Location: Toxicology & Mycotoxin ResearchTitle: Effects of long term exposure to the mycotoxin fumonisin B1 in p53 heterozygous and p53 homozygous transgenic mice Author
|Miller, J. David|
Submitted to: Food and Chemical Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/24/2012
Publication Date: 8/24/2012
Publication URL: http://handle.nal.usda.gov/10113/56432
Citation: Bondy, G.S., Mehta, R., Caldwell, D., Coady, L., Armstrong, C., Savard, M., Miller, J., Chomyshyn, E., Bronson, R., Zitomer, N.C., Riley, R.T. 2012. Effects of long term exposure to the mycotoxin fumonisin B1 in p53 heterozygous and p53 homozygous transgenic mice. Food and Chemical Toxicology. 50(10):3604-3613. DOI: 10.1016/j.fct.2012.07.024. Interpretive Summary: Fumonisin B1 (FB1) is a poison produced by molds that occurs naturally in corn and other grains. It is a potential human carcinogen based on evidence of kidney carcinogenicity in rats and liver carcinogenicity in mice in lifetime feeding studies. The toxicity and carcinogenicity of FB1 is linked to blockage of an enzyme that produces a group of fats known as sphingolipids. Blockage of this enzyme causes the accumulation of sphingolipid precursors known as sphingoid bases. Sphingoid bases are very biologically active. Based on this mechanism of action and on lack of evidence that FB1 can react with genetic material in cells, FB1is considered a non-genotoxic carcinogen. In this study we tested the effects of low level but long-term dietary FB1 exposure to see if the absence of proteins known to suppress tumor development would be more or less sensitive to FB1. Responses to FB1 were similar in mice after 26 week exposure regardless of whether or not they carried the tumor suppressor gene, supporting a non-genotoxic mechanism of FB1-induced liver cancer. The primary site of FB1 toxicity was the liver. It was concluded that the tumor suppressor gene and related pathways play a secondary role in responses to FB1 toxicity and induction of cancer.
Technical Abstract: The fungal toxin fumonisin B1 (FB1) occurs naturally in corn and other grains, and is a potential human carcinogen based on evidence of renal carcinogenicity in rats and hepatocarcinogenicity in mice in lifetime feeding studies. The toxicity and carcinogenicity of FB1 is linked to ceramide synthase inhibition, which leads to elevated levels of bioactive sphingolipids in blood and tissues. 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 testing that has not previously been used to assess the toxicity of mycotoxin food contaminants. 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 week exposure to 0, 5, 50 or 150 mg FB1/kg diet, supporting a non-genotoxic mechanism of FB1-induced tumorigenesis. The primary site of FB1 toxicity was the liver. Hepatic adenomas and cholangiomas were observed in p53+/- and p53+/+ 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.