Center of Excellence in Environmental Toxicology _CEET_ Focus on

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					Center of Excellence in Environmental Toxicology (CEET):
Focus on Lung and Airway Disease                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        CENTER OF EXCELLENCE IN ENVIRONMENTAL TOXICOLOGY
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  CEET
Director: Trevor M. Penning, Ph.D. Deputy Director: Edward A. Emmett, M.D.

 Center of Excellence                                                                                              Exposures in Southeastern Pennsylvania                                                                                                                                                                                                                           Lung and Airway Disease Core                                                                                                                                                                                                                    Genes and Environment Core
 in Environmental Toxicology (CEET)                                                                                (SEPA) linked to Lung and Airway Disease                                                                                                                                                                                                                         (Panettieri & Albelda)                                                                                                                                                                                                                          (Rebbeck & Whitehead)
                                                                                                                    Ozone (90-100th percentile nationwide)
                                                                                                                                                                                                                                                                                                                                                                                    Subdiscipline                                                                                        Member                                                                                                                                     Subdiscipline                                    Member
 The CEET mission is to understand the mechanistic link between                                                     Allergens (Top 5% nationwide)
                                                                                                                                                                                                                                                                                                                                                                                    Signal transduction in the lung                                                                      Amrani, Krymskaya, Panettieri                                                                                                              Genetic Susceptibility                           Whitehead, Blair, Penning,
 environmental exposures and diseases of environmental etiology.                                                    Cigarette Smoke                                                                                                                                                                                                                                                 Antioxidant protection                                                                               Christofidou-Solomidou                                                                                                                      ( Lung disease, melanoma,                       Vachani, Albelda, Lerman, Brose,
 Understanding these processes can lead to early diagnosis,                                                         Fine particle air-pollution (70th percentile)                                                                                                                                                                                                                   Mesothelioma and lung cancer                                                                         Albelda, Penning, Vachani, Blair                                                                                                              testicular cancer, birth defects)             Zoiber, Kanetsky, Rebbeck, Manson
 intervention and prevention strategies. The end result will be to                                                  Car exhaust and fossil fuel combustion                                                                                                                                                                                                                          Asthma                                                                                               Amrani, Apter, Bryant-Stephens, Panettieri, Haczku,                                                                                        Phenotyping Exposure                             Blair, Lee, Manson
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         Penning, Blair
 improve environmental health and medicine in our region.                                                           Asbestos ( Massive shipbuilding industry and
                                                                                                                                                                                                                                                                                                                                                                                    COPD                                                                                                 Amrani, Beers, Panettieri, Christie                                                                                                        Epidemiology and Biostatstics                    Christie, Kanetsky, Manson, McCauley, Rebbeck
                                                                                                                                asbestos factories in SEPA)                                                                                                                                                                                                                         Beryilliosis and Sarcoidosis                                                                         Rossman, Christie                                                                                                                          Genotyping and Bioinformatics                    Whitehead, Rebbeck, Baldwin, Tobias
                                                                                                                    Beryllium ( SEPA identified as high risk)
            Location of Superfund Sites
                                                                     45/92 Superfund Sites
                                                                     Incidence of cancer in Pennsylvania            Mesothelioma                                                                                                                                           Lung Cancer                                                                                                                                                                                                                                                                                                                                                  Lung Cancer Susceptibility Gene Initiative
                                                                     is second highest in nation
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                Detection of (+)-anti-BPDE Adducts in
                                                                     This mean is exceeded by:                      Biomarkers for Mesothelioma                                                                                                                                                                     PAH Activation in Human Lung
                                                                           • 10% for all cancer
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        Bronchoalveolar Cells
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   Predicting human susceptibility:
                                                                           • 28% for lung and bronchial cancer
                                                                                                                    Use of serum mesothelin levels to                                                                                                                     Environmental Pollutant                                                                                                                                                                                                   P450 induction + BP-7,8-diol                                           t(+)
                                                                           • 47% for uterine/cervical cancer                                                                                                                                                                                                                                                                                                                                                                              100
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                (PAH)          ✕        (Gene)         ✕         (Gene)              ✕          (Gene)
                                                                                                                    screen asbestos exposed individuals at                                                                                                                   Tobacco Smoke                                                                                   (CYP peroxidase)                                                                                                       B[a]PDE-dGuo:
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  23.7
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        4.8E4
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    m/z: 570.2 257.1
                                                                     13% of adults in Philadelphia have             risk for mesothelioma.                                                                                                                                                                                                    Benzo[a]pyrene                                         Radical Cation                                                                        50                                                                  c(+)                 Syn adduct?
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    (15 adducts per 106 nucleotides)                          20.6                      26.4
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               Mixtures               Activation            Detoxication                     DNA-Repair
   Proposed: 3   Final: 92    Deleted: 24
                                                                     asthma (9% nationally)                         Mesothelin (SMRP) is a protein produced by
                                                                                                                                                                                                                                                                                                                                        (CYPs, EH)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            0
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          100                                                                           t(+)*
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  23.7                                  1.5E5
                                                                                                                    mesotheliomas that appears in the blood. SMRP                                                                                                                                                                                                                                                                                                                                   B[a]PDE[15N5]-dGuo:                                                                                                                        BP                    AhR                       COMT                          NER
                                                                     High incidence of adverse




