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

Abstract

Fumonisin B 1 (FB 1), a potent mycotoxin prevalent in corn and cereals, causes a variety of toxic effects in different mammalian species. The biochemical responses of FB 1 involve inhibition of ceramide synthase leading to accumulation of free sphingoid bases and a possible involvement of tumor necrosis factor α (TNFα). To further characterize the role of TNFα, toxic response to FB 1 was investigated in male C57BL/6J mice (WT) and a corresponding TNFα receptor knockout (TRK) strain, genetically modified to lack the TNFα1b receptor. The hepatotoxic effects of 5 daily injections of 2.25 mg/kg per day of FB 1 were observed in WT but were reduced in TRK, evidenced by circulating alanine aminotransferase and aspartate aminotransferase levels and histopathological evaluation of the tissue. FB 1 induced TNFα 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 NFκB, expected after the downstream cellular signaling of TNFα, was noted only in the WT. Accumulation of liver sphingosine after FB 1 treatment was similar in both WT and TRK, but the FB 1-induced increases in liver sphinganine and kidney sphingosine and sphinganine were lower in TRK than in WT. Results emphasized the role of TNFα in FB 1-induced hepatotoxicity in mice and the possible relationship of sphingoid base accumulation and TNFα induction. Moreover, the presence of TNFα receptor 1b appears to be important in mediating the hepatotoxic responses of TNFα and FB 1 in mice.