Perinatal exposure to environmental estrogens and asthma pathogenesis

点击翻译按钮获取中文摘要

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.