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.
Human exposure to As via drinking water and food is a huge public health burden that has been estimated to contribute to 1 in 5 deaths in Bangladesh. Public health experts now describe a health epidemic due to As exposures that influence many organ systems and produce both cancerous and non-cancerous diseases. This ViCTER consortium provides a unique opportunity for the Principal Investigator to work with Columbia University to study a well-characterized HEALS cohort with known As exposures and forms a unique collaboration examining mechanistic immunology studies combined with human lung function endpoints and peripheral blood molecular biomarkers, to test the hypothesis that cigarette smoking (as a surrogate for PAH exposure) potentiates the health risks of As exposure.
|Lauer, Fredine T; Denson, Jesse L; Burchiel, Scott W (2017) Isolation, Cryopreservation, and Immunophenotyping of Human Peripheral Blood Mononuclear Cells. Curr Protoc Toxicol 74:18.20.1-18.20.16|
|Parvez, Faruque; Medina, Sebastian; Santella, Regina M et al. (2017) Arsenic exposures alter clinical indicators of anemia in a male population of smokers and non-smokers in Bangladesh. Toxicol Appl Pharmacol 331:62-68|
|Lauer, Fredine T; Denson, Jesse L; Beswick, Ellen et al. (2017) Intracellular Cytokine Detection by Flow Cytometry in Surface Marker-Defined Human Peripheral Blood Mononuclear T Cells. Curr Protoc Toxicol 73:18.19.1-18.19.14|
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|Xu, Huan; Lauer, Fredine T; Liu, Ke Jian et al. (2016) Environmentally relevant concentrations of arsenite and monomethylarsonous acid inhibit IL-7/STAT5 cytokine signaling pathways in mouse CD3+CD4-CD8- double negative thymus cells. Toxicol Lett 247:62-8|
|Xu, Huan; McClain, Shea; Medina, Sebastian et al. (2016) Differential sensitivities of bone marrow, spleen and thymus to genotoxicity induced by environmentally relevant concentrations of arsenite. Toxicol Lett 262:55-61|
|Ezeh, Peace C; Xu, Huan; Wang, Shu Chun et al. (2016) Evaluation of Toxicity in Mouse Bone Marrow Progenitor Cells. Curr Protoc Toxicol 67:18.9.1-18.9.12|
|Ezeh, Peace C; Xu, Huan; Lauer, Fredine T et al. (2016) Monomethylarsonous acid (MMA+3) Inhibits IL-7 Signaling in Mouse Pre-B Cells. Toxicol Sci 149:289-99|
|Xu, Huan; Zhou, Xixi; Wen, Xia et al. (2016) Environmentally Relevant Concentrations of Arsenite Induce Dose-Dependent Differential Genotoxicity Through Poly(ADP-Ribose) Polymerase Inhibition and Oxidative Stress in Mouse Thymus Cells. Toxicol Sci 149:31-41|
|Harper Jr, Tod A; Morré, Jeff; Lauer, Fredine T et al. (2015) Analysis of dibenzo[def,p]chrysene-deoxyadenosine adducts in wild-type and cytochrome P450 1b1 knockout mice using stable-isotope dilution UHPLC-MS/MS. Mutat Res Genet Toxicol Environ Mutagen 782:51-6|
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