Title: Environmental Epigenomics and Adult Disease Susceptibility

Author: Randy L. Jirtle, Ph.D.

Institutions: Duke University Medical Center, Durham, NC 27710 USA

Human epidemiologic and animal data indicate that susceptibility to adult-onset chronic diseases such as cardiovascular disease, diabetes, obesity, and cancer is influenced by persistent adaptations to prenatal and early postnatal nutrition [1]. Two potential epigenomic targets for early nutritional effects are imprinted genes and transposons. Imprinting is an epigenetic form of gene regulation that results in monoallelic parent-of-origin dependent gene expression [2]. IGF2 loss of imprinting is associated with an increased incidence of cancer [3], and Beckwith-Wiedemann syndrome in children conceived by in vitro fertilization [4]. We have now demonstrated in mice that early postnatal dietary methyl deficiency, and even exposure to a nutritionally complete synthetic diet, high in fat but low in fiber, causes biallelic expression of the oncogene, Igf2.

We have also used the viable yellow agouti (A^vy) mouse, which harbors a retrotransposon upstream of the Agouti gene, to investigate the importance of maternal nutrition in determining the susceptibility of offspring to adult diseases [5]. We have shown that maternal dietary supplementation during pregnancy with either methyl donating substances (i.e. folic acid, vitamin B₁₂, choline and betaine) or genistein, a phytoestrogen present in soya products, alters coat color of the offspring via increased CpG methylation at the (A^vy) locus rather than by genetic mutation. Furthermore, this epigenetic change reduces the risk of developing obesity, diabetes,
and cancer in the offspring - a clear example of nature via nurture.

Thus, we have provided evidence that epigenetic alterations of transposons and imprinted genes can directly link exposure to environmental agents during early development to the etiology of adult diseases. Whether one of these environmental agents is low dose ionizing radiation is presently unknown.


REFERENCES

1. Waterland RA, Jirtle RL: Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition 20: 63-68, 2004.
2. Murphy SK, Jirtle RL: Imprinting evolution and the price of silence. Bioessays 25: 577-588, 2003.
3. Cui H, Cruz-Correa M, Giardiello FM, Hutcheon DF, Kafonek DR, Brandenburg S, Wu Y, He X, Powe NR, Feinberg AP: Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 299: 1753-1755, 2003.
4. Niemitz EL, Feinberg AP: Epigenetics and assisted reproductive technology: a call for investigation. Am. J. Hum. Genet. 74: 599-609, 2004.
5. Waterland RA, Jirtle RL: Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Cell. Mol. Biol. 23: 5293-5300, 2003.