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Kenneth A. Voss,¹ Ronald T. Riley,¹ W.P. Norred,¹ Charles W. Bacon,¹ Filmore I. Meredith,¹ Paul C. Howard,² Ronald D. Plattner,³ Thomas F.X. Collins,⁴ Deborah K. Hansen,² and James K. Porter¹

¹Toxicology and Mycotoxin Research Unit, Agricultural Research Service, U.S. Department of Agriculture, Richard Russell Agricultural Research Center, Athens, Georgia, USA; ²National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA; ³National Center for Agricultural Utilization Research, Agricultural Research Service, U.S. Department of Agriculture, Peoria, Illinois, USA; ⁴Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, Maryland, USA

Abstract

Fumonisins are produced by Fusarium moniliforme (= F. verticillioides) and other Fusarium that grow on corn worldwide. They cause fatal toxicoses of horses and swine. Their effects in humans are unclear, but epidemiologic evidence suggests that consumption of fumonisin-contaminated corn contributes to human esophageal cancer in southern Africa and China. Much has been learned from rodent studies about fumonisin B₁ (FB₁) , the most common homologue. FB₁ is poorly absorbed and rapidly eliminated in feces. Minor amounts are retained in liver and kidneys. Unlike other mycotoxins, fumonisins cause the same liver cancer promotion and subchronic (studies 90 days) liver and kidney effects as F. moniliforme. FB₁ induces apoptosis of hepatocytes and of proximal tubule epithelial cells. More advanced lesions in both organs are characterized by simultaneous cell loss (apoptosis and necrosis) and proliferation (mitosis) . Microscopic and other findings suggest that an imbalance between cell loss and replacement develops, a condition favorable for carcinogenesis. On the molecular level, fumonisins inhibit ceramide synthase, and disrupt sphingolipid metabolism and, theoretically, sphingolipid-mediated regulatory processes that influence apoptosis and mitosis. Liver sphingolipid effects and toxicity are correlated, and ceramide synthase inhibition occurs in liver and kidney at doses below their respective no-observed-effect levels. FB₁ does not cross the placenta and is not teratogenic in vivo in rats, mice, or rabbits, but is embryotoxic at high, maternally toxic doses. These data have contributed to preliminary risk evaluation and to protocol development for carcinogenicity and chronic toxicity studies of FB₁ in rats and mice. Key words: developmental toxicology, fumonisins, Fusarium moniliforme (= F. verticillioides) , hepatotoxicity, nephrotoxicity, sphingolipids. -- Environ Health Perspect 109(suppl 2) :259-266 (2001) .

http://ehpnet1.niehs.nih.gov/docs/2001/suppl-2/259-266voss/abstract.html