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Induction of DNA Synthesis in Mouse Liver Following Increases of DNA Adduct Levels Elicited by Very Low Cumulative Doses of the Genotoxic Hepatocarcinogen 7H-dibenzo[c,g]carbazole

Sanofi-Synthelabo Recherche, Department of Toxicology, 2-8 rue de Rouen, 78440 Porcheville, France, olivier.dorchies@sano fi-synthelabo.com

Odette Perin-Roussel

Institut Curie-Recherche, Centre Universitaire, 91405 Orsay Cedex, France

Olivier Gillardeaux

Sanofi-Synthelabo Recherche, Department of Toxicology, 2-8 rue de Rouen, 78440 Porcheville, France

Joan-Albert Vericat

Sanofi-Synthelabo Recherche, Department of Toxicology, 2-8 rue de Rouen, 78440 Porcheville, France

Nigel Oliver Roome

Sanofi-Synthelabo Recherche, Department of Toxicology, 2-8 rue de Rouen, 78440 Porcheville, France

Annick Prenez

Sanofi-Synthelabo Recherche, Department of Toxicology, 2-8 rue de Rouen, 78440 Porcheville, France

François Perin

Institut Curie-Recherche, Centre Universitaire, 91405 Orsay Cedex, France

The purpose of this work was to investigate the administration of very low but repeated doses of a genotoxic carcinogen and an eventual correlation with cellular DNA synthesis. The compound 7H-dibenzo[c,g]carbazole is a genotoxic carcinogen in the mouse liver and was administered topically at the dose of 13.35 µg per animal every 2 days to give a total of 13 applications. Animals were sacrificed 48 hours after every 2 applications until the 10th treatment, then 48 hours after every treatment. Postulated genotoxic effects such as DNA adduct formation were detected by the ³²P-post labeling assay. Liver sections were examined for microscopic changes and DNA synthesis. Results showed an increase of the total DNA adduct level in the liver throughout the study with a slowing down in the level after the sixth application of the compound. This change could correspond to the onset of DNA synthesis and to the moderate hepatocellular apoptosis which was observed. The DNA synthesis, which was considered to be secondary to the cytotoxicity induced by the high level of DNA adducts altering normal cellular activity, could also be the opportunity to fix the DNA adducts into heritable mutations. These results raise the question regarding the risk assessment in humans exposed regularly to very low doses of chemicals in the environment: for non-proliferating tissue, the regular accumulation of DNA adducts could remain silent until a "threshold level" is reached from which stimulation of the DNA synthesis may fix the DNA adducts into heritable mutations, eventually leading to tumors.

Key Words: Dibenzo[c,g]carbazole • DNA adducts • DNA synthesis • mouse liver • carcinogenesis • risk assessment.

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