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

Abstract

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.

• Authors: Genevieve Bondy, Rekha Mehta, Don Caldwell, Laurie Coady, Cheryl Armstrong, Marc Savard, J David Miller, Emily Chomyshyn, Roni Bronson, Nicholas Zitomer, Ronald T Riley
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 50 Issue 10 Pg. 3604-13 (Oct 2012) ISSN: 1873-6351 [Electronic] England
• PMID: 22841953 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Fumonisins
• Tumor Suppressor Protein p53
• fumonisin B1

Topics

• Adenoma, Bile Duct (chemically induced)
• Adenoma, Liver Cell (chemically induced)
• Animals
• Chemical and Drug Induced Liver Injury (pathology)
• Diet
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Fumonisins (toxicity)
• Heterozygote
• Homozygote
• Liver (cytology, drug effects)
• Liver Neoplasms (chemically induced)
• Mice
• Mice, Transgenic
• Random Allocation
• Tumor Suppressor Protein p53 (genetics, metabolism)