Effect of Maternal and Post-Weaning Folate Supply on Gene-Specific DNA Methylation in the Small Intestine of Weaning and Adult Apc+/Min and Wild Type Mice

Abstract

Increasing evidence supports the developmental origins of adult health and disease hypothesis which argues for a causal relationship between adverse early life nutrition and increased disease risk in adulthood. Modulation of epigenetic marks, e.g., DNA methylation and consequential altered gene expression, has been proposed as a mechanism mediating these effects. Via its role as a methyl donor, dietary folate supply may influence DNA methylation. As aberrant methylation is an early event in colorectal cancer (CRC) pathogenesis, we hypothesized low maternal and/or post-weaning folate intake may influence methylation of genes involved in CRC development. We investigated the effects of maternal folate depletion during pregnancy and lactation on selected gene methylation in the small intestine of wild type (WT) and Apc+/Min mice at weaning and as adults. We also investigated the effects of folate depletion post-weaning on gene methylation in adult mice. Female C57Bl6/J mice were fed low or normal folate diets from mating with Apc+/Min males to the end of lactation. A sub-set of offspring were killed at weaning. Remaining offspring were weaned on to low or normal folate diets, resulting in four treatment groups of Apc+/Min and WT mice. p53 was more methylated in weaning and adult WT compared with Apc+/Min mice (p > 0.001). Igf2 and Apc were hypermethylated in adult Apc+/Min compared with WT mice (p = 0.004 and 0.012 respectively). Low maternal folate reduced p53 methylation in adults (p = 0.04). Low post-weaning folate increased Apc methylation in Apc+/Min mice only (p = 0.008 for interaction). These observations demonstrate that folate depletion in early life can alter epigenetic marks in a gene-specific manner. Also, the differential effects of altered folate supply on DNA methylation in WT and Apc+/Min mice suggest that genotype may modulate epigenetic responses to environmental cues and may have implications for the development of personalized nutrition.

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

“…The data revealed distinct alterations in DNA methylation at these loci, in both wild-type and Apc +/Min rats, at the stages of weaning and during adulthood (McKay et al, 2011b). The results of this experiment showed that the same folate exposure alters DNA methylation in a gene-and tissue-specific manner at different life stages.…”

One-Carbon Metabolism Nutrients and Epigenetics: A Mechanistic Link Between Aberrant One-Carbon Metabolism and Cancer Risk?

“…A maternal diet deplete of folic acid fed to Apc +/ Min and wild-type mice had no effect on gene-specifi c DNA methylation in weaning mice from both groups. However, decreased genespecifi c DNA methylation at p53 in the small intestine of adult mice was seen with the depleted maternal folic acid diet (McKay et al 2011b ). Furthermore, a low folic acid diet in the postweaning period increased DNA methylation at the Apc gene in the Apc +/ Min mice but not in the wild-type mice (McKay et al 2011b ).…”

“…However, decreased genespecifi c DNA methylation at p53 in the small intestine of adult mice was seen with the depleted maternal folic acid diet (McKay et al 2011b ). Furthermore, a low folic acid diet in the postweaning period increased DNA methylation at the Apc gene in the Apc +/ Min mice but not in the wild-type mice (McKay et al 2011b ). Sie et al have recently reported signifi cant decreases in DNA methylation of the promoter regions of the Pparγ and ERα genes and in specifi c exons of the p53 and Apc genes in the liver of offspring at weaning due to maternal folic acid supplementation (Sie et al 2013 ).…”

The influence of folate and methionine on intestinal tumour development in the ApcMin/+ mouse model

“…A summary of the 13 studies [39,[57][58][59][60][61][62][63][64][65][66][67][68] is presented in Table 1, with highlights of the significant outcomes from each. Fig.…”

“…Recently, McKay et al [68] published their investigation on effects of maternal folate deficiency on DNA methylation in the offspring. Female C57Bl6/J mice were given either a folate replete (2 mg folic acid/kg diet) or low folate (0.4 mg folic acid/kg diet) diet, from mating with Apc Min/+ males, throughout pregnancy and lactation.…”