Dietary and supplemental maternal methyl-group donor intake and cord blood DNA methylation

<p>Maternal nutrition is critically involved in the development and health of the fetus. We evaluated maternal methyl-group donor intake through diet (methionine, betaine, choline, folate) and supplementation (folic acid) before and during pregnancy in relation to global DNA methylation and hydroxymethylation and gene specific (<i>IGF2 DMR, DNMT1, LEP, RXRA</i>) cord blood methylation. A total of 115 mother-infant pairs were enrolled in the MAternal Nutrition and Offspring's Epigenome (MANOE) study. The intake of methyl-group donors was assessed using a food-frequency questionnaire. LC-MS/MS and pyrosequencing were used to measure global and gene specific methylation, respectively. Dietary intake of methyl-groups before and during pregnancy was associated with changes in <i>LEP, DNMT1</i>, and <i>RXRA</i> cord blood methylation. Statistically significant higher cord blood <i>LEP</i> methylation was observed when mothers started folic acid supplementation more than 6 months before conception compared with 3–6 months before conception (34.6 ± 6.3% vs. 30.1 ± 3.6%, <i>P</i> = 0.011, <i>LEP</i> CpG1) or no folic acid used before conception (16.2 ± 4.4% vs. 13.9 ± 3%, <i>P</i> = 0.036 for <i>LEP</i> CpG3 and 24.5 ± 3.5% vs. 22.2 ± 3.5%, <i>P</i> = 0.045 for <i>LEP</i> mean CpG). Taking folic acid supplements during the entire pregnancy resulted in statistically significantly higher cord blood <i>RXRA</i> methylation as compared with stopping supplementation in the second trimester (12.3 ± 1.9% vs. 11.1 ± 2%, <i>P</i> = 0.008 for <i>RXRA</i> mean CpG). To conclude, long-term folic acid use before and during pregnancy was associated with higher <i>LEP</i> and <i>RXRA</i> cord blood methylation, respectively. To date, pregnant women are advised to take a folic acid supplement of 400 µg/day from 4 weeks before until 12 weeks of pregnancy. Our results suggest significant epigenetic modifications when taking a folic acid supplement beyond the current advice.</p>