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DOSIMETRY AND MODELLING OF METHYLATING AGENT GENOTOXICITY IN TRANSGENIC MICE AND BIOMONITORING OF HUMANS ENVIRONMENTALLY EXPOSED TO METHYLATING AGENTS

Objective

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.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

NATIONAL HELLENIC RESEARCH FOUNDATION
Address
48,Vas. Constantinou Avenue 48
11635 Athens
Greece

Participants (3)

Centre International de Recherche sur le Cancer
France
Address
150 Cours Albert Thomas
69372 Lyon
NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS
Greece
Address
Mikras Asias Street 75
11527 Athens
Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek
Netherlands
Address
137-139,Lange Kleiweg
2280 HV Rijswijk