|Voss, Kenneth - Ken|
Submitted to: Book Chapter
Publication Type: Book / Chapter
Publication Acceptance Date: 1/15/2000
Publication Date: N/A
Citation: Interpretive Summary: Consumption of corn molded with Fusarium moniliforme causes fatal diseases in horses and pigs and cancer in rats. The fungus has also been associated with human cancer. As a result of animal studies, it was discovered that the diseases in horses, pigs and rodents were caused by fungally produced compounds called fumonisins. Since then, detailed studies on fumonisin toxicity have shown that these compounds cause a type of cell death called apoptosis in liver and kidney. In severely damaged livers and kidneys, apoptosis, cell replacement (mitosis) and regeneration occur together creating conditions favorable for cancer development. On the molecular level, fumonisins inhibit an enzyme, ceramide synthase, thereby disrupting metabolism of important compounds called sphingolipids and, theoretically, sphingolipid mediated regulation of apoptosis and mitosis. Sphingolipid effects are correlated with toxicity and also occur at nontoxic doses, suggesting that ceramide synthase inhibition is a critical event leading to toxicity and cancer. These findings, defining target organs and modes of action, are important for understanding fumonisin toxicity to farm animals, for evaluating their impact on human health, and for designing the detailed long-term studies in laboratory animals, which are needed to further define the cancer causing effects of these compounds.
Technical Abstract: Fumonisins are produced by Fusarium moniliforme and other Fusarium which are commonly found on corn. They cause a fatal neurotoxicity known as leukoencephalomalacia in horses and a fatal respiratory condition known as pulmonary edema in swine. There is evidence suggesting they are human carcinogens and the most common homologue, fumonisin B1 (FB1), was hepatocarcinogenic to rats. When fed to rodents for up to 90 days, fumonisins promote liver cancer and cause apoptosis in the target organs, liver and kidney. At higher doses, histopathological findings suggest that an imbalance between cell loss (apoptosis and necrosis) and replacement (mitosis, hyperplasia and repair) occurs in both organs, a condition favorable for carcinogenesis. On the molecular level, fumonisins inhibit ceraamide synthase, thereby disrupting sphingolipid metabolism and, theoretically, sphingolipid mediated regulatory processes influencing apoptosis and mitosis. Sphingolipid effects occur in liver and kidney at doses which are otherwise not toxic, are directly correlated with the severity of the hepatotoxic response, and are reversible upon returning animals to uncontaminated feed. These findings have contributed to preliminary risk evaluations of fumonisins and have provided target organ, dose-response and mechanistic data for designing comprehensive studies to define the carcinogenicity of FB1 in laboratory animals.