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MOLECULAR MECHANISMS INFLUENCING THE BIOMARKER LEVELS OF ENVIRONMENTAL GENOTOXIC EXPOSURE

MOLECULAR MECHANISMS INFLUENCING THE BIOMARKER LEVELS OF ENVIRONMENTAL GENOTOXIC EXPOSURE. Bernadette Schoket. Department of Molecular Environmental Epidemiology National Institute of Environmental Health József Fodor National Centre for Public Health Budapest, Hungary.

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MOLECULAR MECHANISMS INFLUENCING THE BIOMARKER LEVELS OF ENVIRONMENTAL GENOTOXIC EXPOSURE

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  1. MOLECULAR MECHANISMS INFLUENCINGTHE BIOMARKER LEVELS OF ENVIRONMENTALGENOTOXIC EXPOSURE Bernadette Schoket Department of Molecular Environmental Epidemiology National Institute of Environmental Health József Fodor National Centre for Public Health Budapest, Hungary

  2. IMPORTANT ISSUES IN HUMAN BIOMONITORING  The use of surrogate and target tissues to estimate environmental genotoxic exposure  The modulation of biomarker levels by genetic susceptibility factors

  3. AIMS OF THE STUDY  Correlation between smoking-related bulky carcinogen-DNA adduct levels in lung tissues and in peripheral blood lymphocytes The influence of glutathione S-transferase metabolic genotypes on the DNA adduct levels induced by cigarette smoking 

  4. STUDY POPULATION Lung cancer patients undergoing lung resection, N = 212 Normal bronchus Normal peripheral lung Peripheral blood lymphocytes SMOKING STATUS Current Smokers Life-time Non-smokers & & Short-term Ex-smokers Long-term Ex-smokers (  1 year of abstinence )( > 1 year of abstinence ) ‘SMOKERS’ ‘NON-SMOKERS’

  5. Phase I Phase II OH O-conj. X X X DNA damage METHODOLOGY  DETERMINATION OF BULKY CARCINOGEN-DNA ADDUCTS 32P-Postlabelling  DETERMINATION OF GENOTYPES PCR and PCR-RFLP GSTM1 GSTT1 GSTP1 Ile105Val

  6. BULKY DNA ADDUCTS IN TISSUES FROM CURRENT SMOKER LUNG CANCER PATIENTS Lung tumour Normal lungNormal bronchus Blood lymphocytes

  7. LEVELS OF BULKY DNA ADDUCTS IN LUNG TISSUES AND PERIPHERAL BLOOD LYMPHOCYTES

  8. CORRELATION BETWEEN BULKY DNA ADDUCT LEVELS IN NORMAL PERIPHERAL LUNG AND BRONCHIAL TISSUES • Smokers: r=0.83 P<0.0001 (N=38) • Non-smokers: r=0.73 P<0.0001 (N=30)

  9. CORRELATION BETWEEN DNA ADDUCT LEVELS IN LUNG TISSUES AND LYMPHOCYTES FOR SMOKERS AND NON-SMOKERS

  10. GSTM1 AND GSTT1 GENOTYPES AND BULKY DNA ADDUCT LEVELS IN BRONCHUS GSTM1 GSTT1 GSTM1&GSTT1 Smokers Non-smokers Smokers Non-smokers Smokers Non-smokers

  11. THE EFFECT OF GSTP1 Ile105Val GENOTYPE ON BULKY DNA ADDUCT LEVELS IN BRONCHUS Smokers Non-smokers P=0.012 * *

  12. MAIN CONCLUSIONS The dose of exposure and the metabolic capacity of the tissues influence the correlation between target and surrogate tissue  Genetic polymorphisms of xenobiotic-metabolising enzymes may affect the biologically effective dose of genotoxic exposure  Implications for human biomonitoring  low dose - high dose exposure  surrogate - target tissue  metabolic genotypes - biomarker levels

  13. PARTICIPANTS OF THE STUDY National Institute of Environmental Health, Budapest, Hungary Bernadette Schoket Erika Győrffy Lívia Anna National Center for Epidemiology, Budapest, Hungary Judit Segesdi János Minárovits Zoltán Győri National Institute of Pulmonology, Budapest, Hungary Ibolya Soltész Szilárd Kostic Attila Csekeő

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