Published ahead of print on June 4, 2009, doi:10.1164/rccm.200901-0135OC Am. J. Respir. Crit. Care Med., Volume 180, Number 5, September 2009, 462-467 A more recent version of this article appeared on September 1, 2009
Submitted on January 26, 2009 Prenatal Tobacco Smoke Exposure Affects Global and Gene-Specific DNA MethylationCarrie V Breton1,1 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States, 2 Department of Hematology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States, 3 Epigenome Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States, 4 Department of Hematology and the Epigenome Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States * To whom correspondence should be addressed. E-mail: gillilan{at}usc.edu.
Rationale: Prenatal exposure to tobacco smoke increases the risk for diseases later in the child's life that may be mediated through alterations in DNA methylation. Objective: To demonstrate that differences in DNA methylation patterns occur in children exposed to tobacco smoke and that variation in detoxification genes may alter these associations. Methods: Methylation of DNA repetitive elements, LINE1 and AluYb8, was measured using bisulfite conversion and Pyrosequencing in buccal cells of 348 children participating in the Children's Health Study (CHS). Gene-specific CpG methylation differences associated with smoke exposure were screened in 272 CHS children using an Illumina GoldenGate panel. CpG loci that demonstrated a statistically significant difference in methylation were validated by Pyrosequencing. Estimates were standardized across loci using a Z-score to enable cross-comparison of results. Results: DNA methylation patterns were associated with in utero exposure to maternal smoking. Exposed children had significantly lower methylation of AluYb8 (-0.31 SD, p=0.03). Differences in smoking-related effects on LINE1 methylation were observed in children with the common GSTM1 null genotype. Differential methylation of CpG loci in 8 genes was identified through the screen. Two genes, AXL and PTPRO, were validated by Pyrosequencing and showed significant increases in methylation of 0.37 SD (p=0.005) and 0.34 SD (p=0.02) in exposed children. The associations with maternal smoking varied by a common GSTP1 haplotype. Conclusions: Life-long effects of in utero exposures may be mediated through alterations in DNA methylation. Variants in detoxification genes may modulate the effects of in utero exposure through epigenetic mechanisms. Key words: DNA methylation • epigenetics • prenatal • smoke
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