Association between DNA methylation in cord blood and maternal smoking: The Hokkaido Study on Environment and Children’s Health

Miyake, Kunio; Kawaguchi, Akio; Miura, Ryuichi; Kobayashi, Sachiko; Tran, Nguyen Quoc Vuong; Kobayashi, Sumitaka; Miyashita, Chihiro; Araki, Atsuko; Kubota, Takeo; Yamagata, Zentaro; Kishi, Reiko

doi:10.1038/s41598-018-23772-x

Cited by 36 publications

(33 citation statements)

References 59 publications

(83 reference statements)

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“…We successfully replicated almost all of those CpG sites with reported effect sizes ≥5% DNAm change, and 67 sites with reported effect sizes <5% DNAm change. These replicated CpG sites included those that have been reported by multiple studies (such as CpG sites in the MYO1G, CYP1A1, and FRMD4A genes) [10][11][12][13][14]21,23]. Such findings by our group and others suggest that smoking-related DNAm changes in cord blood are shared by different ethnic populations.…”

Section: Discussionsupporting

confidence: 77%

“…There is increasing evidence that maternal smoking may affect a child's global and gene-specific DNA methylation (DNAm) profiles as early as in utero [10][11][12][13][14][15][16][17][18][19][20][21]. An increasing number of genes have been identified for which the DNAm levels at specific CpG sites in newborns were significantly associated with maternal smoking during pregnancy, some of whichsuch as those encoding Aryl-hydrocarbon receptors repressor (AHRR), growth factor independent 1 transcriptional repressor (GFI1), and cytochrome P450, family 1, member A1 (CYP1A1)have been reported by multiple studies [10][11][12][13][14][15][16][17][18][19]21]. Such maternal smoking-related methylation changes may persist throughout childhood [22,23], adolescence [12], and even adulthood, which may be independent of active smoking in the offspring [24].…”

Section: Introductionmentioning

confidence: 99%

“…Our study sought to address several important gaps in the field. To our knowledge, the relevant available genome-wide scale reports have predominantly focused on white populations [11][12][13][14][15][16]18,19], with a few focused on multi-ethnic populations [10,23,24] and Asian populations [21]. It is still less clear whether these findings can be extended to other minority populations.…”

Section: Introductionmentioning

confidence: 99%

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Maternal smoking during pregnancy and cord blood DNA methylation: new insight on sex differences and effect modification by maternal folate levels

Zhang

Hong

et al. 2018

Epigenetics

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Maternal smoking during pregnancy may affect newborn DNA methylation (DNAm). However, little is known about how these associations vary by a newborn's sex and/or maternal nutrition. To fill in this research gap, we investigated epigenome-wide DNAm associations with maternal smoking during pregnancy in African American mother-newborn pairs. DNAm profiling in cord (n = 379) and maternal blood (n = 300) were performed using the Illumina HumanMethylation450 BeadChip array. We identified 12 CpG sites whose DNAm levels in cord blood were associated with maternal smoking, at a false discovery rate <5%. The identified associations in the GFI1 gene were more pronounced in male newborns than in females (P = 0.002 for maternal smoking × sex interaction at cg18146737). We further observed that maternal smoking and folate level may interactively affect cord blood DNAm level at cg05575921 in the AHRR gene (P = 5.0 × 10 for interaction): compared to newborns unexposed to maternal smoking and with a high maternal folate level (>19.2 nmol/L), the DNAm level was about 0.03 lower (P = 3.6 × 10) in exposed newborns with a high maternal folate level, but was 0.08 lower (P = 1.2 × 10) in exposed newborns with a low maternal folate level. Our data suggest that adequate maternal folate levels may partly counteract the impact of maternal smoking on DNAm. These findings may open new avenues of inquiry regarding sex differences in response to environmental insults and novel strategies to mitigate their intergenerational health effects through optimization of maternal nutrition.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Maternal smoking during pregnancy and cord blood DNA methylation: new insight on sex differences and effect modification by maternal folate levels

Zhang

Hong

et al. 2018

Epigenetics

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“…First, our observed effect estimates in DNA methylation associated with PTS are small. However, most studies on DNA methylation changes in newborns in relation to maternal smoking during pregnancy, including meta-analysis of several large cohorts, all identified changes with small magnitudes as low as or less than 0.5% [ 9 , 50 – 52 ]. A previous study defined the mean methylation change in response to PTS for both hyper- and hypomethylation as 2% [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Self-reported prenatal tobacco smoke exposure, AXL gene-body methylation, and childhood asthma phenotypes

et al. 2018

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BackgroundEpigenetic modifications, including DNA methylation, act as one potential mechanism underlying the detrimental effects associated with prenatal tobacco smoke (PTS) exposure. Methylation in a gene called AXL was previously reported to differ in response to PTS.MethodsWe investigated the association between PTS and epigenetic changes in AXL and how this was related to childhood asthma phenotypes. We tested the association between PTS and DNA methylation at multiple CpG loci of AXL at birth using Pyrosequencing in two separate study populations, the Children’s Health Study (CHS, n = 799) and the Newborn Epigenetic Study (NEST, n = 592). Plasma cotinine concentration was used to validate findings with self-reported smoking status. The inter-relationships among AXL mRNA and miR-199a1 expression, PTS, and AXL methylation were examined. Lastly, we evaluated the joint effects of AXL methylation and PTS on the risk of asthma and related symptoms at age 10 years old.ResultsPTS was associated with higher methylation level in the AXL gene body in both CHS and NEST subjects. In the pooled analysis, exposed subjects had a 0.51% higher methylation level in this region compared to unexposed subjects (95% CI 0.29, 0.74; p < 0.0001). PTS was also associated with 21.2% lower expression of miR-199a1 (95% CI − 37.9, − 0.1; p = 0.05), a microRNA known to regulate AXL expression. Furthermore, the combination of higher AXL methylation and PTS exposure at birth increased the risk of recent episodes of bronchitic symptoms in childhood.ConclusionsPTS was associated with methylation level of AXL and the combination altered the risk of childhood bronchitic symptoms.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0532-x) contains supplementary material, which is available to authorized users.

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“… 5 Only few studies explored associations of timing and dose of prenatal smoke exposure with newborn DNA methylation, either epigenome-wide or at specific candidate CpGs. 6–10 These suggested effects of timing or dose on DNA methylation, but maternal smoking timing was often not assessed in detail. Specifically, differentiating between mothers who never smoked, quit before pregnancy, or quit early in pregnancy could be informative.…”

Section: Introductionmentioning

confidence: 99%

Timing- and Dose-Specific Associations of Prenatal Smoke Exposure With Newborn DNA Methylation

Monasso

Jaddoe

Jongste

et al. 2020

Nicotine &Amp; Tobacco Research

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Introduction Fetal 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 Methods This 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. Results Sustained 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. Conclusions Our 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. Implications Our 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.

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Association between DNA methylation in cord blood and maternal smoking: The Hokkaido Study on Environment and Children’s Health

Cited by 36 publications

References 59 publications

Maternal smoking during pregnancy and cord blood DNA methylation: new insight on sex differences and effect modification by maternal folate levels

Maternal smoking during pregnancy and cord blood DNA methylation: new insight on sex differences and effect modification by maternal folate levels

Self-reported prenatal tobacco smoke exposure, AXL gene-body methylation, and childhood asthma phenotypes

Timing- and Dose-Specific Associations of Prenatal Smoke Exposure With Newborn DNA Methylation

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