Abstract 853: The effect of maternal folic acid supplementation during pregnancy and lactation on global DNA methylation in the offspring
Authors: Crowell Julie G. , Sohn Kyoung Jin , Croxford Ruth , Kim Young-In 
Published: June 2012

Background: Folate plays an essential role in biological methylation reactions including that of DNA, aberrations of which have been shown to be mechanistically related to cancer. Intrauterine and early life exposure to folic acid has significantly increased in North America due to mandatory folic acid fortification, widespread supplemental use and periconceptional supplementation. Epigenetic programming occurs during embryogenesis and hence the embryonic stage is highly susceptible to changes in the intrauterine environment, which may influence the risk of developing cancer in adulthood. Although maternal supplementation of methyl group donors has been shown to influence DNA methylation in the offspring, the effect of maternal folic acid supplementation alone on DNA methylation in the offspring is not well established. We therefore investigated the effect of maternal folic acid supplementation provided during pregnancy and lactation on global DNA methylation in the offspring.

Methods: Female C57BL/6 mice were placed on amino acid defined diets containing 2 (control), 5, 8, or 25 mg folic acid/kg diet for 3 weeks prior to mating and throughout pregnancy and lactation. At weaning (3 weeks of age), 20 pups from each maternal diet were killed. The remaining pups (20 from each maternal diet group) were placed on the control diet until they were killed at 18 weeks of age. Plasma and liver folate concentrations were determined at 3 and 18 weeks of age. Global DNA methylation was determined in the liver at both time points using the in vitro methyl-acceptance assay.

Results: At weaning, pups from the 5, 8, and 25 mg folic acid/kg supplemented maternal diets had significantly higher plasma and liver folate concentrations compared with those from the control maternal diet in a dose-responsive manner (p&lt;0.05). At 18 weeks of age, plasma folate concentrations in pups from the 8 and 25 mg folic acid/kg supplemented maternal diets remained significantly higher than those of pups from the control maternal diet (p&lt;0.05), while liver folate concentrations did not differ significantly among pups from the four maternal diet groups. At both time points, hepatic global DNA methylation was significantly lower in pups from mothers on the folic acid supplemented diets compared with pups from the maternal control diet (p&lt;0.05). Although no clear dose-dependence was observed, 25 mg folic acid/kg maternal diet produced the greatest magnitude of decrease in global DNA methylation in pups at both time points.

Conclusion: Our data suggest that maternal folic acid provided during pregnancy and lactation can induce global DNA hypomethylation in the offspring, and that this effect appears to persist into adulthood. The functional ramifications of the observed global DNA hypomethylation as well as its potential mechanistic link to cancer risk in the offspring need to be determined in future studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 853. doi:10.1158/1538-7445.AM2011-853