ARS | Publication request: UNEXPECTED FUMONISIN HEPATOTOXICITY RESPONSES IN TRANSGENIC MOUSE MODELS LACKING THE TUMOR NECROSIS FACTOR ALPHA PATHWAYS

Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: January 15, 2001
Publication Date: March 1, 2001

Technical Abstract: We previously reported that tumor necrosis factor alpha (TNFa) is involved in fumonisin-induced hepatotoxic effects. A short-term repeated treatment of mice with a low dose (2.25 mg/kg/day) of fumonisin B1 (FB1) induced TNFa expression in liver. In the present study we investigated the effect of a similar FB1 treatment in knockout mice lacking either TNFa or both of its receptors and their corresponding controls. The FB1-induced increases in circulating liver enzymes, alanine aminotransferase and aspartate aminotransferase, were enhanced by deletion of TNFa mRNA expression. These increases corresponded with the microscopic findings in liver of both knockout strains. FB1 induced the expression of TNFa in the liver of controls and the double-receptor knockout mice; no TNFa was found in the TNFa knockout strain. Results indicate that the presence of some TNFa is necessary for normal tissue repair and a complete lack of this cytokine or abolition of its effect may aggravate the hepatotoxic responses to fumonisins in mice. These observations corroborated our previous finding, in which over-expression of TNFa was protective against FB1-mediated hepatotoxicity, and with the reported beneficial effects of low-level TNFa on cell growth.