Perinatal exposure to environmental estrogens and asthma pathogenesis

描述（由申请人提供）：哮喘和其他过敏性疾病的患病率在工业国家急剧增加。先天免疫系统的细胞（肥大细胞、嗜碱性细胞和嗜酸性细胞）直接参与过敏性炎症，并可促进分化为辅助性T型2 （Th2）表型，支持B细胞的同型转换以产生IgE和晚期反应。辅助性T细胞系统对过敏原的初始启动通常发生在子宫内或出生后早期，此时Th2细胞通常主导免疫反应。延迟从Th2到Th1优势的正常转化的因素增加了发生过敏性疾病的风险。我们发现，暴露于雌二醇（E2）和环境雌激素通过雌激素受体α的膜形式，强烈增强肥大细胞中过敏介质的合成和释放。此外，在典型过敏性致敏后未产生IgE反应的去卵巢BALB/c小鼠通过植入E2微球进行重组。环境雌激素往往降解缓慢，在食物链中生物积累和生物浓缩，并通过胎盘和母乳转移给后代。目前的建议是建立哮喘动物模型，以确定关键发育时期(s)，在此期间，环境雌激素促进过敏致敏和气道高反应性和炎症。我们还将使用该模型进行初步的离体实验，以确定受环境雌激素功能改变的关键细胞类型。本项目要测试的一般假设是，在关键发育时期，遗传易感动物暴露于环境雌激素，通过调节先天免疫细胞的功能，促进过敏致敏/反应。具体的目标将测试具体的假设：1)在免疫发育的关键时期暴露于环境雌激素可增强哮喘动物模型中的过敏致敏和反应；2)环境雌激素通过调节抗原提呈细胞（APCs）支持Th2反应的潜力，塑造T细胞对正常APCs的反应，和/或增强肥大细胞脱颗粒和细胞因子的产生来增强过敏致敏。更广泛的未来研究将剖析分子机制，以帮助我们确定预防暴露或中断不良雌激素效应的方法。环境污染可能是最近哮喘和其他过敏性疾病增加的一个原因。该项目将建立一个小鼠模型，以研究环境雌激素样化学物质对儿童哮喘发展的影响。

DESCRIPTION (provided by applicant): The prevalence of asthma and other allergic diseases in industrial countries have increased dramatically. Cells of the innate immune system (mast cells, basophils and eosinophils) contribute directly to the allergic inflammation and can promote the differentiation to the T helper type 2 (Th2) phenotype that supports isotype switching of B cell to IgE production and late phase responses. The initial priming of the T helper cell system to allergen frequently occurs in utero or in the early postnatal period, when Th2 cells normally dominate the immune response. Factors that delay the normal conversion from Th2 to Th1 dominance enhance the risk of developing allergic diseases. We have found that exposure to estradiol (E2) and environmental estrogens strongly potentiate the synthesis and release of allergic mediators from mast cells, through a membrane form of estrogen receptor alpha. Further, ovarectomized BALB/c mice that fail to make an IgE response after typical allergic sensitization are reconstituted by implanting E2 pellets. Environmental estrogens tend to degrade slowly, bioaccumulate and bioconcentrate in the food chain, and are transferred to offspring via the placenta and breast milk. The current proposal is to develop an animal model of asthma for identifying critical developmental period(s), during which environmental estrogens promote allergic sensitization and airway hyperreactivity and inflammation. We will also use this model to perform initial ex vivo experiments to identify the key cell type(s) that are functionally altered by environmental estrogens. The general hypothesis to be tested in this project is that exposure of genetically susceptible animals to environmental estrogens during critical developmental period promotes allergic sensitization / reactions by modulating the function of cells of innate immunity. The specific aims that will test the specific hypotheses that: 1) Exposure to environmental estrogens, during a critical period(s) of immune development can enhance allergic sensitization and reactions in an animal model of asthma, and 2) Environmental estrogens enhance allergic sensitization by modulating the potential of antigen presenting cells (APCs) to support Th2 responses, shaping the responses of T cells to normal APCs, and/or enhancing mast cell degranulation and production of cytokines. More extensive future studies will dissect the molecular mechanisms that can help us identify approaches to prevent exposures or interrupt adverse estrogenic effects. Environmental pollution is a likely contributor to the recent increase in asthma and other allergic diseases. This project will develop a mouse model to investigate the effects of environmental estrogen-like chemicals on the development of asthma in children.