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Review
. 2017 Mar;9(3):351-367.
doi: 10.2217/epi-2016-0135. Epub 2017 Feb 17.

Contrasting the effects of intra-uterine smoking and one-carbon micronutrient exposures on offspring DNA methylation

Rebecca C Richmond  1 , Bonnie R Joubert  2
Affiliations
Review

Contrasting the effects of intra-uterine smoking and one-carbon micronutrient exposures on offspring DNA methylation

Rebecca C Richmond et al. Epigenomics. 2017 Mar.

Abstract

Maternal smoking and micronutrient intake during pregnancy are two strong biological candidates for impacting the developing epigenome. The extent to which DNA methylation in offspring is modified by these intrauterine exposures has not been presented in parallel. In this review, we summarize human studies which have investigated genome-wide DNA methylation in the offspring in relation to maternal smoking and one-carbon micronutrient exposure during pregnancy. We contrast the primarily independent efforts for these two categories of exposure, and potential explanations for these differences. We emphasize methodological considerations such as power to detect methylation signals, exposure assessment, control of sources of variability, causal inference and the role of observed methylation changes in mediating downstream outcomes in the offspring.

Keywords: DNA methylation; epigenetic epidemiology; epigenome-wide association study (EWAS); folate; maternal smoking; micronutrients; one-carbon metabolism.

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Conflict of interest statement

Financial disclosures & competing interests

B Joubert is supported by the NIEHS as a federal employee. RC Richmond works in a unit that receives funds from the University of Bristol and the UK Medical Research Council (MC_UU_12013/2) and is funded by a CRUK program grant (C18281/A19169). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. Network visualization of individual studies investigating maternal smoking in relation to offspring DNA methylation.
Squares represent individual studies; numbers represent related PubMed IDs; circles represent gene regions; text represents annotated gene names; arrows represent the links between the studies and the gene regions, in other words, highlighting studies in which CpG sites have been identified in these gene regions at either Bonferroni significance or with replication/validation attempts; the size of the circle is proportional to the number of independent studies in which the gene regions have been identified. N.B. this network plot does not include the recent epigenome-wide association studies meta-analysis for maternal smoking (PMID 27040690).
<b>Figure 2.</b>
Figure 2.. Network visualization of individual studies investigating maternal folate in relation to offspring DNA methylation.
Squares represent individual studies; numbers represent related PubMed IDs; circles represent gene regions; text represents annotated gene names; arrows represent the links between the studies and the gene regions, in other words, highlighting studies in which CpG sites have been identified in these gene regions at either Bonferroni significance or with replication/validation attempts; the size of the circle is proportional to the number of independent studies in which the gene regions have been identified.
<b>Figure 3.</b>
Figure 3.. Comparison of design of a Mendelian randomization study and randomized controlled trial in the context of establishing a causal effect of maternal folate on DNA methylation.
<b>Figure 4.</b>
Figure 4.. Mendelian randomization analysis to establish the causal effect of maternal smoking-associated DNA methylation change in relation to offspring birthweight, using genetic variants robustly associated with DNA methylation (meQTLs).
meQTL: Methylation quantitative trait loci.
See this image and copyright information in PMC

References

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    2. • Describes in detail the profound effect of smoke exposure on DNA methylation profiles which have been identified in response to both personal smoking and perinatal exposure.

    1. Suter MA, Anders AM, Aagaard KM. Maternal smoking as a model for environmental epigenetic changes affecting birthweight and fetal programming. Mol. Hum. Reprod. 2013;19(1):1–6. - PMC - PubMed

    2. • This review paper of single-site and global methylation highlighted then current data which suggested that maternal smoking influences many different regions of the epigenome, and thus emphasized the importance of interrogating associations on an epigenome-wide scale.

    1. Joubert BR, Felix JF, Yousefi P, et al. DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis. Am. J. Hum. Genet. 2016;98(4):680–696. - PMC - PubMed

    2. •• This meta-analysis study consisting of 6685 mother-offspring pairs across 13 cohorts identified over 6000 CpGs which were found to be differentially methylated in relation to maternal smoking in pregnancy, including sites previously identified in smaller EWAS studies as well as many novel loci enriched in pathways and processes critical to development and conditions that can be caused by maternal smoking including orofacial clefts and asthma.

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