Environmental exposures during critical windows of development can permanently reprogram normal physiological responses, promoting the development of adult disease via an epigenetic process termed developmental reprogramming. We have demonstrated that xenoestrogens, including the soy phytoestrogen genistein (GEN), induce non-genomic rapid estrogen receptor (ER) signaling in the developing uterus, phosphorylating the histone methyltransferase EZH2 and inhibiting the ability of this epigenetic regulator to methylate chromatin at H3K27. This epigenetic reprogramming results in increased responsiveness of estrogen-regulated genes to the female hormone estrogen in the adult uterus, promoting development of these hormone-dependent tumors in genetically susceptible rats. Thus, activation of non- genomic (or more appropriately pre-genomic) signaling provides a direct link between xenoestrogen exposure and the cell's epigenetic machinery during tissue development. Importantly, we have also recently documented in these rats that tumors develop in the setting of obesity, a known risk factor for leiomyoma in women. In this R21 application, we will test the hypothesis that interventions that have been shown in other settings to decrease cancer risk, and which can reverse the obesity phenotype, will ameliorate the impact of xenoestrogen exposure on leiomyoma incidence (Specific Aim 1) and that effective interventions do so by reversing epigenetic alterations in histone methylation induced by developmental reprogramming (Specific Aim 2). This application is Significant, as it focuses on two relevant environmental factors, obesity and the soy phytoestrogen GEN, and a disease (uterine leiomyoma) that has a significant adverse effect on women's health. The application is Innovative, as it represents the first attempts to identify interventions that can prevent or reverse the adverse health effects of early life exposures to xenoestrogens. Data obtained in the exploratory project will lay the ground work for studies to identify mechanisms by which dietary, life-style and/or pharmacologic interventions modulate the epigenome to reduce risk of disease, and in the future, identify critical life-cycle windows in which these interventions can be administered to effectively reduce risk, setting the stage for translating these findings to human populations.