in benzo(a)pyrene (BaP)-transformed human bronchial epithelial (HBE) cells. The relationships between p16INK4a methylation and the level of urinary 1-hydroxypyrene (1-OHP) or the frequency of cytokinesis block micronucleus (CBMN) were analyzed. Results: Compared with the control group, PAH-exposed workers exhibited higher levels of urinary 1-OHP (10.62 vs 2.52 mg/L), p16INK4a methylation (7.95% vs 1.14% for 22 "hot" CpG sites), and CBMN (7.28% vs 2.92%) in PBLs. p16INK4a hypermethylation in PAH-exposed workers exhibited CpG site specificity.
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