DNA methylation links prenatal smoking exposure to later life health outcomes in offspring

AbstractMaternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. To test this, we examined the association of prenatal maternal smoking with DNA methylation in 2,821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess, whether methylation markers have causal effects on disease outcomes in the offspring. We identify 69 differentially methylated CpGs in 36 genomic regions (P < 1×10−7), and show that DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

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DNA methylation links prenatal smoking exposure to later life health outcomes in offspring

Clinical Epigenetics ◽

10.1186/s13148-019-0683-4 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 12

Author(s):

Petri Wiklund ◽

Ville Karhunen ◽

Rebecca C. Richmond ◽

Priyanka Parmar ◽

Alina Rodriguez ◽

...

Keyword(s):

Dna Methylation ◽

Health Outcomes ◽

Later Life ◽

Prenatal Smoking ◽

Smoking Exposure

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Maternal smoking status before and during pregnancy and bronchial asthma at 3 years of age: a prospective cohort study from the Japan Environment and Children's Study (JECS)

10.21203/rs.3.rs-966835/v1 ◽

2021 ◽

Author(s):

Kunio Miyake ◽

Megumi Kushima ◽

Ryoji Shinohara ◽

Sayaka Horiuchi ◽

Sanae Otawa ◽

...

Keyword(s):

Bronchial Asthma ◽

Maternal Smoking ◽

Smoking Status ◽

Multivariate Logistic Regression Analysis ◽

Smoking During Pregnancy ◽

Established Risk Factor ◽

Smoking Exposure ◽

Increased Risk ◽

Maternal Smoking During Pregnancy ◽

Prenatal Maternal Smoking

Abstract Background Maternal smoking exposure during pregnancy is an established risk factor for childhood asthma, but the association between maternal pre-pregnancy smoking status and asthma risk is not well understood. This study examined the association between maternal smoking status before and during pregnancy and bronchial asthma at 3 years of age. Methods The data of 75,411 mother-child pairs, excluding the missing data of exposure and outcomes from the Japan Environment and Children's Study (JECS) were used. The association between prenatal maternal smoking status and the risk of bronchial asthma at 3 years of age was determined using multivariate logistic regression analysis. Results The percentage of 3-year-old children with doctor-diagnosed bronchial asthma was 7.2%. The distribution of maternal smoking status before childbirth was as follows: Never = 60.0%, Quit before recognizing current pregnancy = 24.1%, Quit after finding out current pregnancy = 12.3%, and Still smoking = 3.6%. Maternal smoking during pregnancy was significantly associated with an increased risk of bronchial asthma at 3 years of age even after adjusting for pre- and postnatal covariates (adjusted odds ratio [aOR] 1.35, 95% confidence interval [CI] 1.16–1.57). Furthermore, mothers who quit before recognizing current pregnancy (aOR 1.10, 95% CI 1.02–1.18) or who quit after finding out about current pregnancy (aOR 1.11, 95% CI 1.01–1.23) were also significantly associated. Conclusions This study suggested that not only maternal smoking during pregnancy but also maternal smoking exposure of pre-pregnancy or early pregnancy may be associated with an increased risk of bronchial asthma in children.

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Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2018.0120 ◽

2019 ◽

Vol 374 (1770) ◽

pp. 20180120 ◽

Cited By ~ 7

Author(s):

Eilis Hannon ◽

Diana Schendel ◽

Christine Ladd-Acosta ◽

Jakob Grove ◽

Christine Søholm Hansen ◽

...

Keyword(s):

Dna Methylation ◽

Birth Weight ◽

Gestational Age ◽

Maternal Smoking ◽

Evolutionary Medicine ◽

Prenatal Smoking ◽

Smoking During Pregnancy ◽

Significance Threshold ◽

Birth Factors ◽

Obstetric Factors

There is great interest in the role epigenetic variation induced by non-genetic exposures may play in the context of health and disease. In particular, DNA methylation has previously been shown to be highly dynamic during the earliest stages of development and is influenced by in utero exposures such as maternal smoking and medication. In this study we sought to identify the specific DNA methylation differences in blood associated with prenatal and birth factors, including birth weight, gestational age and maternal smoking. We quantified neonatal methylomic variation in 1263 infants using DNA isolated from a unique collection of archived blood spots taken shortly after birth (mean = 6.08 days; s.d. = 3.24 days). An epigenome-wide association study (EWAS) of gestational age and birth weight identified 4299 and 18 differentially methylated positions (DMPs) respectively, at an experiment-wide significance threshold of p < 1 × 10 −7 . Our EWAS of maternal smoking during pregnancy identified 110 DMPs in neonatal blood, replicating previously reported genomic loci, including AHRR . Finally, we tested the hypothesis that DNA methylation mediates the relationship between maternal smoking and lower birth weight, finding evidence that methylomic variation at three DMPs may link exposure to outcome. These findings complement an expanding literature on the epigenomic consequences of prenatal exposures and obstetric factors, confirming a link between the maternal environment and gene regulation in neonates. This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine’.

