Developmental toxicity of bisphenol A and immune-mediated diseases

描述（由申请人提供）：该项目的目的是提供迄今为止最详细的化学双酚A （BPA）对免疫系统发育的影响分析，并将特别测试发育中的BPA暴露会增加三种常见免疫介导疾病的易感性这一假设。拟议的研究是一个大型项目，将改善一个综合的、多学科的研究团队在毒理学、免疫学、免疫发育、肺部和胃肠道疾病方面的协同作用和相互作用。在第一个目标中，将研究发育暴露于双酚a如何影响免疫系统的发育。第二目标将使用哮喘、炎症性肠病和甲型流感病毒感染的小鼠模型来确定发育暴露于BPA如何影响这些疾病的发病、活动和消退。进一步的研究将探索先天免疫和适应性免疫系统细胞成分功能的潜在变化，在第三个目标中，将使用现代免疫学方法（如骨髓嵌合体、过继性转移和疾病特异性功能测定）的组合来确定导致疾病易感性增加的BPA细胞靶点。在人类常见疾病的动物模型中评估BPA如何影响发育中的免疫系统将带来许多好处。首先，BPA与转录因子受体相互作用，但这些相互作用对疾病的影响尚不完全清楚；因此，所了解的将为基因-环境相互作用如何影响免疫发育和功能提供新的信息。其次，在发育过程中暴露于BPA可能会导致其他人类疾病，而且我们将使用的模型系统中激活的许多调节途径在其他疾病中是不受控制的。鉴于污染物、呼吸道感染和慢性炎症性疾病之间的联系日益密切，这些研究将有助于描述这些关系的因果基础，并可能导致发现双酚a的共同分子靶点和预防或减轻环境介导疾病的新策略。最后，除了创造新的科学信息外，拟议的研究还将通过雇用新的实验室工作人员和采购研究试剂和用品，直接推进美国再投资和复苏法案的目标。因此，该项目将对当地和国家经济产生直接、积极的影响。

DESCRIPTION (provided by applicant): The objective of this project is to provide the most detailed analysis to-date of the impact of the chemical bisphenol A (BPA) on immune system development, and will specifically test the hypothesis that developmental BPA exposure enhances susceptibility to three common immune-mediated diseases later in life. The proposed research is a large-scale project that will improve synergy and interactions among an integrated, multi-disciplinary research team with expertise in toxicology, immunology, immune development, and pulmonary and gastrointestinal diseases. In the 1st Aim a determination of how developmental exposure to BPA affects the development of the immune system will be investigated. The 2nd Aim will use mouse models of asthma, inflammatory bowel disease and infection with influenza A virus to determine how developmental exposure to BPA affects the onset, activity, and resolution of these diseases. Further studies will then probe underlying changes in the function of cellular components of the innate and adaptive immune system, and in the 3rd Aim, an identification of the cellular targets of BPA that lead to increased disease susceptibility using a combination of modern immunological approaches such as bone marrow chimeras, adoptive transfer, and disease-specific functional assays will ensue. Evaluating how BPA impacts the developing immune system in the context animal models of common human diseases will deliver many benefits. First, BPA interacts with receptors that are transcription factors, but the contribution of these interactions to disease are not entirely clear; therefore what is learned will provide new information about how gene-environment interactions influence immune development and function. Second, developmental exposure to BPA likely contributes to other human diseases, and many of the regulatory pathways activated in the model systems we will use are deregulated in other diseases. Given the growing link between pollutants, respiratory infection, and chronic inflammatory diseases, these studies will help delineate the causal basis for these relationships, and may lead to the discovery of common molecular targets of BPA and new strategies to prevent or mitigate environmentally-mediated diseases. Finally, in addition to creating new scientific information, the proposed research will directly advance the objectives of the American Reinvestment and Recovery Act by enabling the hiring of new laboratory staff and the procurement of research reagents and supplies. Thus, this project will have direct, positive impact on the local and national economy. PUBLIC HEALTH RELEVANCE: This research addresses growing concern about how bisphenol A impacts development and contributes to human disease, and will improve our understanding of the potential for bisphenol A to affect the developing immune system and lead to poorer health later in life.