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

By Lee, Ken W. K.; Richmond, Rebecca et al. | Environmental Health Perspectives, February 2015 | Go to article overview

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


Lee, Ken W. K., Richmond, Rebecca, Hu, Pingzhao, French, Leon, Shin, Jean, Bourdon, Celine, Reischl, Eva, Waldenberger, Melanie, Zeilinger, Sonja, Gaunt, Tom, McArdle, Wendy, Ring, Susan, Woodward, Geoff, Bouchard, Luigi, Gaudet, Daniel, Smith, George Davey, Relton, Caroline, Paus, Tomas, Pausova, Zdenka, Environmental Health Perspectives


Introduction

Maternal cigarette smoking during pregnancy was and still is common in the industrialized world. In the United States, for example, 30-40% of pregnant women smoked in the 1960s and 1970s, and 16% of pregnant women smoke today (Substance Abuse and Mental Health Services Administration 2012). Prenatal exposure to maternal cigarette smoking (prenatal smoke exposure) has been associated with a number of health problems in the exposed offspring (Oken et al. 2008; Power et al. 2010; Syme et al. 2010). The underlying mechanisms of these associations are not clear but may involve lasting modulations of DNA methylation (DNAm).

DNAm is a chemical modification constituted most commonly by the addition of a methyl group to cytosines in CpG dinucleotides (CpGs) (Relton and Davey Smith 2010). It is catalyzed by two main types of DNA methyltransferases (DNMTs): de novo DNMTs, which play a key role in establishing new DNAm patterns during cell differentiation and embryogenesis; and maintenance DNMTs, which are responsible for copying these patterns from cell to cell during successive mitotic divisions (Jeltsch 2006; Tang et al. 2009). The main function of DNAm is the regulation of gene expression and genomic architecture (Levin and Moran 2011; Tsukahara et al. 2009).

Current research suggests that cigarette smoke is a powerful environmental modifier of DNAm (reviewed by Lee and Pausova 2013). Cigarette smoke contains a large number of chemicals, such as carcinogens, nicotine, and carbon monoxide, that have been shown to modify DNAm in differentiating and dividing cells (Cuozzo et al. 2007; Di et al. 2012; Han et al. 2001; Huang et al. 2013; Mercer et al. 2009; Mortusewicz et al. 2005; Satta et al. 2008; Shahrzad et al. 2007). Consistent with these possible effects, reproducible differences in DNAm have been reported in peripheral blood cells of smokers versus nonsmokers (Breitling et al. 2011; Philibert et al. 2012; Shenker et al. 2013; Zeilinger et al. 2013).

Many chemicals contained in cigarette smoke can easily pass from a pregnant smoker to the developing embryo/fetus (Lambers and Clark 1996). Accordingly, differences in DNAm have been reported in cord blood cells of babies born to smoking versus nonsmoking mothers (Joubert et al. 2012). Whether these DNAm differences persist postnatally in peripheral blood cells of the exposed offspring has not been studied; this is the main subject of the present investigation. Prenatal exposure to cigarette smoke may induce lasting and soma-wide (present in all somatic cells) modifications of DNAm in the exposed offspring, particularly if occurring during early stages of embryogenesis when global erasure and reestablishment of DNAm patterns take place in yet-undifferentiated stem cells (Feng et al. 2010; Smith et al. 2012). These DNAm modifications are then propagated during embryonic development to all somatic cell lineages (including precursors of peripheral blood cells) and maintained throughout life by the action of maintenance DNMTs, which copy these modifications from cell to cell during successive cell divisions (Davies et al. 2012; Faulk and Dolinoy 2011; Jurkowska et al. 2011; Lee and Pausova 2013; Petronis 2010).

To investigate whether DNAm modifications induced by prenatal smoke exposure persist postnatally (at least until adolescence), we first conducted an epigenome-wide association study (EWAS) to search for CpGs methylated differentially between exposed and nonexposed adolescents in one cohort, the Saguenay Youth Study (SYS) (Pausova et al. 2007). Subsequently, we tested whether the identified CpGs were also methylated differentially between exposed and nonexposed newborns, children, and adolescents in another cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) (Boyd et al. 2013).

Methods

Discovery cohort: The Saguenay Youth Study (SYS). Recruitment and assessment of prenatal smoke exposure. …

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