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.
Highlights
Despite the known health risks to both mothers and newborns, maternal smoking during pregnancy remains a significant public health problem in high-income countries and recent reports suggest that ∼12% of mothers in England are still smoking at the time of delivery [1]
We investigated whether any of the CpG sites that reached epigenome-wide significance in our main analysis were identified as being either single nucleotide polymorphism (SNP)-confounded or cross-hybridizing based on a comprehensive assessment reported by Naeem et al [43]
In a large longitudinal birth cohort with genome-wide methylation measured at three different time points in the offspring, we first identified 15 CpG sites that were differentially methylated in cord blood at birth
Summary
Despite the known health risks to both mothers and newborns, maternal smoking during pregnancy remains a significant public health problem in high-income countries and recent reports suggest that ∼12% of mothers in England are still smoking at the time of delivery [1]. It has been proposed that epigenetic modifications such as DNA methylation may mediate the adverse developmental consequences associated with smoking during pregnancy [11]. A recent study of DNA methylation in newborns found no difference in methylation between the offspring of mothers who never smoked and those who smoked early in pregnancy [23]. It has been shown that the effect of in utero exposure on newborn methylation is stronger when the mother smoked past 18 weeks than when she quit earlier in pregnancy [20]. These findings warrant further investigation in an independent study
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