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

在DFG资助的项目中，我们已经证明了雌性大鼠对雌激素受体配体治疗的组织选择性反应性受到终身异黄酮类(IF)暴露的强烈影响。终生IF干预降低了乳房的反应性，而子宫的反应性是被诱导的。其潜在的分子机制仍不清楚。到目前为止，也不知道非经典雌激素敏感组织，如肠、骨和脂肪组织的雌激素敏感性是否也被终身IF暴露所改变。正在进行的研究仅限于女性；到目前为止还没有调查过对男性的影响。根据以前的调查，拟议研究项目的主要目标是：a)进一步探讨异黄酮调节雌激素敏感组织组织选择性反应的分子机制。动物将在不断增加的浓度和特定的发育时间窗内暴露在IF中，以确定关键阶段。将分析表观遗传效应和调节组织内稳态(细胞凋亡、增殖和分化)的分子机制。随后的研究将验证和量化选定候选基因的甲基化变化，研究差异甲基化对基因表达的功能影响，并阐明植物雌激素对表观遗传的调控机制。高脂肪饮食和异黄酮类也被讨论，以调节雌激素敏感组织，特别是乳房，患癌症的易感性。因此，我们将研究高脂饮食和异黄酮对雌激素敏感组织的反应性和异黄酮代谢的联合影响。肥胖是绝经后乳腺癌的已知危险因素。因此，我们将在饮食驱动的肥胖诱导大鼠动物模型中，确定终生但也是急性暴露于异黄酮对肥胖发展的影响。

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.