Background: Early folate nutrition may play an important role in epigenetic programming and can have a permanent effect on disease risk in adulthood. Folate is involved in DNA methylation reactions, aberrations of which have been shown to be related to several chronic diseases, including cancer. Previous studies have shown that methyl donors in the maternal diet and during early development can affect DNA methylation in the offspring. However, it is unknown whether folic acid (FA) supplementation alone, provided during pregnancy and early postnatal life can affect epigenetics in the offspring. We therefore investigated the effect of FA supplementation provided in utero and postnatally on genomic DNA methylation in rats. Methods: Female Sprague-Dawley rats were placed on either a control (2mg FA/kg diet) or supplemented (5mg FA/kg diet) for 3 weeks prior to breeding and remained on the diet throughout pregnancy and lactation. 25 pups from each maternal diet group were sacrificed at weaning (3 weeks of age) for baseline measures. Pups from each maternal diet group were randomized to either the control or supplemented diet (n=25/group) at weaning. At 14 weeks of age, all rats were sacrificed. Genomic DNA methylation was measured in the colon and liver at baseline and 14 weeks of age, using LC/MS and in vitro methyl-acceptance assay, respectively. Plasma folate and homocysteine (Hcy: an accurate inverse indicator of folate status) and liver folate concentrations were also determined at both time points. Results: At both baseline and 14 weeks of age, plasma and liver folate concentrations accurately reflected dietary FA levels (p<0.001) and was higher in the supplemented FA groups. Plasma Hcy was significantly lower in animals fed the supplemented diet (p<0.001). At weaning, genomic DNA methylation in the colonic mucosa was significantly higher in pups from the supplemented maternal diet group (p=0.007). At 14 weeks of age, however, the supplemented pup diet group had a significantly lower genomic DNA methylation than pups on the control diet (p<0.05). Hepatic genomic DNA methylation was significantly lower in pups on the supplemented diet than in pups on the control diet at both time points (p<0.001 and p=0.037, respectively). Conclusion: Our data suggests that FA supplementation provided in utero and postnatally significantly influences genomic DNA methylation in the offspring. The direction of this change was opposite to what was expected in the colon and liver at 14 weeks of age and in the colon at weaning. The potential implications of maternal FA supplementation induced DNA methylation changes in the offspring in the development of cancer in adulthood remain to be elucidated. This is an important issue in North American, given the drastically increased FA intake in women of child bearing age from FA supplementation and mandatory fortification.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 45.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO