title: 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: Bureau of Chemical Safety, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada K1A 0K9. genevieve_bondy@hc-sc.gc.ca
authors: Genevieve
authors: G
authors: Bondy
authors: Rekha
authors: R
authors: Mehta
authors: Don
authors: D
authors: Caldwell
authors: Laurie
authors: L
authors: Coady
authors: Cheryl
authors: C
authors: Armstrong
authors: Marc
authors: M
authors: Savard
authors: J David
authors: JD
authors: Miller
authors: Emily
authors: E
authors: Chomyshyn
authors: Roni
authors: R
authors: Bronson
authors: Nicholas
authors: N
authors: Zitomer
authors: Ronald T
authors: RT
authors: Riley
mesh_terms: D002759:Adenoma, Bile Duct / Q000139:chemically induced; D018248:Adenoma, Liver Cell / Q000139:chemically induced; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D037341:Fumonisins / Q000633:toxicity*; D006579:Heterozygote; D006720:Homozygote; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008113:Liver Neoplasms / Q000139:chemically induced; D051379:Mice; D008822:Mice, Transgenic; D011897:Random Allocation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D037341:Fumonisins; D016159:Tumor Suppressor Protein p53; C056933:fumonisin B1