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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.00770

Maternal smoking during pregnancy induces persistent epigenetic changes into adolescence, independent of postnatal smoke exposure and is associated with cardiometabolic risk

  • 1Telethon Kids Institute, Australia
  • 2Centre for Genetic Origins of Health and Disease, University of Western Australia, Australia
  • 3School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Australia
  • 4Human Development & Health, Faculty of Medicine, University of Southampton, United Kingdom
  • 5Royal Children's Hospital, Australia
  • 6Centre for Molecular and Medical Research, School of Medicine, Deakin University, Australia
  • 7MRC Lifecourse Epidemiology Unit (MRC), United Kingdom
  • 8Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, United Kingdom
  • 9Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Australia
  • 10University of Western Australia, Australia

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. Further, 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 Western Australian Pregnancy Cohort (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 DMCpGs identified were analysed against cardiometabolic risk factors (blood pressure, triacylglycerols (TG), high-density lipoproteins cholesterol (HDL-C) and body mass index).

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 (males and females), diastolic blood pressure (females only) or HDL-C (males only), after Bonferroni correction.

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.

Keywords: DNA Methylation, maternal smoking during pregnancy, epigenetics, Raine Study, Cardiometabolic Health, adolescence

Received: 26 Apr 2019; Accepted: 22 Jul 2019.

Edited by:

Yun Liu, School of Basic Medical Sciences, Fudan University, China

Reviewed by:

Jorg Tost, Institut de Biologie François Jacob, Commissariat à l'Energie Atomique et aux Energies Alternatives, France
Zhiqing Huang, School of Medicine, Duke University, United States  

Copyright: © 2019 Rauschert, Melton, Burdge, Craig, Godfrey, Holbrook, Lillycrop, Mori, Beilin, Pennell and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Rae-Chi Huang, Telethon Kids Institute, Subiaco, Australia,