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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Nicotine and Its Downstream Metabolites in Maternal and Cord Sera: Biomarkers of Prenatal Smoking Exposure Associated with Offspring DNA Methylation

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17249552 ◽

2020 ◽

Vol 17 (24) ◽

pp. 9552

Author(s):

Parnian Kheirkhah Rahimabad ◽

Thilani M. Anthony ◽

A. Daniel Jones ◽

Shakiba Eslamimehr ◽

Nandini Mukherjee ◽

...

Keyword(s):

Dna Methylation ◽

Self Report ◽

Major Constituent ◽

Prenatal Smoking ◽

Nicotine Exposure ◽

Primary Metabolite ◽

Prenatal Nicotine Exposure ◽

Smoking Exposure ◽

Prenatal Nicotine ◽

In Pregnancy

Nicotine is a major constituent of cigarette smoke. Its primary metabolite in maternal and cord sera, cotinine, is considered a biomarker of prenatal smoking. Nicotine and cotinine half-lives are decreased in pregnancy due to their increased rate of metabolism and conversion to downstream metabolites such as norcotinine and 3-hydroxycotinine. Hence, downstream metabolites of nicotine may provide informative biomarkers of prenatal smoking. In this study of three generations (F0-mothers, F1-offspring who became mothers, and F2-offspring), we present a biochemical assessment of prenatal smoking exposure based on maternal and cord sera levels of nicotine, cotinine, norcotinine, and 3-hydroxycotinine. As potential markers of early effects of prenatal smoking, associations with differential DNA methylation (DNAm) in the F1- and F2-offspring were assessed. All metabolites in maternal and cord sera were associated with self-reported prenatal smoking, except for nicotine. We compared maternal self-report of smoking in pregnancy to biochemical evidence of prenatal smoking exposure. Self-report of F0-mothers of F1 in 1989–1990 had more accuracy identifying prenatal smoking related to maternal metabolites in maternal serum (sensitivity = 94.6%, specificity = 86.9%) compared to self-reports of F1-mothers of F2 (2010–2016) associated with cord serum markers (sensitivity = 66.7%, specificity = 78.8%). Nicotine levels in sera showed no significant association with any DNAm site previously linked to maternal smoking. Its downstream metabolites, however, were associated with DNAm sites located on the MYO1G, AHRR, and GFI1 genes. In conclusion, cotinine, norcotinine, and 3-hydroxycotinine in maternal and cord sera provide informative biomarkers and should be considered when assessing prenatal smoking. The observed association of offspring DNAm with metabolites, except for nicotine, may imply that the toxic effects of prenatal nicotine exposure are exerted by downstream metabolites, rather than nicotine. If differential DNA methylation on the MYO1G, AHRR, and GFI1 genes transmit adverse effects of prenatal nicotine exposure to the child, there is a need to investigate whether preventing changes in DNA methylation by reducing the metabolic rate of nicotine and conversion to harmful metabolites may protect exposed children.

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Epigenetic signatures of smoking associate with cognitive function, brain structure, and mental and physical health outcomes in the Lothian Birth Cohort 1936

Translational Psychiatry ◽

10.1038/s41398-019-0576-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Janie Corley ◽

Simon R. Cox ◽

Sarah E. Harris ◽

Maria Valdéz Hernandez ◽

Susana Muñoz Maniega ◽

...

Keyword(s):

