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 FB(1) with human oesophageal cancer in China and South Africa. FB(1) also causes acute pulmonary edema in pigs and equine leucoencephalomalacia. This disease is thought to be a consequence of inhibition by FB(1) of cellular ceramide synthesis in cells. To investigate further on this pathogenesis, the effect of FB(1) was studied on cell viability (3 to 54 microM of FB(1)), protein (2.5 to 20 microM of FB(1)) and DNA syntheses (2.5 to 50 microM of FB(1)), and cellular cycle (3 to 18 microM of FB(1)) of rat C6 glioma cells after 24 h incubation. The results of the viability test show that FB(1) induces 10 +/- 2% and 47 +/- 4% cell death with, respectively, 3 and 54 microM, in C6 cells. This cytotoxicity induced by FB(1) was efficiently prevented when the cells were preincubated 24 h with vitamin E (25 microM). FB(1) displays epigenetic properties since it induced hypermethylation of the DNA (9-18 microM). Inhibition of protein synthesis was observed with FB(1) with an IC(50) of 6 microM showing that C6 glioma cells are very sensitive to FB(1); however, the synthesis of DNA was only slightly inhibited, up to 20 microM of FB1. The flow cytometry showed that the number of cells in phase S decreased significantly as compared to the control p = 0.01 from 18. 7 +/- 2.5% to 8.1 +/- 1.1% for 9 microM FB(1). The number of cells in phase G(2)/M increased significantly as compared to the control (p </= 0.05) from 45.7 +/- 0.4% to 54.8 +/- 1.1% for 9 microM FB(1), whereas no change occurs in the number of cells in the phase G(0)/G(1). These results show that cytotoxic concentrations of FB(1) induce cellular cycle arrest in phase G(2)/M in rat C6 glioma cells possibly in relation with genotoxic events. Copyright 2000 Academic Press.