Genistein induces thymic atrophy: a health concern?

描述（由申请人提供）：在以大豆为基础的配方奶粉喂养的婴儿中，雌激素大豆异黄酮染料木素和大豆黄酮的相对摄入量是食用高大豆饲料的成人的10倍，商业啮齿动物的饮食中也含有高水平的大豆和异黄酮。由于异黄酮的潜在雌激素效应，这引起了人们的关注。我们已经证明，皮下注射染料木素在卵巢切除的成年小鼠胸腺重量产生剂量反应性减少高达80%。染料木黄酮的胸腺效应通过雌激素受体（ER）和非ER介导的机制发生。染料木素可使胸腺细胞数量减少86%，细胞凋亡增加一倍，并降低CD4+CD8-和CD4+CD8+胸腺细胞的相对百分比。这伴随着脾脏CD4+CD8-细胞的相对百分比下降，全身性淋巴细胞减少，以及体液和细胞介导的免疫抑制。染料木黄酮注射剂量为8 mg/kg/天，其血清染料木黄酮水平与大豆喂养的人类婴儿相当，并且该剂量引起胸腺和免疫变化。关键的是，饮食中染料木素的浓度产生的血清染料木素水平低于大豆喂养的婴儿，与以大豆为基础的饲料喂养的啮齿动物产生的胸腺萎缩相当。这些结果提出了一种可能性，即在大豆喂养的婴儿或以大豆为基础的食物喂养的啮齿动物中发现的血清染料木素浓度可能能够产生胸腺和免疫异常，正如之前关于食用大豆为基础的食物的人类婴儿和啮齿动物的免疫变化的报道所表明的那样。本项目的长期目标是了解染料木素对胸腺和免疫系统的作用机制，并确定大豆苷元是否能发挥类似的胸腺和免疫作用。为了实现这一目标，将使用一个涉及染料木素膳食管理的生理学相关系统来确定染料木素除了对细胞数量的影响外，是否影响T细胞和B细胞的功能。研究染料木黄酮胸腺和免疫作用的可逆性，确定胸腺细胞凋亡和抑制胸腺细胞或其骨髓前体增殖在染料木黄酮作用中的作用。我们还将确定大豆黄酮是否对染料木黄酮引起的胸腺和免疫变化具有加法或拮抗作用。最后，基因阵列分析将用于确定染料木素对涉及增殖，凋亡和细胞信号传导的分子途径的影响。这些研究将促进我们对异黄酮对免疫系统影响的理解，也可能与大豆喂养的婴儿和食用大豆饲料的实验室啮齿动物有关。

DESCRIPTION (provided by applicant): Relative consumption of the estrogenic soy isoflavones genistein and daidzein in infants fed soy-based formula is 10- fold greater than adults eating high-soy diets, and commercial rodent diets also contain high levels of soy and isoflavones. This has aroused concern due to potential estrogenic effects on the isoflavones. We have shown that subcutaneous genistein injections in ovariectomized adult mice produced dose-responsive decreases in thymic weight of up to 80%. Genistein's thymic effects occurred through both estrogen receptor (ER) and non-ER mediated mechanisms. Genistein decreased thymocyte numbers up to 86% and doubled apoptosis, and decreased relative percentages of CD4+CD8- and CD4+CD8+ thymocytes. This was accompanied by decreases in relative percentages of splenic CD4+CD8- cells, systemic lymphocytopenia, and suppressed humoral and cell-mediated immunity. Genistein injected at 8 mg/kg/day produced serum genistein levels comparable to those in soy-fed human infants, and this dose caused thymic and immune changes. Critically, dietary genistein at concentrations which produced serum genistein levels less than those in soy-fed infants and comparable to those in rodents fed soy-based feed produced thymic atrophy. These results raise the possibility that serum genistein concentrations found in soy-fed infants or rodents fed soy-based chow may be capable of producing thymic and immune abnormalities, as suggested by previous reports of immune changes in soy-fed human infants and rodents consuming soy-based diets. The long-term objective of this project is to develop a mechanistic understanding of genistein' s action on the thymus and immune system, and determine if daidzein can exert similar thymic and immune effects. To accomplish this objective, a physiologically relevant system involving dietary administration of genistein will be used to determine if genistein affects T and B cell function, in addition to its effects on cell numbers. The reversibility of genistein's thymic and immune effects will be tested, and the roles that thymocyte apoptosis and inhibition of proliferation of thymocytes or their bone marrow precursors play in genistein effects will be established. We will also determine if daidzein has additive or antagonistic effects on thymic and immune changes induced by genistein. Finally, gene array analysis will be used to determine genistein effects on molecular pathways involving proliferation, apoptosis, and cell signaling. These studies will advance our understanding of isoflavone effects on the immune system, and also may have relevance for soy-fed infants and laboratory rodents consuming soy-based feed.