Maternal Smoking During Pregnancy Induces Persistent Epigenetic Changes Into Adolescence, Independent of Postnatal Smoke Exposure and Is Associated With Cardiometabolic Risk.

Sebastian Rauschert,Trevor A Mori,Lawrence J Beilin,Wendy H Oddy,Graham Burdge,Keith M Godfrey,Craig Pennell,Rae-Chi Huang,Karen Lillycrop,Phillip E Melton,Joanna D Holbrook,Jeffrey M Craig

doi:10.3389/fgene.2019.00770

Abstract

Background: Several studies have shown effects of current and maternal smoking during pregnancy on DNA methylation of CpG sites in newborns and later in life. Here, we hypothesized that there are long-term and persistent epigenetic effects following maternal smoking during pregnancy on adolescent offspring DNA methylation, independent of paternal and postnatal smoke exposure. Furthermore, we explored the association between DNA methylation and cardiometabolic risk factors at 17 years of age. Materials and Methods: DNA methylation was measured using the Illumina HumanMethylation450K BeadChip in whole blood from 995 participants attending the 17-year follow-up of the Raine Study. Linear mixed effects models were used to identify differential methylated CpGs, adjusting for parental smoking during pregnancy, and paternal, passive, and adolescent smoke exposure. Additional models examined the association between DNA methylation and paternal, adolescent, and passive smoking over the life course. Offspring CpGs identified were analyzed against cardiometabolic risk factors (blood pressure, triacylglycerols (TG), high-density lipoproteins cholesterol (HDL-C), and body mass index). Results: We identified 23 CpGs (genome-wide p level: 1.06 × 10−7) that were associated with maternal smoking during pregnancy, including associated genes AHRR (cancer development), FTO (obesity), CNTNAP2 (developmental processes), CYP1A1 (detoxification), MYO1G (cell signalling), and FRMD4A (nicotine dependence). A sensitivity analysis showed a dose-dependent relationship between maternal smoking and offspring methylation. These results changed little following adjustment for paternal, passive, or offspring smoking, and there were no CpGs identified that associated with these variables. Two of the 23 identified CpGs [cg00253568 (FTO) and cg00213123 (CYP1A1)] were associated with either TG (male and female), diastolic blood pressure (female only), or HDL-C (male only), after Bonferroni correction. Discussion: This study demonstrates a critical timing of cigarette smoke exposure over the life course for establishing persistent changes in DNA methylation into adolescence in a dose-dependent manner. There were significant associations between offspring CpG methylation and adolescent cardiovascular risk factors, namely, TG, HDL-C, and diastolic blood pressure. Future studies on current smoking habits and DNA methylation should consider the importance of maternal smoking during pregnancy and explore how the persistent DNA methylation effects of in utero smoke exposure increase cardiometabolic risk.

Highlights

Maternal smoking during pregnancy is associated with an increased risk in the offspring of chronic diseases including asthma, certain cancers, and cardiovascular disease in adulthood (Wakschlag et al, 2002; Hofhuis et al, 2003; DiFranza et al, 2004; Oken et al, 2005; Agrawal et al, 2010; Bhattacharya et al, 2014)
Of those exposed to maternal smoking during pregnancy, 60% had fathers who smoked during the pregnancy period, 41% were exposed to passive smoking, and 30% reported smoking themselves
Our findings suggest that maternal smoking during pregnancy induces long-lasting DNA methylation changes in the offspring established by adolescence, which are not greatly modified by postnatal smoke exposure

Summary

Introduction

Maternal smoking during pregnancy is associated with an increased risk in the offspring of chronic diseases including asthma, certain cancers, and cardiovascular disease in adulthood (Wakschlag et al, 2002; Hofhuis et al, 2003; DiFranza et al, 2004; Oken et al, 2005; Agrawal et al, 2010; Bhattacharya et al, 2014). Methylation levels at CpGs most strongly associated with maternal smoking were contained within genes implicated in other studies including MYO1G (myosin 1G), CYP1A1 (cytochrome P450 family 1 subfamily A member 1), GFI1 (growth factor independent 1 transcriptional repressor), CNTNAP2 (contactin-associated protein-like 2) (Rotroff et al, 2016; Rzehak et al, 2016; Tehranifar et al, 2018), and xenobiotics (AHRR, aryl-hydrocarbon receptor repressor) (Finkelstein and Jeong, 2017) These genes have been associated with tumorigenesis and metastasis (in the case of MYO1G, CTNAP2, GFI1, and AHRR), activation of compounds with carcinogenic properties (in the case of CYP1A1 and AHRR), and autism (CNTNAP2), as well as mediating the effect of maternal smoking and birthweight (in the case of GFI1) (Finkelstein, 2017), thereby suggesting a possible epigenetic mechanism linking exposure to smoking during pregnancy with adverse outcomes such as obesity or cancer risk in the offspring. We explored the association between DNA methylation and cardiometabolic risk factors at 17 years of age

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Conclusion