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ToxSci Advance Access originally published online on October 12, 2005
Toxicological Sciences 2006 89(1):108-119; doi:10.1093/toxsci/kfj019
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Published by Oxford University Press 2005.

Toxic Effects of Fumonisin in Mouse Liver Are Independent of the Peroxisome Proliferator-Activated Receptor {alpha}

Kenneth A. Voss*,1, Jie Liu{dagger}, Steven P. Anderson{ddagger},2, Corrie Dunn§, J. David Miller, Joy R. Owen*, Ronald T. Riley*, Charles W. Bacon* and J. Christopher Corton||,3

* Toxicology & Mycotoxin Research Unit, USDA-Agricultural Research Service, Athens, Georgia 30604–5677; {dagger} Inorganic Carcinogenesis, LCC, NCI at NIEHS, Research Triangle Park, North Carolina 27709; {ddagger} GlaxoSmithKline, Research Triangle Park, North Carolina 27709; § CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709; Department of Chemistry, Carleton University, Ottawa, Ontario, Canada K1S 5B6; and || ToxicoGenomics, Chapel Hill, North Carolina 27514

Received May 16, 2005; accepted October 6, 2005

Fumonisin mycotoxins occur worldwide in corn and corn-based foods. Fumonisin B1 (FB1) is a rodent liver carcinogen and suspected human carcinogen. It inhibits ceramide synthase and increases tissue sphinganine (Sa) and sphingosine (So) concentrations. Events linking disruption of sphingolipid metabolism and fumonisin toxicity are not fully understood; however, Sa and So were shown to bind mouse recombinant peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) in vitro. To investigate the role of PPAR{alpha} in fumonisin hepatotoxicity in vivo, wild-type (WT) and PPAR{alpha}-null mice were fed control diets or diets containing 300 ppm FB1, Fusarium verticillioides culture material (CM) providing 300 ppm FB1, or 500 ppm of the peroxisome proliferator WY-14,643 (WY) for 1 week. WY-fed WT mice exhibited hepatomegaly, an effect not found in WY-fed PPAR{alpha}-null mice, and WY did not change liver sphingoid base concentrations in either strain. Hepatotoxicity found in FB1- and CM-fed WT and PPAR{alpha}-null mice was similar, qualitatively different from that found in WY-treated animals, and characterized by increased Sa concentration, apoptosis, and cell proliferation. Transcript profiling using oligonucleotide arrays showed that CM and FB1 elicited similar expression patterns of genes involved in cell proliferation, signal transduction, and glutathione metabolism that were different from that altered by WY. Real-time RT-PCR analysis of gene expression demonstrated PPAR{alpha}-dependence of lipid metabolism gene expression in WY-treated mice, whereas PPAR{alpha}-independent alterations of genes in lipid metabolism, and other categories, were found in CM- and FB1-fed mice. Together, these findings demonstrate that FB1- and CM-induced hepatotoxicity in mice does not require PPAR{alpha}.

Key Words: fumonisin; peroxisome proliferator-activated receptor {alpha}; hepatotoxicity.


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