Carcinogenicity of Fumonisin B₁ in a Two-year Bioassay with Fischer 344 Rats and B6C3F₁ Mice

Abstract

Fusaria are the most common fungi that infect corn (maize) crops world-wide. Ingestion of feed contaminated with Fusarium verticillioides (=F. moniliforme) causes leukoence-phalomalacia in horses, pulmonary edema in pigs, cardiotoxicity in baboons, and hepatic and renal injury in several species. Some isolates of F. verticillioides are rodent carcinogens. Elevated levels of F, verticillioides have been found in corn in areas of the world that have high incidences of esophageal cancer, and led to the discovery of fumonisin B₁ in 1987 as a Fusaria metabolite. Fumonisin B₁ was isolated from F, proliferatum cultures, and was purified as the ammonium salt with a final purity of >96%. The fumonisin B₁ was mixed with rodent feed (autoclaved NIH-31; <60μg/kg fumonisin B₁) and fed to rodents (48/dose/sex) at the following levels : female F344/N Nctr rats -0, 5, 15, 50, 100 mg/kg diet ; male F344/N Nctr rats -0, 5, 15, 50, 150 mg/kg diet; female B6C3F₁/Nctr mice -0, 5, 15, 50, 80 mg/kg diet; male B6C3F₁/Nctr mice -0, 5, 15, 80, 150 mg/kg diet. There were no dose-related changes in the weights or survival in the rats in the 2-year study. Increased incidence of renal tubule adenomas and carcinomas were observed in male F344 rats, but did not occur in the female rats. Renal tubule adenomas and carcinomas did not occur in male rats consuming diets with 0, 5, or 15 mg/kg fumonisin B₁, and occurred in 2/48 and 7/48 of rats consuming 50 mg/ kg fumonisin B₁, and in 5/48 and 10/48 rats consuming 150 mg/kg fumonisin B₁, respectively. Body weights were not affected by dose in the mice ; however, female B6C3F₁/Nctr consuming 80 mg/kg diet fumonisin B₁ had reduced survival. An increase in hepatocellular adenomas and carcinomas was detected in female B6C3F₁ mice, but not in male mice. The frequency of occurrence of adenomas and carcinomas were 16/47 and 10/47 at 50 mg/kg fumonisin B₁ and 31/45 and 9/45 at 80 mg/kg fumonisin B₁, respectively. The mechanism of action of fumonisin B₁ is interruption of de novo sphingolipid synthesis through inhibition of ceramide synthase. Since this enzymatic inhibition results in apoptosis in vivo and in vitro, it suggests that tumor formation arises as a result of compensatory regeneration in the tissues in vivo following fumonisin B₁-induced apoptosis.