Dose–Response Assessment of Mitomycin C Genotoxic Effect on ApoE Knockout Mice.

Polychromatophilic erythrocytes (PCE) are a suitable target to assess both acute and chronic genotoxic stress in in vivo models. Mitomycin C (MMC), an alkylating mutagenic agent forming cross-links between DNA strands, is widely employed to induce genotoxic stress in experiment and, specifically, to evaluate chromosomal genotoxicity in mouse erythrocytes using the in vivo micronucleus test. While most of the available studies focus on acute genotoxic stress caused by high doses of mutagens, there are very few works aimed at studying chronic mutagenic exposures. The aim of the present study was to determine MMC concentration that would induce chromosomal genotoxic, but not cytotoxic, effect in apolipoprotein E gene knockout mice (ApoE–/–) during chronic exposure to this agent. The design of the study included four groups of ApoE–/– mice injected with two different MMC doses, 0.1 and 0.5 mg/kg, once and thrice a week, as well as two control group. Each group consisted of four females and one male. To assess genotoxicity, 1000 PCE isolated from the femoral bone marrow were counted in each sample, the cells with micronuclei were identified, and the percentage of reticulocytes was counted. A dose of 0.5 mg/kg showed a clear cytotoxic effect, as manifested in impaired erythropoiesis (reduced percentage of reticulocytes). A dose of 0.1 mg/kg induced a pronounced genotoxic effect without reaching the threshold of cytotoxicity. These results can be instrumental in selecting MMC doses for the experiments that require the modeling of chronic genotoxic stress in laboratory animals. [ABSTRACT FROM AUTHOR]