Evaluation of genotoxic effects of fumagillin by sister chromatide exchange and chromosomal aberration tests in human cell cultures

Abstract

Fumagillin is a naturally secreted antibiotic of the fungus Aspergillus fumigatus. In veterinary medicine fumagillin is used against nosemosis in bees and microsporidiosis in fish. Since fumagillin is stable in honey in a honey bee hive there is a possible genotoxic risk to beekeepers and consumers of honey contaminated with this substance. The genotoxic effect of fumagillin was evaluated in sisterchromatid exchange (SCE) and chromosome aberration tests in cultured human peripheral blood lymphocytes at three concentrations (1.02, 3.07 and 9.20 _g/mL), with 1:1 water-sugar syrup as the negative control and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as the positive control. The mitotic and proliferative indices were calculated to detect the cytostatic effect of fumagillin. The results revealed that all tested concentrations of fumagillin (1.02, 3.07 and 9.20 _g/mL) significantly (p lt 0.001) increased the SCE frequency per cell and decreased the proliferative activity of human cultured lymphocytes which was manifested in the decrease in mitotic and proliferative indices. Significant increase (p lt 0.001) in aneuploidy and polyploidy was induced by medium and maximum concentrations of fumagillin. Besides, maximum concentrations of fumagillin significantly (p lt 0.001) increased the frequency of monitored structural aberrations of gap, break and insertion type. The results of this study demonstrate the genotoxic potential of fumagillin in vitro.

Fumagilin je prirodni antibiotik Aspergillus fumigatus-a. U veterinarskoj medicini fumagilin se koristi protiv nozemoza kod pčela i mikrosporidioza kod riba. Kako je fumagilin stabilan u medu i pčelinjim košnicama, postoji genotoksični rizik za pčelare i konzumere meda kontaminiranog ovom supstancom. Genotoksič ni efekat fumagilina je procenjivan testovima razmene sestrinskih hromatida i hromozomskih aberacija u kulturi limfocita periferne krvi ljudi u tri koncentracije (1,02, 3,07 and 9,20 _g/mL), gde je kao negativna kontrola korišćen vodeni rastvor šećernog sirupa, a kao pozitivna kontrola N-metil-N'-nitro-N-nitrozoguanidin (MNNG). Citostatični efekat fumagilina je utvrđivan mitotskim i proliferativnim indeksima. Rezultati ukazuju da sve testirane koncentracije fumagilina (1,02, 3,07 and 9,20 _g/mL) signifikantno (p lt 0,001) povećavaju frekvenciju SCE po ćeliji i smanjuju proliferativnu aktivnost kultivisanih ćelija koja je manifestovana smanjenjem mitotskih i proliferativnih indeksa. Signifikantno povećanje (p lt 0,001) aneuploidija i poliploidija je indukovano srednjom i maksimalnom koncentracijom fumagilina. Osim toga, maksimalna koncentracija fumagilina signifikantno (p lt 0,001) povećava frekvenciju praćenih strukturnih aberacija tipa gapova, prekida i insercija. Rezultati ove studije pokazuju genotoksični potencijal fumagilina in vitro.