Submitted to: Toxicologist
Publication Type: Abstract only
Publication Acceptance Date: 1/15/2001
Publication Date: 3/1/2001
Citation: Interpretive Summary:
Technical Abstract: Fumonisin B1 (FB1) is a common contaminant in corn or corn products. It causes several animal diseases, and has been associated with the high incidence of human esophageal cancer and primary liver cancer in South Africa and China. Fumonisin B1 inhibits ceramide synthase, resulting in accumulation of free sphinganine and sphingosine. We previously demonstrated in mice that 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. The objective of the current study was to investigate whether the two events, sphingoid base accumulation and TNFa induction are interdependent. An increase in the expression of TNFa mRNA occurred in LLC-PK1 cells as early as 4 hr after FB1 exposure and decreased to the control level after 8 hr. A positive linear correlation was observed between the expression of TNFa mRNA and FB1 concentration. Increases in intracellular sphinganine and sphingosine detected after 4 hr of FB1 treatment, progressively elevated until 24 hr. Exposure of the cells to sphinganine or sphingosine did not significantly alter the expression of TNFa. Inhibition of sphingoid base accumulation by myriocin, a specific inhibitor of serine palmitoyl-transferase, the first enzyme in de novo sphingolipid biosynthesis, efficiently blocked the FB1-induced accumulation of free sphingoid bases, but did not prevent the induction of TNFa expression by FB1. Results indicate that the accumulation of face sphingoid base-induced by ceramide synthase inhibition is not required for the increased expression of TNFa in LLC-PK1 cells in response to FB1 treatment.