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Title: ROLE OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA IN MODULATING THE EFFECTS OF FUMONISIN B1 IN MOUSE LIVER

Author
item Voss, Kenneth
item OWEN, J - PHARMACY/UNIV OF GEORGIA
item LAUGHTER, A - CIIT, RES TRINGL PARK,NC
item DUNN, C - CIIT, RES TRINGL PARK,NC
item ANDERSON, S - GLAXOSMITHKLINE, NC
item Riley, Ronald
item MILLER, J - CARLETON U.,OTT/ON/CANADA
item CORTON, J - TOXICOGENOMICS, NC

Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: 1/15/2003
Publication Date: 3/1/2003
Citation: Voss, K.A., Owen, J.R., Laughter, A., Dunn, C., Anderson, S.P., Riley, R.T., Miller, J.D., Corton, J.C. 2003. ROLE OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA IN MODULATING THE EFFECTS OF FUMONISIN B1 IN MOUSE LIVER. Toxicologist. v.77. Abstract. p. 7.

Interpretive Summary: Abstract only.

Technical Abstract: Fumonisins are mycotoxins produced by Fusarium verticillioides that induce a broad spectrum of responses in animals and are suspected human esophageal carcinogens. Exposure of rodents to fumonisins causes liver and kidney toxicity and cancer. These effects are likely triggered through inhibition of ceramide synthase by fumonisins resulting in disrupted sphingolipid metabolism and accumulations of the lipids sphingosine and sphinganine in tissues. 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. Wild-type and PPAR-null mice were fed the PPAR agonist WY-14, 643 (WY) (0.05% w/w in the diet), fumonisin-containing (300 ppm fumonisin B1) culture material (CM), or purified fumonisin B1 (300 ppm) in the diet for 8 days. Wild-type and PPAR-null mice responded similarly to the CM or fumonisin B1 diets, exhibiting almost identical hepatic pathology and increases in liver weights, hepatocellular apoptosis, hepatocellular mitoses, sphinganine to sphingosine ratios and tumor necrosis alpha mRNA levels. PPAR-null mice lacked WY-induced liver weight increases and cell proliferation as expected. Using Affymetrix gene chips containing ~9000 mouse genes, transcript profiles of liver gene expression in the wild-type mice showed that the CM and fumonisin B1 treatments exhibited similar profiles that were different than the profile altered by WY and did not alter genes typically associated with peroxisome proliferation. These results demonstrate that PPAR alpha does not mediate the effects of fumonisin.