|Voss, Kenneth - Ken|
Submitted to: Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/11/1999
Publication Date: 3/1/2001
Citation: N/A Interpretive Summary: Fumonisin B1 is a chemical produced by a mold that grows on corn worldwide. It is known to cause several farm animal diseases and causes liver and kidney cancer in rodents. When mice are exposed to fumonisin B1 there is an increase in the production of chemicals that are needed to make another chemical called cytokines. Cytokines are known to be involved in the death and survival of cells in the liver and kidney. It is possible that these cytokines, and in particular one called tumor necrosis factor, are involved in the farm animal diseases and in the fumonisin-induced liver and kidney toxicity seen in rodents. This study determined the response to fumonisin B1 exposure in mice that lacked the protein that is known to bind the cytokine TNF. This mouse type is called a TNF R1 receptor knockout mouse. The liver toxicity of fumonisin B1 was reduced in the mice that lacked the receptor for TNF but there was still an increase in the production of TNF. This shows that the receptor for TNF is involved in the liver toxicity of fumonisin. This work is important because tumor necrosis factor may contribute to the liver and kidney toxicity of fumonisin and because tumor necrosis factor is also known to alter the way an animal responds to infectious agents.
Technical Abstract: Fumonisin B1 (FB1), a mycotoxin produced by Fusarium verticillioides and related fungi infests corn and other cereals, and causes a variety of toxic effects in different mammalian species. Hepatotoxicity is a common toxic response in most species. The cellular responses of FB1 involve inhibition of ceramide synthase leading to accumulation of free sphingoid bases and a corresponding induction of tumor necrosis factor (TNF). We recently reported that FB1 hepatotoxicity was considerably reduced in a mouse strain lacking tumor necrosis factor receptor 2 (TNFR2 or TNFRIb). To further investigate the relative contribution of the two TNF receptors (TNFR1 and TNFR2 or P55 and P75 receptors) we evaluated the hepatotoxicity of FB1 in male C57BL/6J mice (WT) and a corresponding TNFR1 knockout (TNFRKO) strain, genetically modified by a targeted deletion of this receptor. The hepatotoxic effects of 5 daily injections of 2.25 mg/kg/day of FB1 were observed in WT but were reduced in TNFRKO, evidenced by the microscopic evaluation of the liver and increased concentrations of circulating alanine aminotransferase and aspartate aminotransferase. FB1 induced the expression of TNF, and similar increases in free sphinganine and sphingosine in livers of both WT and TNFRKO mice. Results indicated that both P55 and P75 receptors are required for FB1-induced hepatotoxicity and TNF plays an important role in such response in liver.