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Title: FUMONISIN-INDUCED LIVER TOXICITY IN MICE IS INDEPENDENT OF THE PEROXISOME PROLIFERATION-ACTIVATED RECEPTOR ALPHA

Author
item Voss, Kenneth
item LIU, J - NIEHS, RES.TRIANG.PARK,NC
item MILLER, J - CARLETON U.,OTTAWA, CANAD
item OWEN, J - TOX.PROG./U.GEORGIA
item Riley, Ronald
item Bacon, Charles
item CORTON, J - TOXICOGENICS,RTP, NC

Submitted to: Meeting, Center for Food Safety, University of Georgia
Publication Type: Abstract Only
Publication Acceptance Date: 3/1/2005
Publication Date: 7/1/2005
Citation: Voss, K.A., Liu, J., Miller, J.D., Owen, J.R., Riley, R.T., Bacon, C.W., Corton, J.C. 2005. Fumonisin-induced liver toxicity in mice is independent of the peroxisome proliferation-activated receptor alpha. Annual Report for 2004 Center for Food Safety, University of Georgia. Athens, Georgia. University of Georgia. p.

Interpretive Summary: No summary.

Technical Abstract: Fumonisin mycotoxins occur worldwide in corn and foods made from corn. Fumonisin B1 (FB1) causes liver and kidney cancer in rodents and is a suspected human carcinogen. It inhibits the enzyme ceramide synthase and disrupts sphingolipid metabolism and function. The events linking ceramide synthase inhibition to toxicity are not understood and their elucidation is important for understanding fumonisin's mode of action. Sphinganine (Sa) and sphingosine (So) accumulate in tissues of fumonisin-exposed animals as a result of ceramide synthase inhibition and they have been shown to bind mouse recombinant peroxisome proliferator-activated receptor alpha (PPAR-alpha) in vitro. Activation of PPAR-alpha by peroxisome proliferator compounds or other ligands alters the expression of genes involved in lipid metabolism, peroxisome proliferation, and cell proliferation. Therefore, to explore whether PPAR-alpha-dependent pathways are involved in fumonisin toxicity, genetically modified mice lacking PPAR-alpha (PPAR-alpha-null) and their genotypic wild types (WT) were fed control diets or diets containing 300 ppm FB1, F. verticillioides culture material (CM=fungus-contaminated corn produced under controlled laboratory conditions) providing 300 ppm FB1, or 500 ppm of the peroxisome proliferator WY-14,643 for one week. WT but not PPAR-alpha-null mice responded to WY-14,643, exhibiting enlarged livers and hepatocyte proliferation in the absence of increased Sa and So concentrations. FB1 and CM were toxic to both mouse strains and the liver effects were different from those induced by WY14,643 in WT mice. They included, in addition to cell proliferation, increased Sa concentrations and hepatocyte cell death by apoptosis. Gene expression profiles of WT mice fed FB1, CM or WY14,643 were also compared. FB1 and CM elicited similar expression patterns of genes involved in cell proliferation, signal transduction, and glutathione metabolism. In addition, this gene expression pattern differed from that induced by WY-14,643 and involved PPAR-alpha-independent alterations of genes involved in lipid metabolism. The findings indicate that FB1-induced liver toxicity in mice does not require PPAR-alpha and that F. verticillioides does not produce metabolites that have significant peroxisome proliferator activity.