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DNA methylation of GFI1 as a mediator of the association between prenatal smoking exposure and ADHD symptoms at 6 years: the Hokkaido Study on Environment and Children’s Health

Clinical Epigenetics ◽

10.1186/s13148-021-01063-z ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Kunio Miyake ◽

Chihiro Miyashita ◽

Atsuko Ikeda-Araki ◽

Ryu Miura ◽

Sachiko Itoh ◽

...

Keyword(s):

Dna Methylation ◽

Rating Scale ◽

Children's Health ◽

Children’S Health ◽

Prenatal Smoking ◽

Active Smoking ◽

Adhd Symptoms ◽

Smoking During Pregnancy ◽

Smoking Exposure ◽

Increased Risk

Abstract Background Prenatal smoking exposure has been associated with childhood attention-deficit/hyperactivity disorder (ADHD). However, the mechanism underlying this relationship remains unclear. We assessed whether DNA methylation differences may mediate the association between prenatal smoking exposure and ADHD symptoms at the age of 6 years. Results We selected 1150 mother–infant pairs from the Hokkaido Study on the Environment and Children’s Health. Mothers were categorized into three groups according to plasma cotinine levels at the third trimester: non-smokers (≤ 0.21 ng/mL), passive smokers (0.21–11.48 ng/mL), and active smokers (≥ 11.49 ng/mL). The children’s ADHD symptoms were determined by the ADHD-Rating Scale at the age of 6 years. Maternal active smoking during pregnancy was significantly associated with an increased risk of ADHD symptoms (odds ratio, 1.89; 95% confidence interval, 1.14–3.15) compared to non-smoking after adjusting for covariates. DNA methylation of the growth factor-independent 1 transcriptional repressor (GFI1) region, as determined by bisulfite next-generation sequencing of cord blood samples, mediated 48.4% of the total effect of the association between maternal active smoking during pregnancy and ADHD symptoms. DNA methylation patterns of other genes (aryl-hydrocarbon receptor repressor [AHRR], cytochrome P450 family 1 subfamily A member 1 [CYP1A1], estrogen receptor 1 [ESR1], and myosin IG [MYO1G]) regions did not exert a statistically significant mediation effect. Conclusions Our findings demonstrated that DNA methylation of GFI1 mediated the association between maternal active smoking during pregnancy and ADHD symptoms at the age of 6 years.

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Maternal smoking during pregnancy and offpsring's psychiatric morbidity in early adulthood. Findings from the Finnish Family Competence Birth Cohort Study

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.008 ◽

2016 ◽

Vol 33 (S1) ◽

pp. S73-S73

Author(s):

S. Niemelä ◽

S. Mikola ◽

A. Sourander ◽

P. Rautava ◽

M. Sillanpää

Keyword(s):

