Genistein Exacerbation of Asthma in Mice

描述（由申请人提供）：染料木素（genstein， GEN）是一种大豆异黄酮，在体内被认为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。尽管人们假设GEN有有益的影响，但人们担心这种化合物对人类健康，特别是婴幼儿健康的长期影响。最近的流行病学调查结果表明，在婴儿时期食用大豆配方奶粉的年轻人与食用牛奶配方奶粉的年轻人相比，使用哮喘或过敏药物的人数有所增加。哮喘发展的一个重要机制是过敏原反复刺激局部气道组织中的T辅助（Th） 2极化T细胞免疫。我们的研究提供的证据表明，实验动物口服暴露于生理相关浓度的GEN后，发育中的免疫系统，特别是T细胞的功能发生了改变。据推测，发育过程中暴露于GEN会调节Th2细胞因子基因（如IL-4和IL-13）的染色质结构，从而导致成人对呼吸道过敏原三苯三酸酐（TMA）的超敏反应增加。为了验证这一假设，将追求两个具体目标：(1)确定发育暴露于GEN是否会导致成人生活中对呼吸道过敏原TMA的超敏反应增强；(2)确定发育暴露于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与食用这种化合物有关的健康影响提供合理的基础。通过识别可能在增加风险中起重要作用的细胞因子，通过观察生命中的脆弱时期，通过识别可能通过不同机制驱动导致哮喘的免疫过程（以及其他）的环境因素，我们将获得更好的洞察力，从而在干预研究方面做出明智的决定。

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.