Objectif The aims of the project are:i) To investigate the relationships between dose, DNA adducts and somatic mutations in lambda.gt10-lacZ transgenic mice after exposure to methylating agents and to develop biologically-based mathematical models useful for risk assessment;ii) To examine the presence of DNA adducts and somatic mutations in humans environmentally exposed to methylating agents and relate the findings to the animal modelling results;iii) To further develop and refine methodologies for methylated adduct measurements and transgenic mouse mutation assays.Human exposure to small-group alkylating agents appears to be widespread, as indicated by frequent detection of the corresponding DNA and protein adducts in human tissues. It is therefore important to develop methods for assessing the corresponding genetic risks. In the current project, the relationships between exposure levels, the main types of DNA adducts induced (N7-methylguanine, 06-methylguanine, 04-methylthymine and methyl-phosphotriesters) and somatic mutations are examined for four methylating agents: dimethylnitrosamine, dimethylsulphate, methylbromide and dichlorvos. A systematic examination is being carried out (at the lowest possible levels of exposure) of the effects of dose and time on the accumulation of adducts and somatic mutations in a target gene (the lacZ gene) in somatic cells of the recently developed transgenic mouse model. Representative numbers of mutants are being sequenced and correlations between the levels of different adducts and specific mutation types sought. Data on mutations are utilised to set up biologically-based mathematical models which may facilitate chemical-to-chemical and animal-to-human extrapolations.In the context of this part of the project, some methodological work is carried out aimed at improving the lacZ-based transgenic mouse mutation assay and the sensitive detection of methylated adducts.A molecular epidemiology study of DNA adducts and genetic effects (micronuclei, sister-chromatid exchanges and HPRT mutations) in lymphocytes of humans environmentally exposed to the methylating agents methylbromide and dichlorvos is also being carried out. These chemicals are widely employed in agricultural activities. The data thus obtained (in combination with data on exposure) will be analysed with the models constructed under the other activities of the project. Champ scientifique natural sciencesbiological sciencesgeneticsDNAmedical and health scienceshealth sciencespublic healthepidemiologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutationnatural sciencesmathematicsapplied mathematicsmathematical model Programme(s) FP3-ENV 1C - Specific research and technological development programme (EEC) in the field of the environment, 1990-1994 Thème(s) 040204 - Risks to health and the environment from chemical substances Appel à propositions Data not available Régime de financement CSC - Cost-sharing contracts Coordinateur NATIONAL HELLENIC RESEARCH FOUNDATION Contribution de l’UE Aucune donnée Adresse 48,Vas. Constantinou Avenue 48 11635 ATHENS Grèce Voir sur la carte Coût total Aucune donnée Participants (3) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire Centre International de Recherche sur le Cancer France Contribution de l’UE Aucune donnée Adresse 150 cours Albert Thomas 69372 Lyon Voir sur la carte Coût total Aucune donnée NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS Grèce Contribution de l’UE Aucune donnée Adresse Mikras Asias Street 75 11527 ATHENS Voir sur la carte Coût total Aucune donnée Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek Pays-Bas Contribution de l’UE Aucune donnée Adresse 137-139,Lange Kleiweg 2280 HV Rijswijk Voir sur la carte Coût total Aucune donnée
