Maternal and Cord Blood Folate Concentrations Are Inversely Associated with Fetal DNA Hydroxymethylation, but Not DNA Methylation, in a Cohort of Pregnant Canadian Women

Abstract

Background Aberrancies in fetal DNA methylation programming may modify disease susceptibility of the offspring. Maternal folate status has potential to alter fetal DNA methylation. Objectives We examined the association of maternal and cord blood concentrations of folate and unmetabolized folic acid (UMFA), vitamin B-12, vitamin B-6, and choline with fetal DNA methylation and hydroxymethylation and assessed potential modifying effects of 38 fetal genetic variants in 22 genes. Methods Nutrient blood concentrations were measured in 368 pregnant women in early pregnancy (12–16 wk of gestation) and at delivery (37–42 wk of gestation) and in cord blood. DNA methylation and hydroxymethylation in cord blood mononuclear cells were quantified by LC-MS/MS. Pearson partial correlations were used to determine the association between individual nutrients and DNA methylation and hydroxymethylation. Results Serum and RBC folate and plasma UMFA concentrations (primary outcomes) in early pregnancy, at delivery, and in cord blood were not significantly associated with fetal DNA methylation. In contrast, maternal RBC folate in early pregnancy (r = −0.16, P = 0.04) and cord plasma UMFA (r = −0.23, P = 0.004) were inversely correlated with fetal DNA hydroxymethylation. Neither maternal and cord blood concentrations of other nutrients nor fetal genotypes (secondary outcomes) were significantly associated with fetal DNA methylation or hydroxymethylation. Infants born to mothers with RBC folate concentrations in the highest quartile and serum vitamin B-12 concentrations in the lowest quartile in early pregnancy had significantly lower fetal DNA methylation and higher birth weight compared with those born to mothers with lower RBC folate and higher serum vitamin B-12 concentrations (P = 0.01). Conclusions Maternal and cord blood folate concentrations are associated with fetal DNA hydroxymethylation, but not DNA methylation, in a cohort of pregnant Canadian women. The observation that high folate and low vitamin B-12 maternal status in early pregnancy may be associated with decreased fetal DNA methylation and higher birth weight warrants further investigation. This trial was registered at clinicaltrials.gov as NCT02244684.

Effects of maternal and fetal choline concentrations on the fetal growth and placental DNA methylation of 12 target genes related to fetal growth, adipogenesis, and energy metabolism

“…The authors showed that corticotropin-releasing hormone (CRH) methylation in the placenta was increased and serum cortisol level was decreased in cord blood in the supplemented group, suggesting that maternal choline status was associated with CRH methylation in the placenta and with changes in offspring phenotype. It appears paradoxical that increased choline level is associated with decreased DNA methylation at RXRA, while a previous study 42 has similarly reported an inverse association between folate level and fetal DNA hydroxymethylation. Further investigation is warranted to clarify how gestational supply of methyl donors, like choline and folate, affects increased/decreased DNA methylation in the placenta and fetal organs.…”

Nutrients, Mitochondrial Function, and Perinatal Health

“…Pregnant women with the higher dietary methyl-group intake (folate, betaine, choline, and methionine) showed higher global DNA methylation in the third trimester [ 100 ]. Inadequate maternal blood concentrations of some methyl-donor nutrients have been associated with a decrease in overall DNA methylation and a higher birth weight [ 101 ]. Hypo- or hyper-methylation of DNA could be associated with different neonatal and childhood diseases [ 102 ].…”

Vitamin B12status in health and disease: a critical review. Diagnosis of deficiency and insufficiency – clinical and laboratory pitfalls

“…Most importantly, pregnant women are at high risk of developing deficiency as the requirements for vitamin B 12 are exceptionally high during pregnancy as a result of increased metabolic rate and fetal demands. Studies conducted on maternal-fetal dyads demonstrate higher cord blood B 12 concentrations than those of the respective mothers and a direct relationship between the two pools [142][143][144][145].…”