Genistein induces thymic atrophy: a health concern?

说明(申请人提供)：在食用大豆配方奶粉的婴儿中，雌激素大豆异黄酮染料木素和大豆苷元的相对消费量是食用高大豆饮食的成年人的10倍，商业啮齿动物饮食中也含有高水平的大豆和异黄酮。这引起了人们的关注，因为异黄酮类化合物具有潜在的雌激素效应。我们已经证明，去卵巢的成年小鼠皮下注射染料木素可使胸腺重量减少高达80%，呈剂量反应关系。金雀异黄素的胸腺效应通过雌激素受体(ER)和非ER介导的机制发生。金雀异黄素使胸腺细胞数量减少高达86%，细胞凋亡率增加一倍，并降低了CD4+CD8-和CD4+CD8+细胞的相对百分比。伴随而来的是脾中CD4+CD8-细胞的相对百分比下降，全身淋巴细胞减少，体液免疫和细胞免疫受到抑制。每天注射8毫克/公斤的染料木素产生的血清染料木素水平与大豆喂养的人类婴儿相当，并且该剂量会引起胸腺和免疫功能的变化。关键的是，当饮食中的染料木素浓度比大豆喂养的婴儿产生更少的血清染料木素水平，而与以大豆为基础的饲料喂养的啮齿类动物产生类似的浓度时，会导致胸腺萎缩。这些结果提出了这样一种可能性，即在食用大豆饲料的婴儿或啮齿动物中发现的血清染料木素浓度可能会产生胸腺和免疫异常，正如之前关于食用大豆饮食的人类婴儿和啮齿动物的免疫变化的报告所表明的那样。该项目的长期目标是从机制上了解染料木素S对胸腺和免疫系统的作用，并确定大豆苷元是否可以发挥类似的胸腺和免疫作用。为了实现这一目标，将使用一个涉及饮食给药的生理相关系统来确定金雀异黄素除了对细胞数量的影响外，是否还影响T和B细胞功能。将测试金雀异黄素的胸腺和免疫效应的可逆性，并确定胸腺细胞凋亡和胸腺细胞或其骨髓前体细胞增殖抑制在金雀异黄素效应中的作用。我们还将确定大豆苷元对金雀异黄素诱导的胸腺和免疫变化是否具有相加或拮抗作用。最后，基因阵列分析将用于确定金雀异黄素对涉及增殖、凋亡和细胞信号的分子通路的影响。这些研究将促进我们对异黄酮对免疫系统影响的理解，也可能对食用大豆饲料的婴儿和实验室啮齿动物具有相关性。

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.