Genistein induces thymic atrophy: a health concern?

描述（由申请方提供）：喂食大豆配方食品的婴儿中雌激素大豆异黄酮染料木素和大豆苷元的相对消耗量是食用高大豆饮食的成人的10倍，商业啮齿动物饮食也含有高水平的大豆和大豆异黄酮。 这引起了人们的关注，由于潜在的雌激素作用的甾体酮。 我们已经证明，在切除卵巢的成年小鼠皮下注射染料木黄酮产生剂量反应性降低胸腺重量高达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。 染料木素使胸腺细胞数量减少86%，凋亡加倍，并降低CD 4 + CD 8-和CD 4 + CD 8+胸腺细胞的相对百分比。 这伴随着脾脏CD 4 + CD 8-细胞的相对百分比降低，全身淋巴细胞减少，以及抑制体液和细胞介导的免疫。以8 mg/kg/天的剂量注射染料木黄酮，产生的血清染料木黄酮水平与大豆喂养的人类婴儿相当，该剂量引起胸腺和免疫变化。重要的是，饮食中染料木黄酮的浓度，产生血清染料木黄酮水平低于那些在大豆喂养的婴儿和啮齿动物喂养的大豆为基础的饲料产生胸腺萎缩。这些结果提高了大豆喂养的婴儿或啮齿类动物喂养大豆为基础的食物中发现的血清染料木黄酮浓度可能能够产生胸腺和免疫异常，如以前的报告所建议的免疫变化在大豆喂养的人类婴儿和啮齿类动物消耗大豆为基础的饮食。本项目的长期目标是发展对染料木素对胸腺和免疫系统作用的机制理解，并确定大豆黄酮是否可以发挥类似的胸腺和免疫作用。为了实现这一目标，将使用涉及膳食给予染料木黄酮的生理学相关系统来确定染料木黄酮除了对细胞数量的影响之外是否影响T和B细胞功能。染料木黄酮的胸腺和免疫效应的可逆性将被测试，和胸腺细胞凋亡和抑制胸腺细胞或其骨髓前体的增殖染料木黄酮的作用将被建立。 我们还将确定大豆黄酮是否对染料木黄酮诱导的胸腺和免疫变化具有相加或拮抗作用。 最后，基因阵列分析将被用来确定染料木黄酮的分子途径，涉及增殖，凋亡和细胞信号转导的影响。这些研究将促进我们对大豆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.