Peluso, Marco E M Munnia, Armelle Bollati, Valentina Srivatanakul, Petcharin Jedpiyawongse, Adisorn Sangrajrang, Suleeporn Ceppi, Marcello Giese, Roger W Boffetta, Paolo Baccarelli, Andrea A eng P30ES000002/ES/NIEHS NIH HHS/ P42ES017198/ES/NIEHS NIH HHS/ R01 ES021733/ES/NIEHS NIH HHS/ R01ES021733/ES/NIEHS NIH HHS/ R21ES020010/ES/NIEHS NIH HHS/ R21ES021895/ES/NIEHS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2013/10/25 06:00 Toxicol Sci. 2014 Jan;137(1):47-54. doi: 10.1093/toxsci/kft241. Epub 2013 Oct 23. ; International audience ; Tobacco smoke has been shown to produce both DNA damage and epigenetic alterations. However, the potential role of DNA damage in generating epigenetic changes is largely underinvestigated in human studies. We examined the effects of smoking on the levels of DNA methylation in genes for tumor protein p53, cyclin-dependent kinase inhibitor2A, hypermethylated-in-cancer-1 (HIC1), interleukin-6, Long Interspersed Nuclear Element type1, and Alu retrotransposons in blood of 177 residents in Thailand using bisulfite-PCR andpyrosequencing. Then, we analyzed the relationship of this methylation with the oxidative DNA adduct, M(1)dG (a malondialdehyde adduct), measured by (3)(2)P-postlabeling. Multivariate statistical analyses showed that HIC1 methylation levels were significantly increased in smokers compared with nonsmokers (p = .05). A dose response was observed, with the highest HIC1 methylation levels in smokers of >/= 10 cigarettes/day relative to nonsmokers and intermediate values in smokers of 1-9 cigarettes/day (p for trend = .001). No additional relationships were observed. We also evaluated correlations between M(1)dG and the methylation changes at each HIC1 CpG site individually. The levels of this adduct in smokers showed a significant linear correlation with methylation at one of the 3 CpGs evaluated in HIC1: hypermethylation at position 1904864340 was significantly correlated with the adduct M(1)dG (covariate-adjusted regression coefficient (beta) = .224 +/- .101 [SE], p = .05). No other correlations were detected. Our study extends prior work by others associating hypermethylation of HIC1 with smoking; shows that a very specific hypermethylation event can arise from smoking; and encourages future studies that explore a possible role for M(1)dG in connecting smoking to this latter hypermethylation.