Maternal Genistein Alters Coat Color and Protects <i> A ^vy </i> Mouse Offspring from Obesity by Modifying the Fetal Epigenome

TLDR

Genistein, a soy phytoestrogen, is linked to reduced adipose deposition, cancer chemoprevention, altered reproductive performance, and may contribute to lower cancer rates in Asian populations. Maternal genistein supplementation during pregnancy induces hypermethylation of the Agouti promoter, shifts offspring coat color toward pseudoagouti, and protects them from obesity by reducing ectopic Agouti expression.

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.