Maternal One-Carbon Metabolism and Infant DNA Methylation between Contrasting Seasonal Environments: A Case Study from The Gambia.

Background: The periconceptional period is a time in which environmentally induced changes to the epigenome could have significant consequences for offspring health. Metastable epialleles (MEs) are genomic loci demonstrating interindividual variation in DNA methylation with intraindividual crosstissue correlation, suggesting that methylation states are established in the very early embryo before gastrulation. In our previous Gambian studies, we have shown that ME methylation states in the offspring are predicted by maternal concentrations of certain nutritional biomarkers around the time of conception. Objective: We aimed to assess whether the profile of maternal biomarker predictors of offspring methylation differs between rainy and dry seasons in a population of rural Gambians, using a larger set of 50 recently identified MEs. Methods: We measured 1-carbon biomarkers in maternal plasma back-extrapolated to conception, and cytosine-phosphate-guanine (CpG) methylation at 50 ME loci in their infants' blood at a mean age of 3.3 mo (n = 120 mother-child pairs). We tested for interactions between seasonality and effects of biomarker concentrations on mean ME methylation z score. We used backward stepwise linear regression to select the profile of nutritional predictors of methylation in each season and repeated this analysis with biomarker principal components (PCs) to capture biomarker covariation. Results: We found preliminary evidence of seasonal differences in biomarker-methylation associations for folate, choline, and homocysteine (interaction P values ≤0.03). Furthermore, in stratified analyses, biomarker predictors of methylation changed between seasons. In the dry season, vitamin B-2 and methionine were positive predictors. In the rainy season, however, choline and vitamin B-6 were positive predictors, and folate and vitamin B-12 were negative predictors. PC1 captured covariation in the folate metabolism cycle and predicted methylation in dry season conceptions. PC2 represented the betaine remethylation pathway and predicted rainy season methylation. Conclusions: Underlying nutritional status may modify the association between nutritional biomarkers and methylation, and should be considered in future studies.