|Voss, Kenneth - Ken|
Submitted to: Toxicology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 10/11/1999
Publication Date: 3/1/2001
Citation: Interpretive Summary: Fumonisin B1 (FB1) is a toxin which is made by molds. It is found in corn and cereals and is toxic to animals. Understanding the way in which FB1 causes toxicity is important for evaluating its potential effect on humans and for possible development of protective strategies. Tumor necrosis factor alpha is a receptor which regulates many biological effects. Its importance in FB1 liver toxicity was studied. FB1 was given to two strains of mice. One was a control strain and the other lacked a molecule which helps the receptor exert its effects in cells. It was found that, even though the receptor was affected equally by both groups, the toxic response was less severe in mice lacking the receptor. Increases in molecules called sphingoid bases (which also played an important role in FB1 toxicity), which occur in FB1 treated animals, were less pronounced in mice lacking the receptor. Also, the expected increase in another molecule called NFkB, which depends upon the receptor, was found only in the control mice. Together these findings provide more evidence that more than one receptor plays an important role in the events causing FB1 toxicity and increase overall understanding of the way in which FB1 exerts its effects.
Technical Abstract: Fumonisin (B1) (FB1), a mycotoxin found in corn and cereals, causes diverse toxic effects in various mammalian species. Biochemical responses to FB1 involve inhibition of ceramide synthase, accumulation of free sphingoid bases, and the possible involvement of tumor necrosis factor (TNF-alpha). To further characterize the role of TNF-alpha, the toxic response to FB1 was studied in male C57BL/6J (WT) mice and a corresponding strain (TRK) which was genetically modified to lack the TNF-alpha/1b receptor. Five daily injections of FB1 increased serum alanine and aspartate aminotransferase levels and caused microscopic liver lesions in both strains; however, these hepatotoxic effects were reduced in the TRK mice. FB1 induced TNF-alpha expression in livers of both strains to a similar extent (3-4 fold over control); however, increased cellular NFkB, an expected downstream response to TNF-alpha signaling, was noted only in WT mice. Accumulation of liver sphingosine after FB1 treatment was similar in both WT and TRK mice, but FB1-induced increases in liver sphinganine as well as kidney sphingosine and sphinganine were lower in the TRK strain. These findings suggest a role for TNF-alapha and the TNFalpha/1b receptor in mediating FB1-induced hepatotoxicity in mice and a possible relationship between sphingoid base accumulation and TNF-alpha induction.