|Howard, Paul - NCTR-FDA, JEFFERSON, AR|
|Collins, Thomas - CFSAN/FDA, LAUREL, MD|
|Hansen, Deborah - NCTR/FDA, JEFFERSON, AR|
Submitted to: Book Chapter
Publication Type: Book / Chapter
Publication Acceptance Date: December 1, 2000
Publication Date: May 1, 2001
Interpretive Summary: Fumonisins are common toxins produced by Fusarium moniliforme and related molds which grow on corn. They cause fatal diseases of horses and pigs and are suspected of causing cancer in humans. The short-term toxicological and reproductive effects of fumonisins, especially the most commonly found type, fumonisin B1 (FB1) have been studied in laboratory animals. FB1 is poorly absorbed from the gut, is apparently not metabolized, and is rapidly eliminated. Only small amounts are retained, mostly in the liver and kidneys. FB1 is a liver and kidney toxin, causing a type of cell death called apoptosis. In more severely injured tissues, apoptosis and cell replacement (mitosis) occur together. This is important because imbalances in cell death and mitosis may promote cancer development. On the molecular level, fumonisins inhibit the enzyme ceramide synthase, thereby disrupting metabolism of compounds called sphingolipids and, theoretically, sphingolipid mediated regulation of apoptosis and mitosis. Inhibition occurs at low, nontoxic doses and, at least in liver, it is correlated with toxicity. When given to pregnant animals, FB1 did not cause birth defects. Fetal death occurred only at high doses which were toxic to the mother. Determining the effects and modes of action of fumonisins is important for designing critical long-term cancer studies which are needed for evaluating their impact on human health.
Technical Abstract: Fumonisins are produced by Fusarium moniliforme and other Fusarium which are commonly found on corn. Fumonisins cause fatal diseases of horses and swine and there is evidence suggesting they are human carcinogens. In vivo studies of fumonisin B1 (FB1), the most common homologue, in rodents have been undertaken to determine the nature of their biological effects. FB1 is poorly absorbed, not metabolized, rapidly eliminated and only minor amounts are retained in liver and kidneys. FB1 promotes liver cancer and is hepato- and nephrotoxic when fed to rodents for up to 90 days. FB1 induces apoptosis in both organs and, in more advanced lesions, findings suggest that an imbalance between cell loss (apoptosis and necrosis) and replacement (mitosis and repair) occurs, a condition favorable for carcinogenesis. On the molecular level, fumonisins inhibit ceramide 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 and are directly correlated with the severity of the hepatotoxic response. When given to pregnant animals, FB1 does not cross the placenta, is not teratogenic, and embryotoxicity occurs only at high, maternally toxic doses. These findings have contributed to preliminary risk evaluations of fumonisins and were needed for designing comprehensive studies on the carcinogencity of FB1.