There is accumulating evidence that the pathogenesis of adult cancer can be influenced by nutrition in early life. One probable underlying mechanism is through early nutritional effects on epigenetics, i.e. self perpetuating gene regulatory systems that are not dependent on DNA sequence. A particularly relevant epigenetic mechanism involves the methylation of cytosine residues on both strands of palindromic CpG dinucleotides. Mammalian one-carbon metabolism, which provides the methyl groups for biological methylation reactions, is highly dependent on dietary substrates and co-factors. Thus, the requirement to establish and maintain genomic methylation patterns during early development may make it more critical to maintain appropriate levels of these diet-derived components at that time than during later life. We have demonstrated that dietary methyl donor supplementation with extra folic acid, vitamin B12, choline and betaine during early development of viable yellow agouti (A {vy}) mice alters coat color by increasing CpG methylation at the agouti locus. The overall hypothesis of the proposed research is that maternal dietary methyl donor supplementation can alter DNA methylation of imprinted genes in the early embryo, and that these induced epigenetic alterations persist to influence adult cancer susceptibility.
The specific aims of the proposed research are to: 1) determine if maternal dietary methyl donor supplementation during pregnancy and lactation alters breast cancer susceptibility in the offspring to the carcinogenic heterocyclic amine, phenyl-imidazol [4,5-b] pyridine (PhlP), 2) determine if maternal dietary methyl donor supplementation during pregnancy and lactation alters allelic expression and allele-specific DNA methylation of the imprinted insulin-like growth factor 2 (lgf2) gene, and 3) identify other imprinted genes whose methylation and allelic expression are altered by maternal dietary methyl donor supplementation during pregnancy and lactation. Because epigenetic dysregulation of genomic imprinting is implicated in a broad range of human developmental disorders and cancer, understanding the specific biologic mechanisms linking prenatal nutrition to adult expression of imprinted genes may ultimately enable early-life nutritional interventions to prevent adult-onset cancer in humans. ? ?
| Dolinoy, Dana C; Weinhouse, Caren; Jones, Tamara R et al. (2010) Variable histone modifications at the A(vy) metastable epiallele. Epigenetics 5:637-44 |
| Dolinoy, Dana C (2008) The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome. Nutr Rev 66 Suppl 1:S7-11 |
| Dolinoy, Dana C; Jirtle, Randy L (2008) Environmental epigenomics in human health and disease. Environ Mol Mutagen 49:4-8 |
| Luedi, Philippe P; Dietrich, Fred S; Weidman, Jennifer R et al. (2007) Computational and experimental identification of novel human imprinted genes. Genome Res 17:1723-30 |
| Dolinoy, Dana C (2007) Epigenetic gene regulation: early environmental exposures. Pharmacogenomics 8:5-10 |
| Dolinoy, Dana C; Weidman, Jennifer R; Jirtle, Randy L (2007) Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol 23:297-307 |
| Weidman, Jennifer R; Dolinoy, Dana C; Murphy, Susan K et al. (2007) Cancer susceptibility: epigenetic manifestation of environmental exposures. Cancer J 13:9-16 |
| Dolinoy, Dana C; Das, Radhika; Weidman, Jennifer R et al. (2007) Metastable epialleles, imprinting, and the fetal origins of adult diseases. Pediatr Res 61:30R-37R |
| Dolinoy, Dana C; Huang, Dale; Jirtle, Randy L (2007) Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A 104:13056-61 |
| Weidman, Jennifer R; Dolinoy, Dana C; Maloney, Kristin A et al. (2006) Imprinting of opossum Igf2r in the absence of differential methylation and air. Epigenetics 1:49-54 |
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