Dna Methylation ◽

Cognitive Function ◽

Health Outcomes ◽

Physical Health ◽

Birth Cohort ◽

Smoking Status ◽

Brain Mri ◽

Smoking Exposure ◽

Eta Squared ◽

Lothian Birth Cohort

Abstract Recent advances in genome-wide DNA methylation (DNAm) profiling for smoking behaviour have given rise to a new, molecular biomarker of smoking exposure. It is unclear whether a smoking-associated DNAm (epigenetic) score has predictive value for ageing-related health outcomes which is independent of contributions from self-reported (phenotypic) smoking measures. Blood DNA methylation levels were measured in 895 adults aged 70 years in the Lothian Birth Cohort 1936 (LBC1936) study using the Illumina 450K assay. A DNA methylation score based on 230 CpGs was used as a proxy for smoking exposure. Associations between smoking variables and health outcomes at age 70 were modelled using general linear modelling (ANCOVA) and logistic regression. Additional analyses of smoking with brain MRI measures at age 73 (n = 532) were performed. Smoking-DNAm scores were positively associated with self-reported smoking status (P < 0.001, eta-squared ɳ2 = 0.63) and smoking pack years (r = 0.69, P < 0.001). Higher smoking DNAm scores were associated with variables related to poorer cognitive function, structural brain integrity, physical health, and psychosocial health. Compared with phenotypic smoking, the methylation marker provided stronger associations with all of the cognitive function scores, especially visuospatial ability (P < 0.001, partial eta-squared ɳp2 = 0.022) and processing speed (P < 0.001, ɳp2 = 0.030); inflammatory markers (all P < 0.001, ranges from ɳp2 = 0.021 to 0.030); dietary patterns (healthy diet (P < 0.001, ɳp2 = 0.052) and traditional diet (P < 0.001, ɳp2 = 0.032); stroke (P = 0.006, OR 1.48, 95% CI 1.12, 1.96); mortality (P < 0.001, OR 1.59, 95% CI 1.42, 1.79), and at age 73; with MRI volumetric measures (all P < 0.001, ranges from ɳp2 = 0.030 to 0.052). Additionally, education was the most important life-course predictor of lifetime smoking tested. Our results suggest that a smoking-associated methylation biomarker typically explains a greater proportion of the variance in some smoking-related morbidities in older adults, than phenotypic measures of smoking exposure, with some of the accounted-for variance being independent of phenotypic smoking status.

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DNA methylation in infants with low and high body fatness

BMC Genomics ◽

10.1186/s12864-020-07169-7 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Pontus Henriksson ◽

Antonio Lentini ◽

Signe Altmäe ◽

David Brodin ◽

Patrick Müller ◽

...

Keyword(s):

Dna Methylation ◽

Body Composition ◽

Birth Weight ◽

Health Outcomes ◽

Fat Mass ◽

Later Life ◽

Fat Free Mass ◽

Buccal Cells ◽

Body Fatness ◽

High Body

Abstract Background Birth weight is determined by the interplay between infant genetics and the intrauterine environment and is associated with several health outcomes in later life. Many studies have reported an association between birth weight and DNA methylation in infants and suggest that altered epigenetics may underlie birthweight-associated health outcomes. However, birth weight is a relatively nonspecific measure of fetal growth and consists of fat mass and fat-free mass which may have different effects on health outcomes which motivates studies of infant body composition and DNA methylation. Here, we combined genome-wide DNA methylation profiling of buccal cells from 47 full-term one-week old infants with accurate measurements of infant fat mass and fat-free mass using air-displacement plethysmography. Results No significant association was found between DNA methylation in infant buccal cells and infant body composition. Moreover, no association between infant DNA methylation and parental body composition or indicators of maternal glucose metabolism were found. Conclusions Despite accurate measures of body composition, we did not identify any associations between infant body fatness and DNA methylation. These results are consistent with recent studies that generally have identified only weak associations between DNA methylation and birthweight. Although our results should be confirmed by additional larger studies, our findings may suggest that differences in DNA methylation between individuals with low and high body fatness may be established later in childhood.

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Childhood exposure to hunger: associations with health outcomes in later life and epigenetic markers

Epigenomics ◽

10.2217/epi-2019-0333 ◽

2020 ◽

Vol 12 (21) ◽

pp. 1861-1870

Author(s):

Laura Perna ◽

Yan Zhang ◽

Beate Wild ◽

Matthias Kliegel ◽

Andreas Ihle ◽

...

Keyword(s):

Dna Methylation ◽

Depressive Symptoms ◽

Health Outcomes ◽

Multiple Testing ◽

Later Life ◽

Population Based ◽

German Population ◽

Multiple Testing Correction ◽

Childhood Exposure ◽

Infant Exposure

Aim: To assess associations of early exposure to hunger with depressive symptoms and cardiovascular disease (CVD) and to investigate possible epigenetic pathways. Patients & methods: Data were based on a German population-based cohort of older adults (n = 9631). Regression models were performed for health outcomes in later life. An epigenome-wide association study for early-life exposure to hunger was performed in a subgroup (n = 2221) with whole blood DNA methylation data. Results: Childhood exposure to hunger was associated with CVD and depressive symptoms in later life. Prenatal or infant exposure was strongly associated with depressive symptoms. No CpG reached epigenome-wide significance after multiple testing correction. Conclusion: Childhood hunger is a risk factor for depressive symptoms and CVD at older age. DNA methylation could not explain this association.

