Abstract

<div>Abstract<p><b>Background:</b> 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.</p><p><b>Methods:</b> Sixty-nine PAH-exposed workers and 59 control subjects were recruited. Using bisulfite sequencing, we examined the methylation status of <i>p16<sup>INK4α</sup></i> promoter in peripheral blood lymphocytes (PBL) from PAH-exposed workers and in benzo(<i>a</i>)pyrene (BaP)-transformed human bronchial epithelial (HBE) cells. The relationships between <i>p16<sup>INK4α</sup></i> methylation and the level of urinary 1-hydroxypyrene (1-OHP) or the frequency of cytokinesis block micronucleus (CBMN) were analyzed.</p><p><b>Results:</b> Compared with the control group, PAH-exposed workers exhibited higher levels of urinary 1-OHP (10.62 vs. 2.52 μg/L), <i>p16<sup>INK4α</sup></i> methylation (7.95% vs. 1.14% for 22 “hot” CpG sites), and CBMN (7.28% vs. 2.92%) in PBLs. <i>p16<sup>INK4α</sup></i> 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.</p><p><b>Conclusion:</b> PAH exposure induced CpG site–specific hypermethylation of <i>p16<sup>INK4α</sup></i> gene. The degree of <i>p16<sup>INK4α</sup></i> methylation was associated with the levels of DNA damage and internal exposure.</p><p><b>Impact:</b><i>p16<sup>INK4α</sup></i> hypermethylation might be an essential biomarker for the exposure to PAHs and for early diagnosis of cancer. <i>Cancer Epidemiol Biomarkers Prev; 21(1); 182–90. ©2011 AACR</i>.</p></div>

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