Carcinogenicity and mechanism of action of fumonisin B1:: a mycotoxin produced by Fusarium moniliforme (= F-verticillioides)

Fumonisins are fungal metabolites and suspected human carcinogens. They inhibit ceramide synthase in vitro, enhance tumor necrosis factor alpha (TNFalpha) production, and cause apoptosis. Fumonisin B-1 (FB1) was fed to rats and mice for 2 years or, in separate studies, given to rats or mice for up to 4 weeks. Kidney tubule adenomas and carcinomas were found in male rats fed greater than or equal to50 ppm, whereas liver adenomas and carcinomas were found in female mice fed greater than or equal to50 ppm for 2 years. In the short-term studies, increases in tissue concentration of the ceramide synthase substrate sphinganine (Sa) and the Sa to sphingosine (So) ratio were correlated with apoptosis. Further, hepatotoxicity was ameliorated in mice lacking either the TNFR1 or the TNFR2 TN-Falpha receptors. Thus, FB1 was carcinogenic to rodents and the findings support the hypothesis that disrupted sphingolipid metabolism and TNFalpha play important roles in its mode of action. (C) 2002 International Society for Preventive Oncology. Published by Elsevier Science Ltd. All rights reserved.