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Dana C. Dolinoy,^1,2,3 Jennifer R. Weidman,^1,2 Robert A. Waterland,^4,5 and Randy L. Jirtle^1,2,3

¹Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA; ²University Program in Genetics and Genomics, and ³Integrated Toxicology Program, Duke University, Durham, North Carolina, USA; ⁴Department of Pediatrics, and ⁵Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

Abstract
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. Here, we report that maternal dietary genistein supplementation of mice during gestation, at levels comparable with humans consuming high-soy diets, shifted the coat color of heterozygous viable yellow agouti (A^vy/a) offspring toward 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. The extent of this 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 offspring from obesity. Thus, we provide the first evidence that in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome. Key words: developmental origins of adult disease, DNA methylation, epigenetics, viable yellow agouti (A^vy) mouse. Environ Health Perspect 114:567-572 (2006) . doi:10.1289/ehp.8700 available via http://dx.doi.org/ [Online 26 January 2006]

Address correspondence to R.L. Jirtle, Box 3433, Duke University Medical Center, Durham, NC 27710 USA. Telephone: (919) 684-2770. Fax: (919) 684-5584. E-mail: jirtle@radonc.duke.edu

We thank C.A. Smith for technical assistance.

This work was supported by National Institutes of Health grants ES13053, ES08823, CA25951, and T32-ES07031, and U.S. Department of Agriculture CRIS 6250-51000-049.

The authors declare they have no competing financial interests.

Received 28 September 2005 ; accepted 26 January 2006.

Correction

In "Materials and Methods," the authors have clarified that the "modified AIN-93G diet (diet 95092 with 7% corn oil substituted for 7% soybean oil ; Harlan Teklad, Madison, WI) " is phytoestrogen-free.