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Population DNA methylation studies in the Developmental Origins of Health and Disease (DOHaD) framework

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174418000442 ◽

2018 ◽

Vol 10 (3) ◽

pp. 306-313 ◽

Cited By ~ 6

Author(s):

J. F. Felix ◽

C. A. M. Cecil

Keyword(s):

Dna Methylation ◽

Health Outcomes ◽

Early Life ◽

Later Life ◽

Epigenetic Mechanism ◽

Future Research ◽

Developmental Origins ◽

Use Of Resources ◽

Health And Disease

AbstractEpigenetic changes represent a potential mechanism underlying associations of early-life exposures and later life health outcomes. Population-based cohort studies starting in early life are an attractive framework to study the role of such changes. DNA methylation is the most studied epigenetic mechanism in population research. We discuss the application of DNA methylation in early-life population studies, some recent findings, key challenges and recommendations for future research. Studies into DNA methylation within the Developmental Origins of Health and Disease framework generally either explore associations between prenatal exposures and offspring DNA methylation or associations between offspring DNA methylation in early life and later health outcomes. Only a few studies to date have integrated prospective exposure, epigenetic and phenotypic data in order to explicitly test the role of DNA methylation as a potential biological mediator of environmental effects on health outcomes. Population epigenetics is an emerging field which has challenges in terms of methodology and interpretation of the data. Key challenges include tissue specificity, cell type adjustment, issues of power and comparability of findings, genetic influences, and exploring causality and functional consequences. Ongoing studies are working on addressing these issues. Large collaborative efforts of prospective cohorts are emerging, with clear benefits in terms of optimizing power and use of resources, and in advancing methodology. In the future, multidisciplinary approaches, within and beyond longitudinal birth and preconception cohorts will advance this complex, but highly promising, the field of research.

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Invited Commentary: Is DNA Methylation an Actionable Mediator of Prenatal Exposure Effects on Child Health?

American Journal of Epidemiology ◽

10.1093/aje/kwz182 ◽

2019 ◽

Vol 188 (11) ◽

pp. 1887-1889 ◽

Cited By ~ 3

Author(s):

Christine Ladd-Acosta ◽

M Daniele Fallin

Keyword(s):

Dna Methylation ◽

Birth Weight ◽

Repeated Measures ◽

Ethnically Diverse ◽

Molecular Signature ◽

Prenatal Smoking ◽

Mediation Analyses ◽

Adverse Health Outcomes ◽

Smoking Exposure ◽

The Impact

Abstract A substantial body of literature has shown robust associations between prenatal smoking exposure and DNA methylation levels. The pattern of DNA methylation can be used as a molecular signature of past prenatal smoking exposure and might also provide mechanistic insights into associations between prenatal smoking exposure and adverse health outcomes. In this issue of the Journal, Cardenas et al. (Am J Epidemiol. 2019;188(11):1878–1886) evaluated whether DNA methylation mediates the association between prenatal smoking and low birth weight in a tissue that is mechanistically relevant to birth weight—the placenta—using formal mediation analyses. They found that methylation levels, at 5 loci, mediated smoking exposure effects on birth weight but only among children whose mothers smoked during pregnancy. Given the use of formal mediation methods and measurement in a mechanistically relevant tissue, this work has the potential to inform novel directions for intervention. Replication of these findings in larger and more racially and ethnically diverse samples, repeated measures to better tease apart the timing of DNA methylation changes with respect to exposure and birth weight, and continued use of intervention-focused mediation methods are needed before the impact of these findings will be fully realized.

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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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DNA methylation mediates the effect of maternal smoking on offspring birthweight: a birth cohort study of multi-ethnic US mother–newborn pairs

Clinical Epigenetics ◽

10.1186/s13148-021-01032-6 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Richard Xu ◽

Xiumei Hong ◽

Boyang Zhang ◽

Wanyu Huang ◽

Wenpin Hou ◽

...

