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Perinatal exposure to environmental estrogens and asthma pathogenesis

围产期环境雌激素暴露与哮喘发病机制

基本信息

批准号：
8073683
负责人：
TERUMI MIDORO-HORIUTI
金额：
$ 1.47万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-01 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8073683
关键词：
Adult Affect Age Allergens Allergic Allergic Disease Allergic inflammation Animal Model Animals Antibodies Antigen-Presenting Cells Antigens Asthma B-Lymphocytes Basophils Birth Breast Feeding CD4 Positive T Lymphocytes Cell Degranulation Cell physiology Cells Centers for Disease Control and Prevention (U.S.)Chemicals Child Childhood Childhood Asthma Chronic Disease Collaborations Country Dendritic Cells Development Environment Environmental Estrogen Environmental Exposure Environmental Pollutants Environmental Pollution Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogens Exposure to Extrinsic asthma Fetus Food Chain Fostering Future Goals Helper-Inducer T-Lymphocyte Human Milk IgE IgE Receptors Immune Immune response Immune system Immunoglobulin Class Switching Implant Inbred BALB C Mice Infant Inflammation Interleukin-10 Interleukin-4 Life Lipids Mediator of activation protein Membrane Milk Modeling Molecular Morbidity - disease rate Mothers Mus Natural Immunity Ovalbumin Pathogenesis Perinatal Exposure Peritoneal Phase Phenotype Placenta Plasma Prevalence Production Proteins Protocols documentation Reaction Research Research Project Grants Risk Role Shapes Spleen Staging System T cell differentiation T cell response T-Cell Proliferation T-Lymphocyte Testing Th2 Cells Time airway hyperresponsiveness base cell type critical developmental period critical period crosslink cytokine early childhood eosinophil experience fetal in utero in vivo infancy innate immune function innovation mast cell mouse model offspring pollutant postnatal prevent pup reconstitution research study response xenoestrogen

项目摘要

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.

描述（由申请人提供）：哮喘和其他过敏性疾病在工业国家的患病率急剧增加。先天性免疫系统的细胞（肥大细胞、嗜碱性粒细胞和嗜酸性粒细胞）直接促成过敏性炎症，并可促进分化为辅助性T细胞2型（Th 2）表型，其支持B细胞向IgE产生和晚期应答的同种型转换。T辅助细胞系统对变应原的初始引发经常发生在子宫内或出生后早期，此时Th 2细胞通常主导免疫应答。延迟Th 2向Th 1优势的正常转换的因素增加了发生过敏性疾病的风险。我们已经发现，暴露于雌二醇（E2）和环境雌激素强烈增强的合成和释放过敏介质肥大细胞，通过膜形式的雌激素受体α。此外，通过植入E2颗粒重建在典型过敏性致敏后不能产生IgE应答的卵巢切除BALB/c小鼠。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到后代。目前的建议是开发一种哮喘动物模型，以确定关键的发育期，在此期间，环境雌激素促进过敏性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，以确定功能上被环境雌激素改变的关键细胞类型。本项目中待检验的一般假设是，遗传易感动物在关键发育期暴露于环境雌激素，通过调节先天免疫细胞的功能促进过敏性致敏/反应。具体目标将检验以下具体假设：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性致敏和反应，和2）环境雌激素通过调节抗原呈递细胞（APC）支持Th 2应答的潜能，塑造T细胞对正常APC的应答，和/或增强肥大细胞脱粒和细胞因子的产生。更广泛的未来研究将剖析分子机制，可以帮助我们确定方法，以防止暴露或中断不良雌激素效应。环境污染可能是最近哮喘和其他过敏性疾病增加的原因之一。本计画将发展一种小鼠模型，以研究环境中的类雌激素化学物质对儿童哮喘发展的影响。