                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Relative Abundance
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           50       m/z: 575.2 257.1
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               BA                    P4501A1                   GSTM1 (mu)                    • XPA
                                                                                                                    appears to be sensitive marker of mesothelioma
 Diseases/disorders may be prevented                                 pregnancy outcomes                             (black arrow) and may predict development of                                                                                                                                                                        HO                                                                                                                                                  0                                                                                                                                                  5-methylC             P4501A2                   GSTP1 (pi)                    • XPC
                                                                                                                                                                                                                                                                                        (CYP1A1/CYP1B1)                                                                         (AKR1A1, AKR1C1-AKR1C4)                                                                                  100
 Population is faced with environmental justice
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        c(+)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               D[a,l]P               P4501B1                   NAT                           • XPD
                                                                           • 29% of perinatal deaths state-wide     tumors in asbestos exposed individuals (red arrow)
                                                                                                                                                                                                                                                                                                                                                 OH                                                                                                                                                 B[a]PDE-dAdo:
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    m/z:554.2 257.1
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 34.6   5.2E2
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               D[a,h]A         ✕     EH                ✕       NQO1
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     ✕
                                                                                                                                                                                                                                                                                                                                             (-)-BP-7, 8-Diol
 and disparity issues                                                      • 29% of low weight births state-wide    (Robinson, 2003)                                                                                                                                                         O
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          50
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               B[b]F                 AKR1A1                    SULT1A1                       BER
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         1000                                                                                                                                                  B[k]F                 AKR1C1-1C4                UGT1A1                        • hOOG1 (MutM )
 Creates a significant opportunity for PENN to improve environmental health                                         We hypothesize that SMRP could be used to                                                                                                                           HO                                                                                      O                                                                                                                   B[a]PDE[15N5]-dAdo:
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        c(+)*    34.6   1.1E5
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               B[j]F                                                                         • MUTYH (MutY )
                                                                                                                    screen individuals (exposed to asbestos) at                                                                                                                                                                                                                                                                                                                           50        m/z: 559.2 257.1
 through research and outreach                                                                                      high risk for mesothelioma
                                                                                                                                                                                                                                                                                                      OH                                                                             O

                                                                                                                                                                                                                                                                                         (+)-anti-BPDE                                                                 Benzo[a]pyrene-7,8-dione + ROS                                                                                      0
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              4          8       12         16              20              24            28            32        36
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            Time (min)
                                                                                                                                                                                                                                                                                                                                                                                                              Penning & Blair                                                                                                                                                                                After Ruan and Blair

 The Structure of CEET                                                                           IHSFC                                    1.50
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              Phenotype
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              Exposure
                                                                                                                                                                                                                                                                                                                          PAH Activation by AKRs                                                                                                                  Biomarker Core-Reliable Detection of 8-oxo-dGuo                                                                                                                                                                                         state-wide case-control study
                                                                                                                                          1.25
                                                                                                                    Absorbance (420 nm)




