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 (
PPARalpha) in vitro. To investigate the role of
PPARalpha in
fumonisin hepatotoxicity in vivo, wild-type (WT) and
PPARalpha-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
PPARalpha-null mice, and WY did not change liver sphingoid base concentrations in either strain. Hepatotoxicity found in FB1- and CM-fed WT and
PPARalpha-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
PPARalpha-dependence of lipid metabolism gene expression in WY-treated mice, whereas
PPARalpha-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
PPARalpha.