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

Author
item Voss, Kenneth
item LAUGHTER, A - CIIT, RES.TRINGL.PARK,NC
item ANDERSON, A - CIIT, RES.TRINGL.PARK,NC
item DUNN, C - CIIT, RES.TRINGL.PARK,NC
item STAUBER, A - CITT, RES.TRINGL.PARK,NC
item Riley, Ronald
item MILLER, J - CARLTON U., OTT.ONT,CAN.
item CORTON, J - CIIT, RES.TRINGL.PARK,NC

Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: 1/15/2003
Publication Date: 3/1/2003
Citation: VOSS, K.A., LAUGHTER, A., ANDERSON, A., DUNN, C., STAUBER, A.J., RILEY, R.T., MILLER, J.D., CORTON, J.C. 2003. THE 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:

Technical Abstract: Fumonisins are mycotoxins produced by Fusarium monoliforme that induce a broad spectrum of responses in animals and are suspected human esophageal carcinogens. Exposure of rodents to fumonisins results in increases in liver and kidney toxicity including liver cancer. These effects may be through inhibition of ceramide synthase by fumonisins resulting in accumulations 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. Wild-type and PPAR-null mice were exposed to the PPAR agonist WY-14,643 (WY) , fumonisin-containing culture material (CM), or purified fumonisin B1 in the feed for 8 days. Wild-type and PPAR-null mice fed the CM or FB1 diets exhibited almost identical 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 FB1 treatments exhibited similar profiles whereas WY altered a different set of genes. These results demonstrate that PPAR alpha does not mediate the effects of FB1.