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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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