Effect of Phytoestrogens on Estrogen dependent Processes

雌激素对生殖和行为所必需的生理过程的发育和激活具有深远的影响。雌激素的作用是由雌激素受体α (erα)和erβ两种核受体介导的。破坏正常雌激素依赖过程的环境化合物可能通过这些途径中的任何一种起作用。植物雌激素是植物产生的雌激素化合物。特定的植物雌激素在体内破坏epα或erβ依赖途径的程度尚不清楚。了解这些化合物对雌激素依赖过程的影响尤为重要，因为它们现在以片剂形式出售，并被宣传为雌激素替代疗法的天然替代品。据推测，不同的植物雌激素不同地干扰erα和erβ依赖机制，导致不同的生理后果。这一假设将通过三个具体目标进行检验。特异性目标1使用分子和细胞方法来确定从保健食品商店获得的商业制备异黄酮提取物对era和erb依赖性基因在大脑中的表达的影响。补充剂的精确成分将使用高效液相色谱法确定，植物雌激素染料木素和大豆苷元的纯制剂将在补充剂中发现的浓度下进行测试。特异性目的2研究染料木素和大豆黄酮对雌性大鼠雌激素依赖性性行为的影响。具体目标3将确定在生命早期关键阶段暴露于这些植物雌激素对大脑和行为的性别分化的影响。

Estrogen has a profound influence on the development and activation of physiological processes essential for reproduction and behavior. The effects of estrogen are mediated by two nuclear receptors, estrogen receptor alpha (ERalpha) and ERbeta. Environmental compounds which disrupt normal estrogen-dependent processes may act by either of these pathways. Phytoestrogens are estrogenic compounds produced by plants. The degree to which specific phytoestrogens disrupt EPalpha or ERbeta- dependent pathways in vivo is unknown. Understanding the impact of these compounds on estrogen-dependent processes is particularly important now that they are being sold in tablet form and advertised as a natural alternative to estrogen replacement therapy. It is hypothesized that different phytoestrogens differentially interfere with ERalpha and ERbeta-dependent mechanisms, resulting in different physiological consequences. This hypothesis will be examined through three specific aims. Specific Aim 1 uses molecular and cellular approaches to determine the effects of a commercially prepared isoflavone extract obtained from a health food store on ERalpha and ERbeta-dependent gene expression in the brain. The precise composition of the supplement will be determined using high performance liquid chromatography, and pure preparations of the phytoestrogens genistein and daidzein will be tested at the concentration found in the supplement. Specific Aim 2 investigates the impact of genistein and daidzein on estrogen-dependent sex behaviors in female rats. Specific Aim 3 will determine the effects of exposure to these phytoestrogens during early critical life stages on sexual differentiation of the brain and behavior.