Abstract 3123: Air pollution and DNA methylation in tumor suppressor genes
Authors: Zhang Xiao , Baccarelli Andrea , Tarantini Letizia , Nordio Francesco , Bonzini Matteo , Angelici Laura , Marinelli Barbara , Rizzo Giovanna , Cantone Laura , Apostoli Pietro , Bertazzi Pier Alberto , Hou Lifang 
Published: August 2012

Ambient and occupational exposure to particular matter (PM) has been associated with increased risk of lung cancer. Although the carcinogenic potential of several toxic metals in PM was well-recognized, the molecular mechanisms underlying their association with lung cancer risk remain poorly understood. Aberrant tumor suppressor gene promoter methylation has emerged as one of the most important epigenetic mechanisms in the development of human cancers, including lung cancer. However, whether exposure to PM is associated with peripheral blood leukocyte (PBL) DNA methylation in tumor suppressor genes has not been examined. Foundry workers, even in modern foundry facilities, are still exposed to substantially higher levels of airborne PM compared to those found outdoors, and have been associated with increased risk of lung cancer. In the present study of 63 foundry 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). Air pollution measures included concentrations of airborne PM with aerodynamic diameters&lt;10 μm (PM10), &lt;1 μm (PM1), and individual metal particle components in PM10. Blood samples were obtained on the 1st (baseline) and 4th day (post-exposure) of the same work week. 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 (from 4.65 %5mC to 4.89 %5mC, p-value=0.005 for APC; from 2.20 %5mC to 2.34 %5mC, 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 (from 6.36 %5mC to 6.16 %5mC, p-value=0.015 for p53; from 8.17 %5mC to 7.08 %5mC, p-value&lt;0.001 for RASSF1A). In post-exposure samples, APC methylation was positively associated with PM10 (α=0.27, 95% CI: 0.13-0.40) and PM1 (α=0.23, 95% CI: 0.09-0.38). The mean methylation level of p16 or RASSF1A promoter region showed positive (α=0.19, 95% CI: 0.02-0.37) or negative (α=−0.21, 95% CI: −0.37–0.05) association with the level of zinc exposure. We observed hypermethylation of p16 and APC, and hypomethylation of RASSF1A and p53 in a group of healthy foundry workers. Our results suggest that methylation alterations in tumor suppressor genes may be involved in PM-induced lung carcinogenesis. Further studies in larger populations with lung cancer outcomes are required before any firm conclusion can be reached on whether PM exposed individuals with such DNA methylation alterations are at higher risk for lung cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3123. doi:1538-7445.AM2012-3123