Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC)

Abstract

Maternal smoking during pregnancy has been found to influence newborn DNA methylation in genes involved in fundamental developmental processes. It is pertinent to understand the degree to which the offspring methylome is sensitive to the intensity and duration of prenatal smoking. An investigation of the persistence of offspring methylation associated with maternal smoking and the relative roles of the intrauterine and postnatal environment is also warranted. In the Avon Longitudinal Study of Parents and Children, we investigated associations between prenatal exposure to maternal smoking and offspring DNA methylation at multiple time points in approximately 800 mother–offspring pairs. In cord blood, methylation at 15 CpG sites in seven gene regions (AHRR, MYO1G, GFI1, CYP1A1, CNTNAP2, KLF13 and ATP9A) was associated with maternal smoking, and a dose-dependent response was observed in relation to smoking duration and intensity. Longitudinal analysis of blood DNA methylation in serial samples at birth, age 7 and 17 years demonstrated that some CpG sites showed reversibility of methylation (GFI1, KLF13 and ATP9A), whereas others showed persistently perturbed patterns (AHRR, MYO1G, CYP1A1 and CNTNAP2). Of those showing persistence, we explored the effect of postnatal smoke exposure and found that the major contribution to altered methylation was attributed to a critical window of in utero exposure. A comparison of paternal and maternal smoking and offspring methylation showed consistently stronger maternal associations, providing further evidence for causal intrauterine mechanisms. These findings emphasize the sensitivity of the methylome to maternal smoking during early development and the long-term impact of such exposure.

Offspring DNA methylation of the aryl-hydrocarbon receptor repressor gene is associated with maternal BMI, gestational age, and birth weight

“…13 Others have demonstrated that these same methylation sites differed in the offspring of women who smoked during pregnancy, compared to offspring of non-smokers. 12,28 Prior studies demonstrating associations between smoking and AHRR DNA methylation used epigenome-wide methylation assays designed to discover previously unknown associations. 12,13 Given the results of these prior studies demonstrating that AHRR DNA methylation is modifiable during pregnancy, 12 we chose AHRR as a candidate gene to conduct a hypothesis-driven study of perinatal predictors of AHRR DNA methylation in cord blood.…”

The dynamics of smoking-related disturbed methylation: a two time-point study of methylation change in smokers, non-smokers and former smokers

“…We use models adapted from Richmond et al [17]. For each CpG site, we used a linear mixed model with random intercept of individual and the following structure for individual i at time point j (j = 1 at baseline, j = 2 at follow-up) to model the methylation:…”

“…These studies are an important next step in the understanding of the mechanisms of methylation [14]. To our knowledge, there have been only three reports investigating smoking and methylation with repeated measures: two candidate locus studies, one focusing on a small group of young women [15] and another on a small group of individuals attempting to quit smoking [16]; and a family-based study focused on maternal smoking [17]. Studies which cover larger sample sizes and different life stages are needed to better understand the effect of smoking on methylation.…”

Childhood Environmental Tobacco Smoke Exposure

“…Recent evidence from the Avon Longitudinal Study of Parents and Children has demonstrated that prenatal maternal smoking affects epigenetic changes in DNA methylation in the offspring, with persistence of the DNA methylation changes into adolescence. 24 Although research in this area is in the early stages, the long-term impact of parental smoking on the offspring epigenome may underlie part of the atherogenic process.…”