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）：饲养基于大豆的配方奶粉的雌激素大豆异黄酮染料和大麦葡萄酒的相对消耗比吃高肥大饮食的成年人大10倍，并且商业啮齿动物饮食还含有高水平的大豆和异黄酮。 由于潜在的雌激素对异黄酮的影响，这引起了人们的关注。 我们已经表明，在卵巢切除成年小鼠中注射皮下染料木黄酮在胸腺重量的剂量响应性降低高达80％。 染料木黄酮的胸腺效应是通过雌激素受体（ER）和非ER介导的机制发生的。 染料木黄酮降低了胸腺细胞数量高达86％，凋亡增加了一倍，并降低了CD4+CD4+CD4+CD8+胸腺细胞的相对百分比。 这伴随着脾脏CD4+CD8细胞的相对百分比降低，全身性淋巴细胞减少症以及抑制的体液和细胞介导的免疫力。以8 mg/kg/day注射的染料木黄酮与大豆喂养的人类婴儿相当的血清染料木黄酮水平，这种剂量引起胸腺和免疫变化。至关重要的是，在浓度下，产生血清染料木黄酮水平的饮食染料木黄酮比大豆喂养婴儿的染料木黄酮水平小，并且与饲养的基于大豆的饲料的啮齿动物相当。这些结果增加了在大豆喂养的婴儿或饲养基于大豆的CHOW的啮齿动物中发现的血清染料木黄酮浓度的可能性，可能能够产生胸腺和免疫异常，这是先前关于大豆喂养的人类婴儿和消耗大豆饮食的大豆喂养的人和啮齿动物的免疫变化的报道所表明的。该项目的长期目的是对染料木黄酮对胸腺和免疫系统的作用有一种机械理解，并确定大麦泽林是否可以发挥相似的胸腺和免疫作用。为了实现这一目标，除了其对细胞数量的影响外，还将使用涉及染料木黄酮饮食的生理相关系统来确定染料木黄酮是否影响T和B细胞功能。将测试染料木黄酮的胸腺胸腺和免疫作用的可逆性，并将确定胸腺细胞凋亡和抑制胸腺细胞增殖或其骨髓前体在以及旋ast依的作用中起作用的作用。 我们还将确定戴兹因对染料木黄酮引起的胸腺和免疫变化是否具有累加或拮抗作用。 最后，基因阵列分析将用于确定涉及增殖，凋亡和细胞信号传导的分子途径的染料木黄酮对分子途径的影响。这些研究将提高我们对异黄酮对免疫系统影响的理解，并且可能与大豆喂养的婴儿和消耗大豆饲料的实验室啮齿动物有关。