Prenatal Exposure to Maternal Cigarette Smoking and DNA Methylation: Epigenome-Wide Association in a Discovery Sample of Adolescents and Replication in an Independent Cohort at Birth through 17 Years of Age

Abstract

Background: Prenatal exposure to maternal cigarette smoking (prenatal smoke exposure) had been associated with altered DNA methylation (DNAm) at birth.Objective: We examined whether such alterations are present from birth through adolescence.Methods: We used the Infinium HumanMethylation450K BeadChip to search across 473,395 CpGs for differential DNAm associated with prenatal smoke exposure during adolescence in a discovery cohort (n = 132) and at birth, during childhood, and during adolescence in a replication cohort (n = 447).Results: In the discovery cohort, we found five CpGs in MYO1G (top-ranking CpG: cg12803068, p = 3.3 × 10–11) and CNTNAP2 (cg25949550, p = 4.0 × 10–9) to be differentially methylated between exposed and nonexposed individuals during adolescence. The CpGs in MYO1G and CNTNAP2 were associated, respectively, with higher and lower DNAm in exposed versus nonexposed adolescents. The same CpGs were differentially methylated at birth, during childhood, and during adolescence in the replication cohort. In both cohorts and at all developmental time points, the differential DNAm was in the same direction and of a similar magnitude, and was not altered appreciably by adjustment for current smoking by the participants or their parents. In addition, four of the five EWAS (epigenome-wide association study)–significant CpGs in the adolescent discovery cohort were also among the top sites of differential methylation in a previous birth cohort, and differential methylation of CpGs in CYP1A1, AHRR, and GFI1 observed in that study was also evident in our discovery cohort.Conclusions: Our findings suggest that modifications of DNAm associated with prenatal maternal smoking may persist in exposed offspring for many years—at least until adolescence.Citation: Lee KW, Richmond R, Hu P, French L, Shin J, Bourdon C, Reischl E, Waldenberger M, Zeilinger S, Gaunt T, McArdle W, Ring S, Woodward G, Bouchard L, Gaudet D, Davey Smith G, Relton C, Paus T, Pausova Z. 2015. Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. Environ Health Perspect 123:193–199; http://dx.doi.org/10.1289/ehp.1408614

DNA methylation and healthy human aging

“…This balance of responsiveness to stimuli and heritability results in a unique mechanism for lasting signatures of prior exposures that accumulate over the lifetime (Cortessis et al ., 2012; Feil & Fraga, 2012). As an example of a specific exposure that has been shown to leave a lasting signature, cigarette smoke has been linked to changes in DNA methylation at the AHRR locus both in smokers and in children of smokers (Saxonov et al ., 2006; Monick et al ., 2012; Joubert et al ., 2012; Shenker et al ., 2013; Sun et al ., 2013 Elliott et al ., 2014; Lee et al ., 2015; Shah et al ., 2014). Smoking‐associated DNA methylation changes have also been found in genes involved in inflammatory networks, important candidates in the risk of age‐related diseases such as heart disease and stroke (Breitling et al ., 2012; Dogan et al ., 2014).…”

Epigenome-Wide Association Study of Wellbeing

“…Methylation changes can be caused by external conditions, such as long-term stress exposure (Klengel et al, 2014;Romens et al, 2015), (prenatal, maternal) smoking exposure (Allione et al, 2015;Lee et al, 2015) and dietary modifications at conception (Dominguez-salas et al, 2014). There are no epigenetic studies of the association between DNA methylation and WB, but some epigenetic studies have been performed involving complex traits related to WB.…”

Chromosome aberrations frequency in peripheral blood lymphocytes in young tobacco smoking and non-smoking people

“…Several recent studies identified smoking-related DNA methylation sites (26,27) that can cause chromosome brakes and change gene expression levels. They represent an important molecular mechanism underlying development of smoking-related disease.…”