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    (n=1600)
                                                                                              Biorespositories                                                                                                                                                                                                                                                                                                                                                               in Bronchoalveolar Cells
                          Oxidative Stress                                                    Feldman, Manson,                            1.00                                                                                                                                                     (AKR1A1, AKR1C)                                                                                                                                                                                                                                                                                                                                           Carcinogens
                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Stable isotope dilution LC/MRM/MS analysis of 8-oxo-dGuo in cellular DNA                                                                                                                     • NNK
                        Blair and Ischiropoulos                                                   Vachani                                                                                                                                                                                                                                                                                CONJUGATE FORMATION                                                                                                                                                                                                                                                                                                       Lung Cancer
                                                                                                                                          0.75                                                                                                                            HO                                                                  HO                                         glucuronide                                                                                                              Control                                                           Under oxidative stress                                                       • PAH
      Endocrine &                                        Lung &                                Toxicogenomics                                                                                                                                                                      OH                                                                     OH                             sulfate
                                                    Airway Disease                                                                        0.50                                                                                                                                                                                                                                           O-methylated catechol
 Reproduction Disruption                                                                      Baldwin and Tobias                                                                                                                                                                                                                                     catechol                                                                                                            9.9e2 cps                                                                                      1.0e4            1.1e4 cps                                                   Candidate Genes/Enzymes
                                                                                                                                                                                                                                                                                    CYP1A1/1B1
   Manson and Gerton                              Panettieri and Albelda                                                                                                                                                                                                                                                                                          O2                                                                                               0.8e3 m/z 284 → 168                                                                                                   m/z 284→ 168                                                  • Phase I (activation)
                                                                                                                                          0.25                                                                                                                                                                                                                                                                                                                                                                                                                          0.8e4
                             Genes &                                                          Toxicoproteomics                                                                                                                                                                                                                                                                                                                                                                  12.6                                                                                                                                                                   • Phase II (detoxification)
                                                                                                                                                                                                                                                                                                                                                                   H2O2                  OXIDATIVE STRESS                                                          0.6e3                                                                                                0.6e4                         12.6
                           Environment                                                              Yuan                                                                                                                                                                                                                                         1e                                                                                                                        8-oxo-dGuo                                                                                                                                                                  • DNA Repair
                                                                                                                                            0                                                                                                                                                            NAD(P)+                                                                                                                                                                                                                                                                                  8-oxo-dGuo
                       Rebbeck and Whitehead                                                                                                                                                                                                                                                                                                                                                                                                                       0.4e3  (2.5/107 dGuo)                                                                                0.4e4
                                                                                                                                                 Mesothelioma
                                                                                                                                                                 Non-exposed
                                                                                                                                                                 Asb-exposed
                                                                                                                                                                                    Infection
                                                                                                                                                                               Inflammatory
                                                                                                                                                                                Transudates
                                                                                                                                                                                 Malignancy
                                                                                                                                                                                                        Plaques
                                                                                                                                                                                                Gross thickening




                                                                                                                                                                                                                                     Asbestosis
                                                                                                                                                                                                                                            IPF
                                                                                                                                                                                                                                    Sarcoidosis
                                                                                                                                                                                                                                           SLE
                                                                                                                                                                                                                                       RA lung
                                                                                                                                                                                                                                      Other ILD
                                                                                                                                                                                                                                   Tuberculosis
                                                                                                                                                                                                                    Lung cancer
                                                                                                                                                                                                                   Breast cancer
                                                                                                                                                                                                                    Other cancer




                                                                                                                                                                                                                                                                               O
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                (599/107 dGuo)




                                                                                                                                                                                                                                                                                                                                                                                                                                                Intensity (cps)