Maternal Smoking ◽

Psychiatric Morbidity ◽

Early Adulthood ◽

Education Level ◽

Birth Cohort Study ◽

Prenatal Smoking ◽

Psychiatric Diagnoses ◽

Smoking During Pregnancy ◽

Smoking Exposure ◽

Maternal Smoking During Pregnancy

IntroductionPrenatal smoking exposure is one of the most common insults during the fetal period prevalence varying from 5 to 19% in the European countries [1].ObjectivesPrenatal smoking exposure increases the risk of psychiatric morbidity in the offspring, externalizing disorders in particular. However, less is known whether maternal smoking during pregnancy increases the risk for anxiety disorders [1].AimsTo study the associations between maternal smoking during pregnancy and offspring psychiatric morbidity in early adulthood in a Finnish birth cohort study.MethodsA prospective data collection from 10th gestational week (GW10) to early adulthood (n = 475, 37% from the original sample). Information on self-reported smoking during pregnancy was collected using questionnaires at GW10 and GW28. Offspring psychiatric diagnoses and clinically relevant symptoms were assessed using Development and Well-being Assessment (DAWBA)-interviews at age 18 to 20 years. Information on parental alcohol use, depressive mood, anxiety, and education level, as well as offspring's gender, education level, and birth weight were used as covariates.ResultsMaternal smoking during pregnancy associated independently associated with PTSD (OR = 6.9, 95% CI 1.3–35.6, P = 0.021), and conduct disorder (OR = 2.7, 95% CI 1.02–6.9, P = 0.046) in a multivariate analysis after adjusting for other psychiatric diagnoses, offspring and parental variables (OR = 1.9, 95% CI 0.5–6.9, P = 0.359).ConclusionsIn addition to conduct problems, prenatal nicotine exposure may increase the offspring's risk for posttraumatic stress disorder (PTSD). This relationship may be explained, in part, by effects on nicotinic acetylcholine receptors and uteroplacental mechanisms [1].Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Associations of prenatal maternal smoking with offspring hyperactivity: causal or confounded?

Psychological Medicine ◽

10.1017/s0033291713000986 ◽

2013 ◽

Vol 44 (4) ◽

pp. 857-867 ◽

Cited By ~ 23

Author(s):

K. M. Keyes ◽

G. Davey Smith ◽

E. Susser

Keyword(s):

Maternal Smoking ◽

Population Based ◽

Similar Degree ◽

Prenatal Smoking ◽

Tobacco Exposure ◽

Smoking During Pregnancy ◽

Pregnancy Cohort ◽

Smoking Exposure ◽

Prenatal Maternal Smoking ◽

Paternal Smoking

BackgroundThe relationship between prenatal tobacco exposure and hyperactivity remains controversial. To mitigate limitations of prior studies, we used a strategy involving comparison of maternal and paternal smoking reports in a historical sample where smoking during pregnancy was common.MethodData were drawn from a longitudinally followed subsample of the Child Health and Development Study (n = 1752), a population-based pregnancy cohort ascertained in 1961–1963 in California. Maternal prenatal smoking was common (33.4%). Maternal and paternal smoking patterns were assessed at three time points by mother report. Hyperactivity was assessed at the mean of age of 10 years based on mother report to a personality inventory.ResultsUnadjusted, maternal smoking during pregnancy was associated with offspring hyperactivity [β = 0.22, 95% confidence interval (CI) 0.11–0.33] and, to a similar degree, when the father smoked (β = 0.18, 95% CI 0.07–0.30). After adjustment, maternal smoking remained robustly predictive of offspring hyperactivity (β = 0.25, 95% CI 0.09–0.40) but father smoking was not (β = 0.02, 95% CI −0.20 to 0.24). When examined among the pairs matched on propensity score, mother smoking was robustly related to offspring hyperactivity whether the father smoked (β = 0.26, 95% CI 0.03–0.49) or did not smoke (β = 0.30, 95% CI 0.04–0.57). By number of cigarettes, associations with hyperactivity were present for 10–19 and 20+ cigarettes per day among mothers.ConclusionsIn a pregnancy cohort recruited in a time period in which smoking during pregnancy was common, we document associations between prenatal smoking exposure and offspring hyperactivity. Novel approaches to inferring causality continue to be necessary in describing the potential adverse consequences of prenatal smoking exposure later in life.

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Mediation by Placental DNA Methylation of the Association of Prenatal Maternal Smoking and Birth Weight

American Journal of Epidemiology ◽

10.1093/aje/kwz184 ◽

2019 ◽

Vol 188 (11) ◽

pp. 1878-1886 ◽

Cited By ~ 11

Author(s):

Andres Cardenas ◽

Sharon M Lutz ◽

Todd M Everson ◽

Patrice Perron ◽

Luigi Bouchard ◽

...

Keyword(s):

