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ToxSci Advance Access published online on October 12, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj019
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Published by Oxford University Press 2005.
Received May 16, 2005
Accepted October 6, 2005

Environmental Toxicology

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

Kenneth A. Voss 1*, Jie Liu 2, Steven P. Anderson 3, Corrie Dunn 4, J. David Miller 5, Joy R. Owen 1, Ronald T. Riley 1, Charles W. Bacon 1, and J. Christopher Corton 6

1 Toxicology & Mycotoxin Research Unit, USDA-Agricultural Research Service, Athens, GA 30604-5677
2 Inorganic Carcinogenesis, LCC, NCI at NIEHS, Research Triangle Park, NC 27709
3 GlaxoSmithKline, Research Triangle Park, NC 27709; Present address: Bayer Corporation, Research Triangle Park, NC 27709
4 CIIT Centers for Health Research, Research Triangle Park, NC 27709
5 Department of Chemistry, Carleton University, Ottawa, Ontario, Canada K1S 5B6
6 ToxicoGenomics, Chapel Hill, NC 27514; Current address: Toxicogenomics Program, National Health and Environmental Effects Research Lab, US-EPA, Research Triangle Park, NC 27711

* To whom correspondence should be addressed.
Kenneth A. Voss, E-mail: kvoss{at}saa.ars.usda.gov


  Abstract

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 one 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}.


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