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ETHENO (e)-BRIDGED ADDUCTS IN DNA ARE FORMED BY A NUMBER OF ENVIRONMENTAL AND ENDOGENOUSLY PRODUCED GENOTOXINS, SOME WITH WIDESPREAD HUMAN EXPOSURE. TO ASSESS THE ROLE OF THESE PROMUTAGENIC DNA LESIONS IN HUMAN CARCINOGENESIS, FOUR KEY COMPOUNDS REPRESENTATIVE OF THIS CLASS (VINYL CHLORIDE, URETHANE, VINYL CARBAMATE AND ITS EPOXIDE) WILL BE INVESTIGATED AS FOLLOWS:
(A) QUANTIFICATION OF e-ADDUCTS IN DNA OF RODENT TISSUES, MAMMALIAN CELLS AND DROSOPHILA, BY THE MOST SENSITIVE METHOD AVAILABLE (RECENTLY DEVELOPED AT IARC), AND MEASUREMENT OF PERSISTENCE AND REPAIR OF e-ADDUCTS IN EXCISION REPAIR-PROFICIENT AND DEFICIENT CHO CELL LINES AND DROSOPHILA.
(B) CHARACTERIZATION OF MUTATIONAL SPECTRA IN THREE REPORTER GENES: HPRT (CHO CELLS), VERMILION (DROSOPHILA) AND LACI (BIG BLUE TRANSGENIC MICE). (C) DETERMINATION OF GENETIC ACTIVITY PROFILES (MUTATIONS,
CLASTOGENICITY AND HYPERMUTABILITY) IN CHO CELLS AND DROSOPHILA AND OF DNA DAMAGE IN TRANSGENIC MICE (COMET ASSAY). - - - - -
(D) ESTIMATION OF TD5O VALUES AND MEASUREMENT OF COVALENT BINDING INDICES (CBI) IN RODENTS FOR A LARGER SERIES OF e-ADDUCT FORMING AGENTS. (E) FINALLY, GENETIC, REPAIR AND DNA BINDING DATA WILL BE USED TO CLASSIFY THESE AGENTS ACCORDING TO THEIR MECHANISM OF ACTION, TO ESTABLISH QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS AND TO PREDICT CARCINOGENIC POTENCY FOR THIS CLASS OF COMPOUNDS. ALTOGETHER, THIS NOVEL APPROACH WILL CORRELATE FOR THE FIRST TIME, DNA BINDING DATA WITH ALL GENETIC ENDPOINTS IN VARIOUS SYSTEMS AND WITH TUMORIGENIC POTENCY IN RODENTS AND HUMANS. THESE DATA WILL ALSO ALLOW TO EXAMINE THE ORIGIN OF BACKGROUND LEVELS OF e-ADDUCTS IN HUMAN TISSUES AND THEIR RELEVANCE FOR CARCINOGENIC RISK ASSESSMENT.
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