Lifelong exposure to dietary isoflavones - Identification of molecular mechanisms involved in tissue specific modulation of estrogen sensitivity

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In the DFG-funded project we have demonstrated that tissue-selective responsiveness to treatment with estrogen receptor ligands in female rats is strongly affected by lifelong exposure to isoflavones (IF). Lifelong IF intervention reduced the responsiveness of the breast, whereas the responsiveness of the uterus was induced. The underling molecular mechanisms are still unclear. So far, it is also not known whether estrogen sensitivity of non classical estrogen-sensitive tissues, such as the intestine, bone and adipose tissue, is also modified by lifelong IF exposure. Ongoing studies have been limited to females; effects on males have not been investigated so far.Based on these previous investigations, the major aims of the proposed research project are:a.) Further investigation of the molecular mechanisms involved in the modulation of tissue-selective responsiveness of estrogen-sensitive tissues by isoflavones. Animals will be exposed to IF at increasing concentrations and during specific developmental time windows to identify critical phases. Epigenetic effects and modulation of molecular mechanisms involved in the regulation of tissue homeostasis (apoptosis, proliferation, and differentiation) will be analyzed. Subsequent studies will validate and quantify methylation changes of selected candidate genes, investigate functional consequences of differential methylation with respect to gene expression, and clarify the mechanism of epigenetic regulation by phytoestrogens.b.) High-fat diet but also isoflavones are discussed to modulate the susceptibility of estrogen-sensitive tissue, especially the breast, to develop cancer. Therefore we will investigate the combined effects of high-fat diet and isoflavones on the responsiveness of estrogen-sensitive tissues and isoflavone metabolism.c.) Adiposity is a known risk factor for postmenopausal breast cancer. Consequently we will determine the effects of lifelong but also acute exposure to isoflavones on the development of adiposity in a diet-driven rat animal model of adiposity induction.