Dose-Response of the Mitomycin C Genotoxic Effect on the ApoE Knockout Mice

Abstract

Polychromic erythrocytes have been accepted as a suitable target for micronucleus (MN) evaluation in both acute and cumulative injury. Mitomycin C (MMC) also has a wide range of genotoxicity, including inhibition of DNA synthesis, clastogenesis and mutagenesis. As an immediate clastogen requiring exclusively intracellular reductive activation, MMS initiates efficient DNA crosslinking. The in vivo micronucleus assay has established itself as a standard assay for evaluating chromosomal genotoxicity in mouse erythrocytes. Most of the studies are focused on the study of acute acute effects, which is caused by high doses of the mutagen. In turn, there are no or very few studies aimed at studying the chronic effects of MMS. The aim of the study is to create a chronic genotoxic effect of MMS without lethal outcome in ApoE–/– mice when selecting the optimal dose of MMS. The design of the study included 6 groups of ApoE–/– mice, two doses of MMC at a concentration of 0.1 and 0.5 mg/kg, single and three doses. Each group consisted of four females and one male. To assess genotoxicity, 1000 polychromic erythrocytes (PChE) extracted from the femoral bone marrow were counted on each sample, PChE with micronuclei were detected, and the proportion of reticulocytes was counted. A dose of 0.5 mg/kg showed a clear cytotoxic effect, expressed in a violation of erythropoiesis, and more precisely in a decrease in the proportion of reticulocytes. In our study, the concentration of the mutagen, namely 0.1 mg/kg, was shown to cause a clear genotoxic effect without reaching the threshold of cytotoxicity. Dose-response studies in rodents can provide useful information on the mechanisms of toxicity and dose selection for long-term toxicity studies.