4.6 Article

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

Journal

CLINICAL EPIGENETICS
Volume 13, Issue 1, Pages -

Publisher

BMC
DOI: 10.1186/s13148-021-01161-y

Keywords

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

Funding

  1. NHLBI [R01 HL105447, R01 HL 105460]
  2. Office of Dietary Supplements (ODS)
  3. NIH [UH3 OD023288]
  4. National Center for Advancing Translational Sciences [UL1TR000128]
  5. [P51 OD011092565]

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Maternal smoking during pregnancy impacts multiple organ systems in the fetus and offspring, with lifelong deficits in pulmonary function and increased risk of respiratory issues. Vitamin C supplementation can ameliorate the adverse effects of maternal smoking on placental DNA methylation and gene expression, potentially improving placental function and respiratory health outcomes in offspring. Further research is needed to validate candidate loci and elucidate the causal pathway between placental methylation changes and outcomes in offspring exposed to maternal smoking.
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. .

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