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      Intensity (cps)
                                                                                                 Biomarkers                                                                                                                                                                                                                                                                                                                                                        0.2e3                                                                                                0.2e4
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                new candidate genes
                                                                                                    Lee                                                                                                                                                                   HO                                                                    O                                        PROOXIDANT STATE                                                                        0.0                                                                                      0.0                                                                               Genome-wide                                    Genome-wide Association
                                                                                                                                                                                                                                                                                   OH                                                                     O                                                                                                                                                                                                                                                                                                SNP genotyping                                     Expression Arrays
                                                                                                                                                                                                                                                                                                           NADP H                                                                                                                                                                                                                                                                                                                                                                                                microRNA
                                                                                                                                                                                                                                                                           (+)-anti-BPDE
                                                                                                                                                                                                                                                                                                                                        o-semiquinone anion radical                                                                                                                             7.6e3 cps                                                               0.8e4            8.8e3 cps
                                                                                                                                                                                                                                                                                                                                                                  O2                                                                                               0.6e4                        m/z 289→ 173                                                                             m/z 289→ 173
                                                                                                                                                                Healthy Pleural Other Other                                          Inflammatory                                                                                                                                                                                                                                                                                                                       0.6e4
                                                                                                                                                                controls effusions   cancers                                           diseases                                                                                                                    O2                    OXIDATIVE STRESS                                                          0.4e4
                                                                                                                                                                                                                                                                                                                                                1e
                                                                                                                                                                                                                                                                                                                                                                                         glucuronide                                                                                                        12.6                                                        0.4e4                     12.6                                     Objectives: (1) to identify genetic loci that increase susceptibility to lung carcinogens;
                                                                                                                                                                                                                                                                           DNA-adducts                                                                                                                                                                                                              [15N5]-8-oxo-dGuo                                                                     [15N5]-8-oxo-dGuo
                                                                    Community                                                                                                                                                                                                                                                                                                            sulfate
                                                                                                                                                                                                                                                                                                                                                                                                                                                                   0.2e4                                                                                                0.2e4
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     and (2) identify new candidate genes
       Prevention Programs                                                                                                                                                        Other pleural                          Other lung diseases                                                                                                                                             O-methylated catechol
                                                                     Outreach                                                                                                      effusions
       Patient Education                                                                                                                                                                                                                                                                                                                                                                 ADDUCT FORMATION                                                                      0.0                                                                                        0.0
                                                                   South Eastern                                                                                                                                                                                                                                                               O                                                                                                                                           0        2     4       6     8 10 12 14                                                 0      2         4    6       8 10 12 14
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      Whitehead, Penning, Blair, Lerman, Rebbeck, Brose, Zoiber, Vachani, Baldwin
       Health Care Professionals                                                                                                                                                                                                                                                                                                                                                         amino acids
                                                                   Pennsylvania                                                                                                                                                                                                                                                                           O                              GSH
                                                                    Urban Focus                                                                                                                                                                                                                                                                                                          RNA                                                                                                                  using immunoaffinity purification method
                                                                                                                                                                                                                                   Vachani and Albelda                                                                                                                                   DNA                  Penning & Blair




                                                                                                                     Asthma                                                                                                                                                                                                        Ozone Effects on Airway Smooth Muscle (ASM)
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       Focus on Lung and Airway Disease
                                                                                                                                                                                                                                                                                                                                                                            *
                                                                                                                                                                                                                                   Cytokines                                                                                                                           *                     Naive
                                                                                                                                                                                                                                                                                                                    250
                                                                                                                                                                                                                                                                                                                                                              *                                                                        PGH2                                                     ?                                                                                                                                      Validate mesothelin as a biomarker for mesothelioma
                                                                                                                                                                                                                                                                                             % Maximum of control




                                                                                                                                                                                                                                                                                                                                                                                             O3                                                     AKR1C3                                          O3
                                                                                                                                                                                                                                                                                              (mg tension/mg wt)