Dna Methylation ◽

Birth Weight ◽

Maternal Smoking ◽

Cell Types ◽

Prenatal Smoking ◽

Association Analyses ◽

Lower Birth Weight ◽

Cpg Sites ◽

Prenatal Maternal Smoking ◽

Infant Birth

Abstract Prenatal maternal smoking is a risk factor for lower birth weight. We performed epigenome-wide association analyses of placental DNA methylation (DNAm) at 720,077 cytosine-phosphate-guanine (CpG) sites and prenatal maternal smoking among 441 mother-infant pairs (2010–2014) and evaluated whether DNAm mediates the association between smoking and birth weight using mediation analysis. Mean birth weight was 3,443 (standard deviation, 423) g, and 38 mothers (8.6%) reported smoking at a mean of 9.4 weeks of gestation. Prenatal maternal smoking was associated with a 175-g lower birth weight (95% confidence interval (CI): −305.5, −44.8) and with differential DNAm of 71 CpGs in placenta, robust to latent-factor adjustment reflecting cell types (Bonferroni-adjusted P < 6.94 × 10−8). Of the 71 CpG sites, 7 mediated the association between prenatal smoking and birth weight (on MDS2, PBX1, CYP1A2, VPRBP, WBP1L, CD28, and CDK6 genes), and prenatal smoking × DNAm interactions on birth weight were observed for 5 CpG sites. The strongest mediator, cg22638236, was annotated to the PBX1 gene body involved in skeletal patterning and programming, with a mediated effect of 301-g lower birth weight (95% CI: −543, −86) among smokers but no mediated effect for nonsmokers (β = −38 g; 95% CI: −88, 9). Prenatal maternal smoking might interact with placental DNAm at specific loci, mediating the association with lower infant birth weight.

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Relationship between antisocial behaviour, attention-deficit hyperactivity disorder and maternal prenatal smoking

The British Journal of Psychiatry ◽

10.1192/bjp.187.2.155 ◽

2005 ◽

Vol 187 (2) ◽

pp. 155-160 ◽

Cited By ~ 76

Author(s):

T. M. M. Button ◽

A. Thapar ◽

P. McGuffin

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Attention Deficit ◽

Maternal Smoking ◽

Structural Equation ◽

Structural Equation Models ◽

Antisocial Behaviour ◽

Prenatal Smoking ◽

Smoking During Pregnancy ◽

Hyperactivity Disorder ◽

Maternal Smoking During Pregnancy

BackgroundThere is substantial evidence that maternal smoking during pregnancy is associated with both antisocial behaviour and symptoms of attention-deficit hyperactivity disorder (ADHD) in offspring. However, it is not clear whether maternal smoking during pregnancy is independently associated with antisocial behaviour or whether the association arises because antisocial behaviour and ADHD covary.AimsTo examine the relationship between maternal smoking during pregnancy, antisocial behaviour and ADHD in offspring.MethodQuestionnaires concerning behaviour and environmental factors were sent to twins from the CaStANET study and data analysed using a number of bivariate structural equation models.ResultsMaternal prenatal smoking contributed small but significant amounts to the variance of ADHD and of antisocial behaviour. The best fitting bivariate model was one in which maternal prenatal smoking had a specific influence on each phenotype, independent of the effect on the other phenotype.ConclusionsBoth antisocial behaviour and ADHD symptoms in offspring are independently influenced by maternal prenatal smoking during pregnancy.

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Epigenetics and DOHaD: from basics to birth and beyond

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174417000733 ◽

2017 ◽

Vol 8 (5) ◽

pp. 513-519 ◽

Cited By ~ 74

Author(s):

T. Bianco-Miotto ◽

J. M. Craig ◽

Y. P. Gasser ◽

S. J. van Dijk ◽

S. E. Ozanne

Keyword(s):

Dna Methylation ◽

Chronic Disease ◽

Chronic Diseases ◽

Early Life ◽

Later Life ◽

Metabolic Health ◽

Number Of Children ◽

Early Life Environment ◽

Increased Risk ◽

Early Life Exposures

Developmental origins of health and disease (DOHaD) is the study of how the early life environment can impact the risk of chronic diseases from childhood to adulthood and the mechanisms involved. Epigenetic modifications such as DNA methylation, histone modifications and non-coding RNAs are involved in mediating how early life environment impacts later health. This review is a summary of the Epigenetics and DOHaD workshop held at the 2016 DOHaD Society of Australia and New Zealand Conference. Our extensive knowledge of how the early life environment impacts later risk for chronic disease would not have been possible without animal models. In this review we highlight some animal model examples that demonstrate how an adverse early life exposure results in epigenetic and gene expression changes that may contribute to increased risk of chronic disease later in life. Type 2 diabetes and cardiovascular disease are chronic diseases with an increasing incidence due to the increased number of children and adults that are obese. Epigenetic changes such as DNA methylation have been shown to be associated with metabolic health measures and potentially predict future metabolic health status. Although more difficult to elucidate in humans, recent studies suggest that DNA methylation may be one of the epigenetic mechanisms that mediates the effects of early life exposures on later life risk of obesity and obesity related diseases. Finally, we discuss the role of the microbiome and how it is a new player in developmental programming and mediating early life exposures on later risk of chronic disease.

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