Genistein Exacerbation of Asthma in Mice

说明(申请人提供)：染料木素(Genistein，GEN)是一种大豆异黄酮类化合物，已被认为在体内主要作为内分泌干扰物而不是酪氨酸激酶抑制剂来调节其生物学功能。尽管Gen有假定的有益效果，但人们担心这种化合物对人类健康的长期影响，特别是对婴儿和幼儿的影响。最近的流行病学调查结果表明，在婴儿时期喂食大豆配方奶粉的年轻人，与喂食牛奶配方奶粉的年轻人相比，哮喘或过敏药物的使用量有所增加。哮喘发病的一个重要机制是变应原反复刺激局部呼吸道组织中辅助性T细胞(Th)2极化的T细胞免疫。我们的研究提供了证据表明，实验动物口服生理浓度的GEN后，发育中的免疫系统，特别是T细胞的功能发生了变化。据推测，发育过程中暴露于GEN可调节Th2细胞因子基因(如IL-4和IL-13)的染色质结构，从而导致成年后对呼吸道变应原偏苯三酸酐(TMA)的超敏反应增加。为了验证这一假设，将追求两个特定的目标：(1)确定发育中暴露于GEN是否会导致成年后对呼吸道变应原TMA的超敏反应增强；(2)确定发育中暴露于GEN是否会导致DNA去甲基化和Th2细胞因子基因(如IL-4和IL-13)的染色体重塑。这项调查的结果将为了解这种化合物的消费对健康的影响提供合理的基础。通过识别可能在增加风险方面起重要作用的细胞因子，通过观察生命中的脆弱时期，以及通过识别可能通过不同机制驱动导致哮喘的免疫过程的环境因素，我们将获得更好的洞察力，以便做出关于干预研究的明智决定。

DESCRIPTION (provided by applicant): Genistein (GEN), a soy isoflavone, has been suggested to mediate its biological function mainly as an endocrine disruptor instead of a tyrosine kinase inhibitor in vivo. Despite the hypothesized beneficial effects of GEN, there are concerns about the long-term effects of this compound on human health, especially that of infants and young children. The recent epidemiological findings indicate that there is an increase in the use of asthma or allergy drugs in young adults who have been fed soy formula during infancy as compared to those who have been fed cow milk formula. One important mechanism for development of asthma is that allergens repeatedly stimulate T helper (Th) 2-polarized T-cell immunity in local airway tissue. Our studies have provided evidence that the developing immune system, especially the function of T cells, was altered following oral exposure to GEN at physiologically relevant concentrations in experimental animals. It is hypothesized that developmental exposure to GEN modulates the chromatin structure of Th2 cytokine genes (e.g., IL-4 and IL-13) and, thus, leads to an increase in the hypersensitivity responses to respiratory allergen trimellitic anhydride (TMA) in adult life. To test this hypothesis, two specific aims will be pursued: (1) To determine if developmental exposure to GEN leads to an enhancement in hypersensitivity responses to respiratory allergen TMA in adult life; (2) To determine if developmental exposure to GEN leads to DNA demethylation and chromosome remodeling of Th2 cytokine genes such as IL-4 and IL-13. Results of this investigation will provide a rational basis for understanding the health implications associated with the consumption of this compound. By identifying possible cytokines that are important at increasing risks, by looking at vulnerable periods in life, and by identifying environmental factors which through different mechanisms may be driving the immunological processes (amongst others) that lead to asthma, we will gain a better insight with which to make informed decisions regarding intervention studies.