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Genistein methylates the fetal epigenome

1 September 2006: Genistein, the major phytoestrogen in soy, is linked to diminished female reproductive performance and to cancer chemoprevention and decreased adipose deposition. Dietary genistein may also play a role in the decreased incidence of cancer in Asians compared with Westerners, as well as increased cancer incidence in Asians immigrating to the United States.

We previously demonstrated that maternal methyl donor supplementation of mice during gestation with folic acid, choline, vitamin B12 and betaine markedly changed the coat color of viable yellow agouti (Avy) offspring by altering the epigenome rather than mutating the genome; a clear example of nature via nurture (Waterland and Jirtle, Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23: 5293-5300, 2003). Maternal dietary genistein supplementation of mice during gestation was shown in this paper to also shift the coat color of Avy offspring from yellow to pseudoagouti.

This marked phenotypic change was significantly associated with increased methylation of six cytosine-guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene even though genistein is not a methylated compound. The extent of DNA methylation was similar in endodermal, mesodermal, and ectodermal tissues, indicating that genistein acts during early embryonic development. Moreover, this genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting the offspring from obesity. This study provides the first evidence that in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome.

A number of important implications result from these findings. Firstly, they demonstrate that it is essential to determine the effects of environmental factors on the epigenome during prenatal and early postnatal development, rather than just in adults. Secondly, since phytoestrogen content in laboratory animal feed is highly variable, genistein's effect on fetal DNA methylation patterns could significantly influence the interpretation of hormone and other rodent assay studies as well as confound the interpretation of gene expression arrays and DNA methylation studies. Finally, it needs to be determined if the relatively high genistein intake of infants consuming soy formulas is beneficial or has unintended deleterious effects on the human epigenome, especially in the United States and other countries where the food supply is fortified with folic acid.