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Gender-specific methylation differences in relation to prenatal exposure to cigarette smoke.

ABSTRACT: Epigenetic alterations may mechanistically explain the developmental origins of adult disease, namely the hypothesis that many complex adult chronic diseases originate as a result of conditions encountered in utero. If true, epigenetically regulated imprinted genes, critical to normal growth and development, may partially mediate these outcomes. We determined the influence of in utero exposure to cigarette smoking on methylation at two differentially methylated regions (DMRs) regulating Insulin-like Growth Factor 2 (IGF2) and H19, and how this might relate to birth weight of infants born to 418 pregnant women. Smoking status was ascertained through self-report and medical records. Bisulfite pyrosequencing was used to measure methylation in umbilical cord blood DNAs. Least squares DNA methylation means at each DMR and birth weight were compared between infants of smokers and non-smokers, using generalized linear models. While there were no significant differences at the H19 DMR, infants born to smokers had higher methylation at the IGF2 DMR than those born to never smokers or those who quit during pregnancy (49.5%, SD=8.0 versus 46.6%, SD=5.6 and 45.8%, SD=6.3, respectively; p=0.0002). The smoking-related increase in methylation was most pronounced in male offspring (p for sex interaction=0.03), for whom approximately 20% of smoking-related low birth weight was mediated by DNA methylation at the IGF2 DMR. Our findings suggest that IGF2 DMR plasticity is an important mechanism by which in utero adjustments to environmental toxicants are conferred. Larger studies to replicate these findings are required.

SUBMITTER: Murphy SK

PROVIDER: S-EPMC3627389 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Gender-specific methylation differences in relation to prenatal exposure to cigarette smoke.

Murphy Susan K SK Adigun Abayomi A Huang Zhiqing Z Overcash Francine F Wang Frances F Jirtle Randy L RL Schildkraut Joellen M JM Murtha Amy P AP Iversen Edwin S ES Hoyo Cathrine C

Gene 20111220 1

Epigenetic alterations may mechanistically explain the developmental origins of adult disease, namely the hypothesis that many complex adult chronic diseases originate as a result of conditions encountered in utero. If true, epigenetically regulated imprinted genes, critical to normal growth and development, may partially mediate these outcomes. We determined the influence of in utero exposure to cigarette smoking on methylation at two differentially methylated regions (DMRs) regulating Insulin- ...[more]

PMID: 22202639

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Project description:IntroductionFetal changes in DNA methylation may underlie associations of maternal smoking during pregnancy with adverse outcomes in children. We examined critical periods and doses of maternal smoking during pregnancy in relation to newborn DNA methylation, and associations of paternal smoking with newborn DNA methylation.Aims and methodsThis study was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We assessed parental smoking during pregnancy using questionnaires. We analyzed associations of prenatal smoke exposure with newborn DNA methylation at 5915 known maternal smoking-related cytosine-phosphate-guanine sites (CpGs) in 1261 newborns using linear regression. Associations with false discovery rate-corrected p-values < .05 were taken forward.ResultsSustained maternal smoking was associated with newborn DNA methylation at 1391 CpGs, compared with never smoking. Neither quitting smoking early in pregnancy nor former smoking was associated with DNA methylation, compared with never smoking. Among sustained smokers, smoking ≥5, compared with <5, cigarettes/d was associated with DNA methylation at seven CpGs. Paternal smoking was not associated with DNA methylation, independent of maternal smoking status.ConclusionsOur results suggest that CpGs associated with sustained maternal smoking are not associated with maternal smoking earlier in pregnancy or with paternal smoking. Some of these CpGs show dose-response relationships with sustained maternal smoking. The third trimester may comprise a critical period for associations of smoking with newborn DNA methylation, or sustained smoking may reflect higher cumulative doses. Alternatively, maternal smoking limited to early pregnancy and paternal smoking may be associated with DNA methylation at specific other CpGs not studied here.ImplicationsOur results suggest that quitting maternal smoking before the third trimester of pregnancy, and possibly lowering smoking dose, may prevent differential DNA methylation in the newborns at CpGs associated with sustained smoking. If the relevance of DNA methylation for clinical outcomes is established, these results may help in counseling parents-to-be about quitting smoking.

Project description:Background: How prenatal smoke exposure affects DNA methylation leading to atopic disorders remains to be addressed. Epigenetic biomarkers informative of prenatal smoke exposure and atopic disorders are wanting. Since most children suffering from atopic dermatitis (AD) continue to develop asthma later in life, we explored whether prenatal smoke exposure e induces DNA methylation and searched for predictive epigenetic biomarkers for smoke related atopic disorders. Methods: Methylation differences associated with smoke exposure were screened by Illumina methylation panel for children from the Taiwan birth panel study cohort initially. Information about development of atopic dermatitis (AD) and risk factors were collected. Cord blood cotinine levels were measured to represent prenatal smoke exposure. CpG loci that demonstrated a statistically significant difference in methylation were validated by methylation-dependent fragment separation (MDFS). Differential methylation in three genes (TSLP, GSTT1, and CYB5R3) was identified through the screen and their functions were investigated. Results: Among these, only thymic stromal lymphopoietin (TSLP) gene displayed significant difference in promoter methylation percentage after being validated by MDFS (p=0.029). TSLP gene was further investigated in a larger sample of 92 children from the cohort. Methylation status of the TSLP 5′-CpG island (CGI) was found to be significantly associated with prenatal smoke exposure (OR=3.59, 95%CI=1.49-8.64; cotinine level 0.10 ng/ml, sensitivity= 77%; specificity = 61%) and with AD (OR=4.77, 95%CI=1.47-15.53). The degree of TSLP 5′CGI methylation inversely correlated with TSLP protein expression levels (per unit: β=－6.69 ng/ml; 95% CIs, －12.80~－0.59; p=0.032). Conclusions: The effect of prenatal tobacco smoke exposure on the risk for AD may be mediated through DNA methylation. Cord blood methylated TSLP 5′CGI may be a potential epigenetic biomarker for environmentally-related atopic disorders.

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Gender-specific methylation differences in relation to prenatal exposure to cigarette smoke.

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Gender-specific methylation differences in relation to prenatal exposure to cigarette smoke.

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