Abstract B22: Altered methylation profiles of imprinted genes in response to prenatal exposure to cigarette smoke in the Newborn Epigenetic STudy (NEST) cohort

Background: Early life environmental exposures have adverse consequences on health and development but the mechanisms underlying these effects are unclear. Epigenetic deregulation resulting from cigarette smoke exposure may contribute, and imprinted genes may be particularly vulnerable since imprinting is established and maintained in large part through DNA methylation. We hypothesize that epigenetic alterations in response to conditions encountered in utero partially explains the origins of adult disease. To better understand these mechanisms we analyzed data from the N ewborn E pigenetics ST udy ( NEST )-a cohort study with the overarching goal of identifying epigenetic marks that may be perturbed by environmental exposures in early life to influence children9s health. NEST has already shown that epigenetic alterations are associated with environmental exposures and are often sex-specific and exacerbated in African Americans. Objective: We sought to determine if in utero exposure to cigarette smoking alters DNA methylation profiles at the differentially methylated region (DMRs) of seven imprinted regulatory regions: MEG3, MEG3-IG, MEST, NNAT, PLAGL1/ZAC, and SGCE/PEG 1. Methods: The NEST cohort participants were born between 2005-2008 at obstetrics care facilities in Durham County, North Carolina. We analyzed a sub-set of our cohort, 561 pregnant women, for which we had DNA methylation data and smoking status through self-report and medical records. Bisulfite pyrosequencing was used to measure methylation in umbilical cord blood DNAs. DNA methylation means at each DMR were compared between children of mothers who smoked throughout pregnancy (Smoker), never smoked (Never), or quit smoking following knowledge of pregnancy (Quitter) using generalized linear models. Results: We did not find any significant differences in methylation at the MEG3-IG, MEST, PLAGL1/ZAC, or PEG3 DMRs among all infants born to smokers, quitters, or never smokers. Stratification by gender revealed that girls born to mothers classified as quitters had a 2.3% (p=0.009) increase in methylation at the MEG3 DMR and girls of smokers had a 1.9% (p=0.06) increase in methylation at this DMR compared to girls born to never smoking mothers. For the NNAT DMR we saw significantly increased methylation for girls born to smokers compared to never smoker (2.3%) and quitters (2.5%) p= 0.02). Lastly we found a decrease in mean methylation at the PEG3 DMR in girls born to quitters as compared to girls of never smokers (35.8% vs. 36.7% p=0.06). Girls of smokers had a mean methylation of 36.1% at the PEG3 DMR. Conclusions: Prenatal cigarette smoke exposure was associated with sex-specific aberrant methylation at MEG3, NNAT, PEG3 DMRs only for girls born to mothers who smoked throughout pregnancy or quit during prenatal period compared to mothers who never smoked. These findings support our hypothesis that in utero environmental exposures result in epigenetic alterations that may be the origins of adult disease including cancer. Citation Format: Monica D. Nye, Cathrine Hoyo, Frances Wang, Amy P. Murtha, Joellen M. Schildkraut, Joanne Kurtzberg, Randy L. Jirtle, Zhiqing Huang, Susan K. Murphy. Altered methylation profiles of imprinted genes in response to prenatal exposure to cigarette smoke in the Newborn Epigenetic STudy (NEST) cohort. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B22. doi:10.1158/1538-7755.DISP13-B22