Decreased fumonisin hepatotoxicity in mice with a targeted deletion of tumor necrosis factor receptor 1

Fumonisin B-1 (FB1), a mycotoxin produced by Fusarium verticillioides and r elated fungi infests corn and other cereals, and causes a variety of toxic effects in different mammalian species. Hepatotoxicity is a common toxic re sponse in most species. The cellular responses of FB, involve inhibition of ceramide synthase leading to accumulation of free sphingoid bases and a co rresponding induction of tumor necrosis factor alpha (TNF alpha). We recent ly reported that FB, hepatotoxicity was considerably reduced in a mouse str ain lacking tumor necrosis factor receptor 2 (TNFR2 or TNFR1b). To further investigate the relative contribution of the two TNF alpha receptors (TNFR1 and TNFR2 or P55 and P75 receptors) we evaluated the hepatotoxicity of FB, in male C57BL/6J mice (WT) and a corresponding TNFR1 knockout (TNFRKO) str ain, genetically modified by a targeted deletion of this receptor. The hepa totoxic effects of five daily injections of 2.25 mg/kg per day of FB, were observed in WT but were reduced in TNFRKO, evidenced by the microscopic eva luation of the liver and increased concentrations of circulating alanine am inotransferase and aspartate aminotransferase. FB, induced the expression o f TNFa. and similar increases in free sphinganine and sphingosine in livers of both WT and TNFRKO mice. Results indicated that both P55 and P75 recept ors are required for FB1-induced hepatotoxicity and TNF alpha plays an impo rtant role in such response in mouse liver. (C) 2001 Elsevier Science Irela nd Ltd. All rights reserved.