Synergistic Immunosuppression by PAHs and Arsenite

该ViCTER应用程序补充了PI的RO 1，旨在了解 多环芳烃（PAHs）和砷单独以及 在小鼠和人类暴露后的组合。基本的RO 1赠款测试的假设， 砷与烟草烟雾中的多环芳烃产生协同免疫抑制作用， 抑制PAH大体积加合物的DNA修复。PI的实验室已经证明了协同免疫抑制， 多环芳烃和砷在小鼠体内和体外在人外周血单核细胞（HPBMC）。这 ViCTER赠款支持三个高度互动的项目，这些项目大大扩展了 父RO 1授予。所有这三个项目都依赖于孟加拉国的HEALS队列， 哥伦比亚大学和芝加哥大学关于饮用水砷暴露的研究。的 本研究由我们的合作者Factor-Litvak博士（哥伦比亚大学超级基金项目）设计， HEALS研究的主要流行病学家，以2x2设计检查200名研究受试者，每组50人， 男性吸烟者和非吸烟者也暴露于低砷或高砷的水中。在目标1中，Burchiel博士 实验室将用已知的砷和PAH暴露数据检查从这些组中获得的HPBMC。伯奇尔医生 我将与另外两名PI合作，Parvez博士（项目2，哥伦比亚大学）和Santella博士（项目3，哥伦比亚大学 为了验证人体在体内暴露于香烟烟雾和砷会产生 T细胞增殖、T细胞分化和T细胞/HPBMC细胞因子协同免疫抑制 生产项目1依赖于项目2来测量细胞因子的产生以及提供相关的健康信息。 终点，包括肺功能和上呼吸道感染评估。项目1也依赖于项目3 测量研究受试者尿液中暴露的生物标志物（1-羟基芘，1-OHP）和PAH-DNA HPBMC中的加成物。Parvez博士的项目2将评估其他人感兴趣的几个肺功能终点。 研究人员还研究了氧化应激和细胞因子产生的机制， 患有炎症性肺病Santella博士（项目3）长期以来一直对PAH-DNA加合物感兴趣 并从这项研究中受益，帮助检验高砷暴露 促进PAH加合物的形成，这可能是一个有用的生物标志物的共同暴露。项目2执行 研究招募，以及样本采集、记录保存和数据收集的总体协调， 和分析，由行政核心监督。总之，这个ViCTER计划是高度 整合，使所有研究者受益，并将为免疫学和肺疾病领域增加大量新知识。 香烟烟雾（多环芳烃的替代品）和砷暴露对健康的影响， 公共卫生负担。

This ViCTER application supplements an RO1 from the PI that seeks to understand the mechanisms of immunosuppression produced by polycyclic aromatic hydrocarbons (PAHs) and arsenic alone and in combination following exposure of mice and humans. The underlying RO1 grant tests the hypothesis that arsenic produces synergistic immunosuppression with PAHs which are contained in tobacco smoke by inhibiting DNA repair of PAH bulky adducts. The PI's lab has demonstrated synergistic immunosuppression by PAHs and arsenic in vivo in mice and in vitro in human peripheral blood mononuclear cells (HPBMC). This ViCTER grant supports three highly interactive projects which significantly expand the original aims of the parent RO1 grant. All three projects rely upon the HEALS cohort in Bangladesh that has been studied by Columbia University and the University of Chicago with regard to drinking water arsenic exposures. The present study has been designed by our collaborator Dr. Factor-Litvak (Columbia Univ Superfund Program), the key epidemiologist for the HEALS study, to examine 200 study subjects in a 2x2 design of 50 per group of male smokers and nonsmokers who are also exposed to low or high arsenic in water. In Aim 1, Dr. Burchiel's lab will examine HPBMC obtained from these groups with known arsenic and PAH exposure data. Dr. Burchiel will work with the other two PI's, Dr. Parvez (Project 2, Columbia Univ) and Dr. Santella (Project 3, Columbia Univ), to test the hypothesis that in vivo exposure of humans to cigarette smoke and arsenic produces synergistic immunosuppression of T cell proliferation, T cell differentiation, and T cell/HPBMC cytokine production. Project 1 relies upon Project 2 to measure cytokine production as well as to provide relevant health endpoints, including lung function and upper airway infection assessments. Project 1 also relies upon Project 3 to measure biomarkers of exposure in the urine from study subjects (1-hydroxypyrene, 1-OHP) and PAH-DNA adducts in HPBMC. Dr. Parvez's Project 2 will assess several lung function endpoints of interest to the other investigators as well as examine mechanisms of oxidative stress and cytokine production that may correlate with inflammatory lung disease. Dr. Santella (Project 3) has had a longstanding interest in PAH-DNA adducts in HPBMC and benefits from this study by assisting in testing the hypothesis that high arsenic exposure potentiates PAH adduct formation, which might be a useful biomarker of co-exposures. Project 2 performs the recruitment for the study, and the overall coordination of sample collection, record keeping and data collection, and analysis which is overseen by an Administrative Core. In summary, this ViCTER program is highly integrated, benefits all investigators, and will add substantial new knowledge to immunologic and pulmonary health effects of combined cigarette smoke (surrogate for PAHs) and arsenic exposures, which present a huge public health burden.