Abstract
Exposure to ambient air particles matter (PM) has been associated with increased risk of lung cancer. Aberrant tumor suppressor gene promoter methylation has emerged as a promising biomarker for cancers, including lung cancer. Whether exposure to PM is associated with peripheral blood leukocyte (PBL) DNA methylation in tumor suppressor genes has not been evaluated. In 63 male healthy steel workers with well-characterized exposure to metal-rich particles nearby Brescia, Italy, we evaluated whether exposure to PM and metal components was associated with PBL DNA methylation in 4 tumor suppressor genes (i.e., APC, p16, p53 and RASSF1A). Blood samples were obtained on the 1st (baseline) and 4th day (post-exposure) of the same work week and DNA methylation was measured using pyrosequencing. A linear mixed model was used to examine the correlations of the exposure with promoter methylation levels. Mean promoter DNA methylation levels of APC or p16 were significantly higher in post-exposure samples compared to that in baseline samples (p-values = 0.005 for APC, and p-value = 0.006 for p16). By contrast, the mean levels of p53 or RASSF1A promoter methylation was decreased in post-exposure samples compared to that in baseline samples (p-value = 0.015 for p53; and p-value < 0.001 for RASSF1A). In post-exposure samples, APC methylation was positively associated with PM10 (β = 0.27, 95% CI: 0.13-0.40), and PM1 (β = 0.23, 95% CI: 0.09-0.38). In summary, ambient PM exposure was associated with PBL DNA methylation levels of tumor suppressor genes of APC, p16, p53 and RASSF1A, suggesting that such methylation alterations may reflect processes related to PM-induced lung carcinogenesis.
Highlights
Ambient and occupational exposure to particular matter (PM) has been associated with increased risk of lung cancer [1,2]
We have reported blood leukocyte global hypomethylation in subjects exposed to PM and metal components [10,11,12] and benzene [13]
In the present study, we showed that the mean methylation levels of promoter CpG sites were significantly associated with the exposure to PM and certain metal components
Summary
Ambient and occupational exposure to particular matter (PM) has been associated with increased risk of lung cancer [1,2]. Experimental and epidemiologic studies suggest that PM mass and metal components may induce critical carcinogenesisrelated biological changes, including oxidative stress, immune deficiency, and chronic inflammation, which have recently been shown to alter gene expression via DNA methylation mechanism [3]. Experimental evidence from in vitro studies has shown that DNA methylation states in specific genes may change rapidly in response to environmental stressors. Whether DNA methylation in tumor suppressor genes changes in response to short-term exposure to environmental chemicals is yet to be determined. Even transient DNA methylation changes may reflect condition of cellular stress associated with altered apoptosis, cell cycle control, and cell proliferation that may lead to the accumulation of persistent epigenetic and genetic damage after repeated exposures or in the presence of other pro-carcinogenic insults [18]
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