|Laughter, A - CIIT, RES TRIANGL PARK,NC|
|Dunn, C - CIIT, RES TRIANGL PARK,NC|
|Stauber, A - CIIT, RES TRIANGL PARK,NC|
|Corton, J - CIIT, RES TRIANGL PARK,NC|
Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: January 15, 2001
Publication Date: March 1, 2001
Interpretive Summary: No Interpretive Summary Required. Abstract presented at the 40th Annual Meeting of the Society of Toxicology, San Francisco, California, March 25-29, 2001.
Technical Abstract: Fumonisins are mycotoxins produced by Fusarium moniliforme that are suspected human esophageal carcinogens. Exposure of rodents to fumonisins results in alterations in the balance between cell proliferation and apoptosis in the liver and kidney. These effects may be through inhibition of ceramide synthase by fumonisins resulting in accumulation of the lipids sphingosine and sphinganine. As fumonisin B1 can act as a weak peroxisome proliferator (PP), we hypothesized that fumonisin toxicity may be partly mediated through the PP- activated receptor alpha (PPAR), an important regulator of lipid metabolism in the liver. Mice lacking an intact PPAR gene lacked fumonisin-containing culture material (CM)-induced hepatocyte apoptosis but retained hepatocyte proliferation. Apoptosis was blacked at a step downstream of inhibition of ceramide synthase as basal and CM-induced levels of sphinganine and sphingosine were actually higher in PPAR-null mice than in wild-type mice. In contrast mice lacking an intact TNF alpha gene, a potential mediator of fumonisin- and PP- induced effects were more sensitive to CM-induced increases in hepatocyte proliferation and apoptosis. Increased sensitivity in these mice may be due to further increases in sphinganine levels after CM exposure over that observed in wild-type mice. Finally, gene array experiments demonstrate that DM and a PP (WY-14,643) regulate different sets of genes. We conclude that a subset of CM-induced responses, namely alteration of sphingolipid levels and hepatocyte apoptosis are dependent on PPAR and that TNF acts as a negative modulator of fumonisin-induced effects.