Impact of vitamin C supplementation on placental DNA methylation changes related to maternal smoking: association with gene expression and respiratory outcomes

Lyndsey E Shorey-Kendrick, Cindy T McEvoy, Shannon M O'Sullivan, Kristin Milner, Brittany Vuylsteke, Robert S Tepper, David M Haas, Byung Park, Lina Gao, Annette Vu, Cynthia D Morris, Eliot R Spindel, Lyndsey E Shorey-Kendrick, Cindy T McEvoy, Shannon M O'Sullivan, Kristin Milner, Brittany Vuylsteke, Robert S Tepper, David M Haas, Byung Park, Lina Gao, Annette Vu, Cynthia D Morris, Eliot R Spindel

Abstract

Background: Maternal smoking during pregnancy (MSDP) affects development of multiple organ systems including the placenta, lung, brain, and vasculature. In particular, children exposed to MSDP show lifelong deficits in pulmonary function and increased risk of asthma and wheeze. Our laboratory has previously shown that vitamin C supplementation during pregnancy prevents some of the adverse effects of MSDP on offspring respiratory outcomes. Epigenetic modifications, including DNA methylation (DNAm), are a likely link between in utero exposures and adverse health outcomes, and MSDP has previously been associated with DNAm changes in blood, placenta, and buccal epithelium. Analysis of placental DNAm may reveal critical targets of MSDP and vitamin C relevant to respiratory health outcomes.

Results: DNAm was measured in placentas obtained from 72 smokers enrolled in the VCSIP RCT: NCT03203603 (37 supplemented with vitamin C, 35 with placebo) and 24 never-smokers for reference. Methylation at one CpG, cg20790161, reached Bonferroni significance and was hypomethylated in vitamin C supplemented smokers versus placebo. Analysis of spatially related CpGs identified 93 candidate differentially methylated regions (DMRs) between treatment groups, including loci known to be associated with lung function, oxidative stress, fetal development and growth, and angiogenesis. Overlap of nominally significant differentially methylated CpGs (DMCs) in never-smokers versus placebo with nominally significant DMCs in vitamin C versus placebo identified 9059 candidate "restored CpGs" for association with placental transcript expression and respiratory outcomes. Methylation at 274 restored candidate CpG sites was associated with expression of 259 genes (FDR < 0.05). We further identified candidate CpGs associated with infant lung function (34 CpGs) and composite wheeze (1 CpG) at 12 months of age (FDR < 0.05). Increased methylation in the DIP2C, APOH/PRKCA, and additional candidate gene regions was associated with improved lung function and decreased wheeze in offspring of vitamin C-treated smokers.

Conclusions: Vitamin C supplementation to pregnant smokers ameliorates changes associated with maternal smoking in placental DNA methylation and gene expression in pathways potentially linked to improved placental function and offspring respiratory health. Further work is necessary to validate candidate loci and elucidate the causal pathway between placental methylation changes and outcomes of offspring exposed to MSDP. Clinical trial registration ClinicalTrials.gov, NCT01723696. Registered November 6, 2012. https://ichgcp.net/clinical-trials-registry/NCT01723696 .

Keywords: DNA methylation; MSDP: maternal smoking during pregnancy; MethylationEPIC; Nicotine; RCT: randomized clinical trial; Vitamin C.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Manhattan plots of differential placental DNAm between a placebo and vitamin C smokers and b placebo smokers and never-smokers. The horizontal red line marks Bonferroni adjusted significance (unadjusted p < 0.05/714666 CpGs = 6.99 e−08). The top 3 Bonferroni significant CpGs per comparison are annotated to the nearest proximal gene
Fig. 2
Fig. 2
Selection of candidate CpG sites used for functional enrichment analysis, eQTM analysis, and association with FEF75 and wheeze at 12 months of age. a Venn diagram showing overlap of nominally significant DMCs between groups (n = 9541 CpGs overlapping). b Heatmap showing the magnitude and direction of methylation change (delta beta) between sample groups (P–N: placebo vs never-smoker; V–P: vitamin C vs placebo). Only the CpGs with a reversal in the direction of methylation change with vitamin C supplementation (n = 9059 CpGs “partially restored”) were considered in downstream analyses
Fig. 3
Fig. 3
Volcano plots of differentially methylated regions (DMRs) in placenta between a placebo and vitamin C smokers and b placebo smokers and never-smokers. DMRs with a Šidák adjusted p value < 0.05 are shown in red. The top 20 DMRs per comparison are annotated with the nearest gene and number of CpGs. The x-axis denotes the average delta-beta between sample groups across the DMR region
Fig. 4
Fig. 4
Overlap of genes containing restored DMRs and candidate loci nominally associated with respiratory outcomes (12 month FEF75 and/or composite wheeze score) and candidate lung development genes [61]
Fig. 5
Fig. 5
Top CpGs associated with a 12 month FEF75 and b composite wheeze score

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Source: PubMed

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