Epigenetic properties of fumonisin B-1: Cell cycle arrest and DNA base modification in C6 glioma cells

Fumonisin B-1 produced by the fungus Fusarium moniliforme is a member of a new class of sphinganine analogue mycotoxins that occur widely in the food chain. Epidemiological studies associate FB1 with human oesophageal cancer in China and South Africa. FB1 also causes acute pulmonary edema in pigs an d equine leucoencephalomalacia. This disease is thought to be a consequence of inhibition by FB1 of cellular ceramide synthesis in cells. To investiga te further on this pathogenesis, the effect of FB1 was studied on cell viab ility (3 to 54 mu M of FB1), protein (2.5 to 20 mu M of FB1) and DNA synthe ses (2.5 to 50 mu M of FB1), and cellular cycle (3 to 18 mu M of FB1) of ra t C6 glioma cells after 24 h incubation. The results of the viability test show that FB1 induces 10 +/- 2% and 47 +/- 4% cell death with, respectively , 3 and 54 mu M, in C6 cells. This cytotoxicity induced by FB1 was efficien tly prevented when the cells were preincubated 24 h with vitamin E (25 mu M ). FB1 displays epigenetic properties since it induced hypermethylation of the DNA (9-18 mu M). Inhibition of protein synthesis was observed with FB1 with an IC50 of 6 mu M showing that C6 glioma cells are very sensitive to F B1; however, the synthesis of DNA was only slightly inhibited, up to 20 mu M of FB1. The flow cytometry showed that the number of cells in phase S dec reased significantly as compared to the control p = 0.01 from 18.7 +/- 2.5% to 8.1 +/- 1.1% for 9 mu M FB1. The number of cells in phase G(2)/M increa sed significantly as compared to the control (p less than or equal to 0.05) from 45.7 +/- 0.4% to 54.8 +/- 1.1% for 9 mu M FB1, whereas no change occu rs in the number of cells in the phase G(0)/G(1). These results show that c ytotoxic concentrations of FB1 induce cellular cycle arrest in phase G(2)/M in rat C6 glioma cells possibly in relation with genotoxic events. (C) 200 0 Academic Press.