Evaluation of genotoxic effects of fumagillin by cytogenetic tests in vivo.

Abstract

Fumagillin is a naturally secreted antibiotic of the fungus Aspergillus fumigatus. It is used in veterinary medicine against microsporidiosis of bees and fish. In this study, the genotoxicity of fumagillin (in the form of fumagillin dicyclohexylamine) was evaluated in mouse bone-marrow cells using the mitotic index (MI), the chromosome aberration (CA) assay, and the micronucleus (MN) test. Fumagillin was administered to BALB/c mice by gavage, at doses of 25, 50, 75 mg/kg body weight (bw), repeated for 7 days at 24-h intervals, with water-sugar syrup as a negative control and cyclophosphamide (40 mg/kg bw) as a positive control. All experimental doses of fumagillin induced a significant decrease (p<0.001) in MI (3.47+/-0.04%, 3.17+/-0.01%, and 2.27+/-0.02%, respectively) in comparison with the negative control (6.00+/-0.01%). Fumagillin significantly (p<0.001) increased the frequency of MN (4.98+/-0.35, 8.45+/-0.57, and 12.02+/-0.37, respectively) over negative control (1.04+/-0.28). Significantly increased frequencies (p<0.01 or p<0.001) of numerical chromosomal aberrations (aneuploidies and polyploidies) and structural chromosomal aberrations such as gaps, breaks, and centric rings were observed at the highest experimental dose of fumagillin (75 mg/kg bw) compared with the negative control. However, with respect to the induction of Robertsonian translocations, both the intermediate (50 mg/kg bw) and highest (75 mg/kg bw) experimental dose caused a significant (p<0.001) increase (7.12+/-0.26 and 9.00+/-0.10, respectively) in comparison with the negative control (0.00+/-0.00). Chromosomes 4 and 19 participated in these Robertsonian translocations. Regarding total cytogenetic changes, a significant increase (p<0.001) was observed in both the intermediate dose group (17.36+/-1.83) and the highest dose group (59.49+/-1.92) compared with the negative control (7.00+/-1.35). These results suggest that fumagillin has genotoxic (clastogenic) potential in mammals in vivo.

• Authors: Zoran Stanimirovic, Jevrosima Stevanovic, Vladan Bajic, Ivica Radovic
• Journal: Mutation research (Mutat Res) Vol. 628 Issue 1 Pg. 1-10 (Mar 30 2007) ISSN: 0027-5107 [Print] Netherlands
• PMID: 17258933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Cyclohexanes
• Fatty Acids, Unsaturated
• Sesquiterpenes
• fumagillin

Topics

• Animals
• Anti-Bacterial Agents (toxicity)
• Bone Marrow Cells (drug effects)
• Chromosome Aberrations
• Cyclohexanes (toxicity)
• DNA Damage
• Fatty Acids, Unsaturated (toxicity)
• Female
• Male
• Mice
• Mice, Inbred BALB C
• Micronucleus Tests
• Mitotic Index
• Sesquiterpenes (toxicity)