Effects of long term exposure to the mycotoxin fumonisin B1 in p53 heterozygous and p53 homozygous transgenic mice

► The p53+/− mouse was used to assess the toxicity and carcinogenicity of fumonisin B1. ► Fumonisin B1 was hepatotoxic and hepatocarcinogenic to male mice. ► p53 and related pathways play a secondary role in responding to fumonisin B1. ► Responses in p53+/− mice indicate that fumonisin B1 is a non-genotoxic carcinogen. ► Hepatotoxicity BMD modelling was consistent with the NOEL for rat nephrotoxicity. The fungal toxin fumonisin B1 (FB1) is a potential human carcinogen based on evidence of renal carcinogenicity in rats and hepatocarcinogenicity in mice. The toxicity and carcinogenicity of FB1 is linked to ceramide synthase inhibition. Based on this mechanism of action and on lack of evidence of genotoxicity, FB1 is considered a non-genotoxic carcinogen. The p53 heterozygous (p53+/−) mouse is a cancer-prone model used for carcinogenesis. The effects of chronic dietary FB1 exposure were characterized in p53+/− mice to confirm non-genotoxicity using a model which is more sensitive to genotoxic than non-genotoxic carcinogens and to clarify the relationship between p53 expression, altered sphingolipid metabolism, and FB1-induced carcinogenesis. Responses to FB1 were similar in p53+/− and p53+/+ mice after 26weeks exposure to 0, 5, 50 or 150mg FB1/kg diet, supporting a non-genotoxic mechanism of action. Hepatic adenomas and cholangiomas were observed in mice exposed to 150mg/kg FB1. For a 10% increase in hepatic megalocytosis, the estimated 95% lower confidence limit of the benchmark dose (BMDL10) ranged from 0.15 and 1.11mg FB1/kg bw/day. Based on similar responses in p53+/− and p53+/+ mice, p53 and related pathways play a secondary role in responses to FB1 toxicity and carcinogenesis.