Maternal folate supply and sex influence gene-specific DNA methylation in the fetal gut

Scope: Epidemiological evidence supports the developmental origins of health and disease hypothesis that developmental under/over-nutrition increases adulthood disease risk. Epigenetic markings are one potential mechanism mediating these effects. Altered folate supply may influence methyl group availability for DNA methylation. We reported low folate supply in utero was associated with reduced global DNA methylation in the murine small intestine of adult offspring. We hypothesised that aberrant methylation would be observed during early development. Methods and results: Female C57BL/6J mice were fed diets containing 2mg folic acid/kg or 0.4mg folic acid/kg 4wk before mating and during pregnancy. At 17.5 day gestation, gene methylation in fetal gut was analysed by Pyrosequencing (R). Low folate reduced overall methylation of Slc394a by 3.4% (p = 0.038) but did not affect Esr1 or Igf2 differentially methylated region (DMR) 1. There were sex-specific differences in Slc394a and Esr1 methylation (2.4% higher in females (p = 0.002); 4% higher in males (p = 0.0014), respectively). Conclusion: This is the first study reporting causal effects of maternal folate depletion on gene-specific methylation in fetal gut. These observations support reports that altered methyl donor intake during development affects DNA methylation in the offspring. The consequences of epigenetic changes for health throughout the life course remain to be investigated.