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：
7529198
负责人：
TERUMI MIDORO-HORIUTI
金额：
$ 18.88万
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/7529198
关键词：
Adult Affect Age Allergens Allergic Animal Model Animals Antibodies Antigen-Presenting Cells Antigens Asthma B-Lymphocytes Basophils Birth Breast Feeding CD4 Positive T Lymphocytes Cell Degranulation Cell Differentiation process Cell physiology Cells Centers for Disease Control and Prevention (U.S.)Chemicals Child Childhood Childhood Asthma Chronic Disease Collaborations Country Dendritic Cells Development Disease 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 Proliferation T-Lymphocyte Testing Th2 Cells Time airway hyperresponsiveness base cell type critical developmental period critical period crosslink cytokine early childhood eosinophil experience fetal immune function in utero in vivo infancy 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）：工业国家的哮喘和其他过敏性疾病的患病率显着增加。先天免疫系统（肥大细胞，嗜碱性粒细胞和嗜酸性粒细胞）的细胞直接促进过敏性炎症，并可以促进与T辅助型2型2（TH2）表型的分化，该表型支持B细胞转换为IgE至IgE产生的同种型和晚期反应。 T辅助细胞系统对过敏原的初始启动经常发生在子宫内或产后早期，当时Th2细胞通常主导免疫反应。延迟正常转化从Th2到Th1优势的因素会增强患过敏性疾病的风险。我们已经发现，通过雌激素受体α的膜形式，暴露于雌二醇（E2）和环境雌激素强烈增强了从肥大细胞的合成和释放。此外，通过植入E2颗粒来重组典型的过敏敏化后，无法做出IgE反应的卵巢切除型BALB/C小鼠。环境雌激素倾向于在食物链中缓慢降解，生物含量和生物浓缩，并通过胎盘和母乳转移到后代。当前的建议是开发一种哮喘动物模型，以鉴定关键的发育时期，在此期间，环境雌激素会促进过敏敏化和气道高反应性和炎症。我们还将使用此模型执行初始的离体实验，以识别环境雌激素在功能上改变的关键细胞类型。在该项目中要检验的一般假设是，在关键发育期间，遗传易感动物暴露于环境雌激素会通过调节先天免疫细胞的功能来促进过敏敏化 /反应。在关键时期，在免疫发育的关键时期，将测试特定假设的具体目的，即：1）暴露于环境雌激素可以增强哮喘动物模型中的过敏敏化和反应，而2）环境雌激素可以增强对抗原细胞的潜在（APC响应th2）的潜力，从而增强过敏性敏感性，从而响应TH2的响应，以响应Th2 2的响应，shaps sap whats th22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可以帮助我们确定防止暴露或中断不良雌激素作用的方法的分子机制。环境污染可能是造成哮喘和其他过敏性疾病的近期增加的原因。该项目将开发小鼠模型，以研究环境雌激素样化学物质对儿童哮喘发育的影响。