|Howard, Paul - NCTR-USFDA, JEFFERSON, AR|
|Lorentzen, Ronald - CFSAN-USFDA,WASHINGTON,DC|
|Bucci, Thomas - PATHOL.ASSOC.INT,[NCTR]AR|
Submitted to: American Seed Trade Association Conference Proceedings
Publication Type: Proceedings
Publication Acceptance Date: February 17, 2000
Publication Date: July 15, 2000
Interpretive Summary: Fumonisins are toxins produced by Fusarium moniliforme and other Fusarium fungi. They are found worldwide in corn and corn-based foods. Fumonisins are toxic to animals. Consumption of F. moniliforme or fumonisin-contaminated corn and human esophageal cancer rates in areas of Africa and China have been correlated. F. moniliforme and fumonisin caused liver cancer when fed to male rats of strain BD IX. When fed (4 levels per species/sex) to male and female rats of a different strain (F344) or to mice for two years, fumonisin also caused tumors. However, the type of tumor differed by species and sex. In male F344 rats, kidney tumors were induced but, in contrast to strain BD IX, no liver tumors were found. Fumonisin induced liver tumors in the female mice. Tumors were not found in female rats or male mice. Fumonisins inhibit a key enzyme needed for synthesis of fats called sphingolipids. It is theorized that this inhibition triggers other biomolecular events in cells which lead first to disrupted sphingolipid function and ultimately to toxicity or cancer. Studies to further compare relationships between fumonisins, sphingolipids, and disease are needed. Understanding why species, strain, and sex differences in response to fumonisins occur will help determine the role of fumonisins in human cancer.
Technical Abstract: Fumonisin B1 (FB1) and other fumonisins are produced by Fusarium moniliforme and other Fusarium which are common in corn. FB1 causes leukoencephalomalacia in horses, pulmonary edema in swine, and liver and kidney disease in many species. Epidemiological evidence suggests that fumonisins are human carcinogens. Liver tumors were also found in female, but not male, B6C3F1 mice fed >50 ppm FB1. However, kidney adenomas and carcinomas, but no liver tumors, were found in male F344 rats fed >50 ppm FB1, whereas FB1 had no tumorigenic effect in female F344 rats. Thus, FB 1 is carcinogenic to animals but significant species, strain, and sex related differences in tumorigenic response exists. On the molecular level, fumonisins inhibit ceramide synthase, thereby disrupting sphingolipid metabolism and, theoretically, regulatory processes which mediate vital cell functions such as apoptosis and mitosis. The latter are early features of fumonisin toxicity and may play a role in carcinogenesis. Following FB1 exposure, sphingolipid disruption in liver and kidney is correlated with the severity of toxic response. Studies to elucidate the relationships between fumonisins, sphingolipids, apoptosis, and disease will be useful for understanding species, strain, and sex differences in responses to fumonisins and, in conjunction with epidemiological studies, for determining the role of fumonisins in human cancer.