Compensatory regeneration as a mechanism for renal tubule carcinogenesis of fumonisin B-1 in the F344/N/Nctr BR rat

Fumonisin B-1 (FB1) is a fungal metabolite of Fusarium verticillioides (= F . moniliforme), a fungus that grows on many crops worldwide. Previous studi es demonstrated that male ED IX rats consuming diets containing 50 ppm fumo nisin B1 developed hepatocellular carcinomas. In our recent studies, diets containing FB1 at 50 ppm or higher concentrations induced renal tubule carc inomas in male F344/N/Nctr BR rats and hepatocellular carcinomas in female B6C3F(1)/Nctr BR mice. The carcinogenicity of FB1 in rats and mice is not d ue to DNA damage, as several laboratories have demonstrated that FB1 is not a genotoxin. FB, induces apoptosis in cells in vitro. Including FB1 in the diets of rats results in increased hepatocellular and renal tubule epithel ial cell apoptosis. In studies with F344/N/Nctr BR rats consuming diets con taining up to 484 ppm FB1 for 28 days, female rats demonstrated more sensit ivity than male rats in the induction of hepatocellular apoptosis and mitos is. Conversely, induction of renal tubule apoptosis and regeneration were m ore pronounced in male than in female rats. Induction of renal tubule apopt osis and hyperplasia correlated with the incidence of renal tubule carcinom as that developed in the 2-year feeding study with FB, in the F344/N/Nctr B R rats. The data are consistent with the hypothesis that the induction Of r enal tubule carcinomas in male rats could be partly due to the continuous c ompensatory regeneration of renal tubule epithelial cells in response to th e induction of apoptosis by fumonisin B-1.