全氟辛烷磺酸（PFOS）诱导机体哮喘倾向的机理研究

As a new type of persistent organic pollutant, perfluorooctane sulfonate (PFOS) has aroused scientists' great concern in recent years due to its ubiquitous distribution in the ecosystems including humans. Furthermore, it has been undergoing biological concentration and magnification, leading to excessive accumulation among the higher trophic levels of the food chain, such as human beings. Immune system is considered to be one of the most important and sensitive systems to xenobiotic compounds, and as a major target for toxic effects of xenobiotics, our research, as well as that of other investigators, has reported the immunotoxicity of PFOS in rodents. Based on the previous studies, the applicant firstly reported that the PFOS-induced immunotoxicity was mainly shown as the excursion of TH1/TH2 (TH2-polarized immune response) and the inflammatory response of lymphocytes; and the results from our sero-epidemiologic survey firstly reported in Environmental Health Perspective (EHP) showed that the PFOS concentration in serum was positively correlated with the levels of clinical immunity markers (IgE, AEC and ECP) in asthmatics. Asthma, in fact, is the most obvious Th2-related chronic inflammatory disorder. So, based on the above results, we may hypothesize that PFOS exposure may improve the liability of sickening for asthma. However, the internal relationships between both and the mechanisms are still unclear. In the present study, we plan to dynamically discuss the mechanism of the PFOS-induced imbalance of Th immune response and inflammatory response from the new visual angles of CD4+T-cell-mediated immune balance by building the asthma mice model and case-control human model; and at the same time, using the vitro and vivo experimental studies to elucidate the mechanisms and internal special links of PFOS exposure on asthma, which would provide the new theory in the evaluation of the PFOS-induced toxicology and mechanism.

全氟辛烷磺酸（PFOS）是在生态系统中已得到广泛污染的一种新型持久性有机污染物，且人类机体内PFOS负荷呈逐年增高趋势。国内外研究学者发现免疫系统是对PFOS最为敏感的系统之一。在前期研究中，申请人发现PFOS对免疫系统的毒性效应主要体现在TH2型免疫应答的极化及促炎性反应；并通过血清学研究首次报道了PFOS与哮喘免疫生物标记物（IgE、AEC和ECP）的相关关系。哮喘是一种以TH2型免疫应答为主的慢性炎症性疾病，因此基于以上研究结果我们推测PFOS暴露可能增加机体患有哮喘的倾向；但其内在的参与因素和具体作用机理并不清楚。本研究拟通过小鼠哮喘模型结合人群病例-对照研究，从调控CD4+T细胞介导的免疫平衡这一新视角探讨PFOS暴露诱导机体哮喘倾向内在机理，阐明PFOS对哮喘发生发展的具体作用环节及其细胞生物学改变，可为人们深入了解PFOS的毒性危害及其毒作用机理提供新的科学依据。

全氟辛烷磺酸（PFOS）是在生态系统中已得到广泛污染的一种新型持久性有机污染物，且人类机体内PFOS 负荷呈逐年增高趋势。国内外研究学者发现免疫系统是对PFOS 最为敏感的系统之一。在前期研究中，申请人发现PFOS 对免疫系统的毒性效应主要体现在TH2型免疫应答的极化及促炎性反应；并通过血清学研究首次报道了PFOS与哮喘免疫生物标记物（IgE、AEC 和ECP）的相关关系。哮喘是一种以TH2型免疫应答为主的慢性炎症性疾病， 因此基于以上研究结果我们推测PFOS暴露可能增加机体患有哮喘的倾向；但其内在的参与因素和具体作用机理并不清楚。本研究通过小鼠哮喘模型结合人群病例-对照研究，从调控CD4+T 细胞介导的免疫平衡这一新视角深入探讨了PFOS暴露诱导机体哮喘倾向内在机理，阐明PFOS 对哮喘发生发展的具体作用环节及其细胞生物学改变。研究结果显示：基于临床病例（哮喘）-对照研究发现，机体PFASs暴露水平与哮喘儿童TH1/TH2免疫应答紊乱和向TH2型极化低密切相关，且随着PFASs浓度水平的增高，哮喘儿童肺功能缺损程度和哮喘激惹状况更加严重，表明PFASs可能通过诱导TH1/TH2平衡紊乱来增加机体哮喘倾向的风险；通过建立哮喘小鼠模型，明确PFOS暴露与哮喘小鼠的炎症损伤的关系，发现PFOS/PFOA可能通过诱导T-bet/GATA-s比例失调来介导TH1/TH2平衡紊乱；进一步通过体外细胞模型揭示PFOS/PFOA通过上调p-STAT6水平来调控核转录因子GATA-3和细胞因子IL-4、IFN-γ的表达是诱导机体TH1/TH2平衡紊乱的机制之一；这些研究结果将为人们深入了解PFOS 的毒性危害及其毒作用机理提供新的科学依据。通过执行本项目，在国际核心期刊发表SCI论文20篇；培养博士研究生1人，硕士研究生5人；2名博士研究生和3名硕士研究生继续进行本项目相关研究。