Keyword(s):

Dna Methylation ◽

Health Outcomes ◽

Cord Blood ◽

Birth Cohort ◽

Fetal Growth ◽

Maternal Smoking ◽

Cpg Sites ◽

Smoking Exposure ◽

Lower Birthweight

Abstract Background Maternal smoking affects more than half a million pregnancies each year in the US and is known to result in fetal growth restriction as measured by lower birthweight and its associated long-term consequences. Maternal smoking also has been linked to altered fetal DNA methylation (DNAm). However, what remains largely unexplored is whether these DNAm alterations are merely markers of smoking exposure or if they also have implications for health outcomes. This study tested the hypothesis that fetal DNAm mediates the effect of maternal smoking on newborn birthweight. Methods This study included mother–newborn pairs from a US predominantly urban, low-income multi-ethnic birth cohort. DNAm in cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip. After standard quality control and normalization procedures, an epigenome-wide association study (EWAS) of maternal smoking was performed using linear regression models, controlling for maternal age, education, race, parity, pre-pregnancy body mass index, alcohol consumption, gestational age, maternal pregestational/gestational diabetes, child sex, cord blood cell compositions and batch effects. To quantify the degree to which cord DNAm mediates the smoking-birthweight association, the VanderWeele-Vansteelandt approach for single mediator and structural equational model for multiple mediators were used, adjusting for pertinent covariates. Results The study included 954 mother–newborn pairs. Among mothers, 165 (17.3%) ever smoked before or during pregnancy. Newborns with smoking exposure had on average 258 g lower birthweight than newborns without exposure (P < 0.001). Using a false discovery rate (FDR) < 0.05 as the significance cutoff, the EWAS identified 38 differentially methylated CpG sites associated with maternal smoking. Of those, 17 CpG sites were mapped to previously reported genes: GFI1, AHRR, CYP1A1, and CNTNAP2; 8 of those, located in the first three genes, were Bonferroni significantly associated with newborn birthweight and mediated the smoking-birthweight association. The combined mediation effect of the three genes explained 67.8% of the smoking-birthweight association. Conclusions Our study not only lends further support that maternal smoking alters fetal DNAm in a multiethnic population, but also suggests that fetal DNAm substantially mediates the maternal smoking–birthweight association. Our findings, if further validated, indicate that DNAm modification is likely an important pathway by which maternal smoking impairs fetal growth and, perhaps, even long-term health outcomes.

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Epigenetic Mechanisms of Maternal Dietary Protein and Amino Acids Affecting Growth and Development of Offspring

Current Protein and Peptide Science ◽

10.2174/1389203720666190125110150 ◽

2019 ◽

Vol 20 (7) ◽

pp. 727-735 ◽

Cited By ~ 2

Author(s):

Yi Wu ◽

Zhibin Cheng ◽

Yueyu Bai ◽

Xi Ma

Keyword(s):

Amino Acids ◽

Dna Methylation ◽

Dietary Protein ◽

Growth And Development ◽

Later Life ◽

Biological Macromolecules ◽

Epigenetic Mechanisms ◽

Maternal Circulation ◽

Energy Processing ◽

Living Organisms

Nutrients can regulate metabolic activities of living organisms through epigenetic mechanisms, including DNA methylation, histone modification, and RNA regulation. Since the nutrients required for early embryos and postpartum lactation are derived in whole or in part from maternal and lactating nutrition, the maternal nutritional level affects the growth and development of fetus and creates a profound relationship between disease development and early environmental exposure in the offspring’s later life. Protein is one of the most important biological macromolecules, involved in almost every process of life, such as information transmission, energy processing and material metabolism. Maternal protein intake levels may affect the integrity of the fetal genome and alter DNA methylation and gene expression. Most amino acids are supplied to the fetus from the maternal circulation through active transport of placenta. Some amino acids, such as methionine, as dietary methyl donor, play an important role in DNA methylation and body’s one-carbon metabolism. The purpose of this review is to describe effects of maternal dietary protein and amino acid intake on fetal and neonatal growth and development through epigenetic mechanisms, with examples in humans and animals.

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