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item Voss, Kenneth
item Liu, Jie
item Anderson, Steven
item Dunn, Corrie
item Miller, J. David
item Owen, Joy
item Riley, Ronald
item Bacon, Charles
item Corton, J. Christopher

Submitted to: Toxicological Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/6/2005
Publication Date: 2/1/2006
Citation: Voss, K.A., Liu, J., Anderson, S.P., Dunn, C., Miller, J., Owen, J.R., Riley, R.T., Bacon, C.W., Corton, J. 2006. Toxic effects of fumonisin in mouse liver are independent of the peroxisome proliferator-activated receptor alpha. Toxicological Sciences. 89(1):108-119.

Interpretive Summary: Fumonisins are fungal toxins found in corn and corn-based food. They cause liver disease and cancer in rodents and are considered possible risk factors for cancer in man. To better understand how fumonisins might impact human health, it is important to identify the cell signaling pathways that they affect. Fumonisins disrupt metabolism and cause accumulation of fats known as sphinganine and sphingosine, which have been shown to bind a signaling molecule known as the peroxisome proliferator-activated receptor alpha (PPAR-alpha) under some conditions. PPAR-alpha governs the expression of genes involved in fat metabolism and cell growth and division, processes that are involved in both cancer development and fumonisin toxicity. We fed fumonisin B1 (FB1), corn cultures of a common fumonisin-producing fungus (CM), or Wyeth 14,643 (WY, a liver toxin that acts through PPAR-alpha) to genetically modified mice lacking PPAR-alpha and to their unmodified wild-type counterparts. FB1 and CM caused similar liver effects. Liver toxicity caused by WY was different in that the apoptosis (a type of cell death) and increased sphinganine and sphingosine levels characteristically caused by fumonisin were not present. FB1 and CM caused similar expression patterns of genes involved in fat metabolism and other processes. These patterns were independent of the PPAR-alpha and were distinct from the PPAR-alpha-dependent gene expression patterns caused by WY. These results are important because they show that PPAR-alpha-signaling does not play an important mechanistic role in fumonisin toxicity.

Technical Abstract: Fumonisins are mycotoxins that occur in corn and corn-based foods. Fumonisin B1 (FB1) causes cancer in rodents and is a suspected human carcinogen. FB1 inhibits ceramide synthase and increases tissue sphinganine (Sa) and sphingosine (So) concentrations, however, the sequence of events linking ceramide synthase inhibition, increased Sa and So, and toxicity in vivo remains elusive. Sa and So have been shown to bind mouse recombinant peroxisome proliferator-activated receptor alpha (PPAR-alpha) in vitro, suggesting that they might be ligands for PPAR-alpha in vivo. To investigate whether PPAR-alpha plays a role in fumonisin hepatotoxicity, PPAR-alpha-null mice and their genotypic wild types (WT) were fed control diet or diets containing 300 ppm FB1, F. verticillioides culture material (CM) providing 300 ppm FB1, or 500 ppm of the peroxisome proliferator Wyeth-14,643 for one week. WT but not PPAR-alpha-null mice responded to Wyeth-14,643, exhibiting hepatomegaly and heptatocellular hypertrophy. The hepatotoxicity caused by Wyeth-14,643 did not include increased liver Sa, Sa/So ratios or apoptosis and thus differed from that induced by FB1 and CM in both the WT and PPAR-alpha mice. Transcript profiling showed that FB1 and CM elicited similar and unique (compared to WY) expression patterns of genes involved in cell proliferation, signal transduction, and glutathione metabolism. TaqMan analysis of gene expression demonstrated PPAR-dependence of lipid metabolism gene expression in WY-treated mice but PPAR-independent alterations of genes in lipid metabolism and other categories in the CM- and FB1-fed groups. Taken together, these findings demonstrate that FB1- and CM-induced hepatotoxicity in mice does not require PPAR-alpha.