Tolerance to fumonisin toxicity in a mouse strain lacking the P75 tumor necrosis factor receptor

Fumonisin B-I (FB1), a potent mycotoxin prevalent in corn and cereals, causes a variety of toxic effects in different mammalian species. The biochemical responses of FB1 involve inhibition of ceramide synthase leading to accumulation of free sphingoid bases and a possible involvement of tumor necrosis factor alpha (TNF alpha). To further characterize the role of TNF alpha, toxic response to FB1 was investigated in male C57BL/6J mice (WT) and a corresponding TNF alpha receptor knockout (TRK) strain, genetically modified to lack the TNF alpha lb receptor. The hepatotoxic effects of 5 daily injections of 2.25 mg/kg per day of FB1 were observed in WT but were reduced in TRK, evidenced by circulating alanine aminotransferase and aspartate aminotransferase levels and histopathological evaluation of the tissue. FB1 induced TNF alpha expression in the livers of both WT and TRK mice to a similar extent (3-4 fold over control); however, a corresponding increase of cellular NF kappa B. expected after the downstream cellular signaling of TNF alpha, was noted only in the WT. Accumulation of liver sphingosine after FB1 treatment was similar in both WT and TRK, but the FB1-induced increases in liver sphinganine and kidney sphingosine and sphinganine were lower in TRK than in WT. Results emphasized the role of TNF alpha in FB1-induced hepatotoxicity in mice and the possible relationship of sphingoid base accumulation and TNF alpha induction. Moreover, the presence of TNF alpha receptor lb appears to be important in mediating the hepatotoxic responses of TNF alpha and FB1 in mice. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.