Submitted to: Journal of Toxicology and Applied Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/1/2000
Publication Date: 7/1/2001
Citation: Interpretive Summary: Fumonisin B1 is a toxic chemical produced by a mold that commonly occurs on corn. It is the cause of several farm animal diseases and also causes tumors in animals. It has been proposed that the way it causes all these diseases is through changes in the way cells make a diversity of fats called sphingolipids that are known to be important in determining whether cells live or die. It is also known that fumonisins cause changes in the production of a group of chemicals called cytokines and in particular, one called tumor necrosis factor. Tumor necrosis factor also is known to affect the birth and death of cells. The question we asked was "is it possible that the effects on the sphingolipids are the cause of the increase in tumor necrosis factor"? We tested one class of the sphingolipids that we know are affected by fumonisin. This one class is called free sphingoid bases. We found that even when we prevented the free sphingoid bases from increasing in the cells given fumonisin, that the tumor necrosis factor still increased. Therefore, the increase in tumor necrosis factor in cells given fumonisin is not due to the increase in free sphingoid bases. Future studies will determine if changes in other classes of sphingolipids can affect production of tumor necrosis factor.
Technical Abstract: Previous studies have shown that fumonisin B1 (FB1) inhibits ceramide synthase, resulting in accumulation of free sphinganine and sphingosine. Tumor necrosis factor alpha (TNFa) plays an important role in FB1 toxicity and the expression of TNFa MRNA in liver and kidney is increased following FB1 exposure in mice. The objective of the current study was to investigate whether or not these two events (sphingoid bases accumulation and TNFa induction) are dependent on each other. An increase in expression of TNFa MRNA was detected in LLC-PK1 cells as early as 4 hr after FB1 treatment but decreased to the control levels after 8 hr. A positive linear correlation was observed between the expression of TNFa MRNA and FB1 concentration. Increases of intracellular sphingoid bases were also detected after 4 hr of FB1 treatment, and progressively increased until 24 hr. Exposure of the cells to sphinganine or sphingosine did not significantly alter the expression of TNFa. Inhibition of sphingoid base biosynthesis by ISP-1, a specific inhibitor of serine palmitoyltransferase, the first enzyme in de novo sphingolipid biosynthesis, efficiently blocked the accumulation of free sphingoid bases in response to FB1, but it did not prevent the induction of TNFa expression. Results indicate that FB1-induced increase in TNFa expression is independent of sphingoid base accumulation induced by ceramide synthase inhibition in LLC-PK1 cells.