Genistein induces thymic atrophy: a health concern?

金雀异黄素会引起胸腺萎缩：健康问题吗？

• 批准号: 6868236
• 负责人: Paul S. Cooke
• 金额: $ 24.95万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868236
• 关键词: B lymphocyte; T lymphocyte; apoptosis; atrophy; cell proliferation; cellular immunity; dietary constituent; enzyme linked immunosorbent assay; female; gene expression; genistein; immunopathology; laboratory mouse; microarray technology; pathogenic diet; soybeans; thymus; thymus disorder

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.

描述（由申请人提供）：食用大豆配方奶粉的婴儿中雌激素大豆异黄酮金雀异黄酮和大豆黄酮的相对消耗量是食用高大豆饮食的成年人的 10 倍，并且商业啮齿动物饮食也含有高水平的大豆和异黄酮。 由于异黄酮具有潜在的雌激素作用，这引起了人们的关注。 我们已经证明，在切除卵巢的成年小鼠中皮下注射金雀异黄酮可产生剂量反应性胸腺重量下降高达 80%。 金雀异黄素的胸腺作用通过雌激素受体 (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%，使细胞凋亡加倍，并降低 CD4+CD8- 和 CD4+CD8+ 胸腺细胞的相对百分比。 伴随着脾CD4+CD8-细胞相对百分比的下降、全身性淋巴细胞减少以及体液和细胞介导的免疫抑制。以 8 毫克/公斤/天注射的金雀异黄素产生的血清金雀异黄素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。至关重要的是，饮食中的染料木黄酮浓度产生的血清染料木黄酮水平低于大豆喂养的婴儿的血清染料木黄酮水平，并且与饲喂大豆饲料的啮齿动物的血清染料木黄酮水平相当，但会导致胸腺萎缩。这些结果提出了一种可能性，即在大豆喂养的婴儿或食用大豆饲料的啮齿动物中发现的血清金雀异黄素浓度可能能够产生胸腺和免疫异常，正如之前关于大豆喂养的人类婴儿和食用大豆的啮齿动物的免疫变化的报告所表明的那样。基于饮食。该项目的长期目标是深入了解金雀异黄素对胸腺和免疫系统的作用机制，并确定黄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，将使用涉及金雀异黄酮膳食施用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之外，是否还影响 T 和 B 细胞功能。将测试金雀异黄素胸腺和免疫作用的可逆性，并确定胸腺细胞凋亡和抑制胸腺细胞或其骨髓前体细胞增殖在金雀异黄酮作用中的作用。 我们还将确定黄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花素对涉及增殖、凋亡和细胞信号传导的分子途径的影响。这些研究将增进我们对异黄酮对免疫系统影响的理解，并且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。