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 Department of Molecular Environmental Epidemiology National Institute of Environmental Health József Fodor National Centre for Public Health Budapest, Hungary

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  The use of surrogate and target tissues to estimate environmental genotoxic exposure  The modulation of biomarker levels by genetic susceptibility factors

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 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    

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

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

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

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

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

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

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

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

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  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

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 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