                                                                                                                                                                                                                                                                                                                    200
                                                                                                                                                                                                                                                                                                                                                      *                                      Af                                                                                                                                                                                                                  AKR 1C3
                                                                                                                                                                                                                                                            CD38 cADPR
                                                                                                                                                                                                R
                                                                                                                                                                                                                                     GPCR
                                                                                                                                                                                                                                                PLC
                                                                                                                                                                                                                                                                                                                    150                                                                      Af+O3
                                                                                                                                                                                                                                                                                                                                                                                                                                  ?
                                                                                                                                                                                                                                                                                                                                                                                                                                      O3                 PGH2α
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       Elucidate major pathways of PAH activation in human lung cells by
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       expression, metabolic and DNA-adduct profiling
                                                                                                                                                                                                                                     α β
                                                                                                                                                                                                                                                       PIP2                                                         100                                                                                                                                                                                                                                                                                          β-actin
                                                                                                                                                                                                                     GEF                   γ
                                                                                                                                                                                                                                                                                                                                                                                                                                AKR1C3                                                        FP
                                                                                                                                                                                                                                                                                                                                                                                                                      PGD2                     11βPGF2α                                                                 Broncho
                                                                                                                                                                                                                                               DAG                                                                   50                                                                                                                                                                     Receptor                   constriction




                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                1µg AKR1C1
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                1µg AKR1C2
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                5ng AKR1C3
                                                                                                                                                                                                      RhoA-GDP                                                                                                                                                                                                                                                                                                                                        Human
                                                                                                                                                                       Calcium                                             RhoA-GTP                   IP3
                                                                                                                                                                                                                                                                                                                      0
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  Airway Smooth                                                                        Establish sensitive and reliable methods for biomonitoring human exposure
                                                                                                                                                                                                                                                                    Calcium                                                                                                                                           15dPGJ2              NKkB                                           Gq coupling
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       to lung carcinogens (anti-BPDE-N2-dGuo adducts and 8-oxo-dGuo)
                                                                                                                                                                                                                                                                                                                      10 -9       10 -8     10 -7   10 -6                  10 -5     10 -4                                                                                                                                                         Muscle cells
                                                                                                                                                                       sensitization                                                                                homeostasis                                                           log [Carbachol]
                                                                                                                                                                                                              Rho Kinase                              SR      RyR
                                                                                                                                                                                                                                                                                                                                                                                                                                      Inflammation
                                                                                                                                                                                                                                                      Ca2+                                                                        Air                 Ozone                                                                                                       LC/MS Detection of 11β-PGF2α Produced by AKR1C3
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       Elucidate mechanisms of ozone induced hyperresponsiveness in airway
                                                                                                                                                                                                                                                          CaM
                                                                                                                                                                                                                     MLC             Ca2+-       Ca2+-CaM
                                                                                                                                                                                                                                                                                                                              -           +           -            +                                                                                                                                                                                                                                                                   smooth muscle
                                                                                                                                                                          MLC
                                                                                                                                                                       Phosphatase                                                   CaM-                                                                                                                                       Rantes
                                                                                                                                                                                                                   MLC-P
                                                                                                                                                                                                                                     MLCK       MLCK                                                                                                                                                                                                                                                                                                                                                                                   Initiate lung cancer susceptibility gene initiative across Pennsylvania
                                                                                                                                                                                                                                                                                                                                                                                CD38
                                                                                                                                                                                     Actin-myosin                                                                                                                                                                                                                                                                                                                                                                                                                                      (consortium with Hershey Medical College and Lincoln University)
                                                                                                                                                                                    cross bridging
                                                                                                                                                                                                                                                                                                                                                                                GAPDH
                                                                                                                                                                                            Force Generation                                                                                                                                                                                                                                                                                                                                                                                                                           Targeted Pilot Project Funding with Abramson Cancer Center
                                                                                                                                                                                                                                                                                                                                                                                                                                           2             4                        6             8        10       12     14    16      18        20             22        24        26         28       30
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       Partner with Abramson Cancer Center to form a program in Environmental
                                                                                                                                                                                           What are the gene and gene products that mediate ozone effects on ASM?
                                                                                                                                                                                           Does autocrine secretion of cytokines modulate ASM force generation induced by cytokines?
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           TIme
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         Penning, Panettieri, Haczku, Blair
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       Carcinogenesis

                             http://www.med.upenn.edu/ceet/

				
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