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

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 26 weeks exposure to 0, 5, 50 or 150 mg FB₁/kg diet, supporting a non-genotoxic mechanism of action. Hepatic adenomas and cholangiomas were observed in mice exposed to 150 mg/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 1.11 mg 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.