title: Effects of Chronic Ochratoxin A Exposure on p53 Heterozygous and p53 Homozygous Mice.
abstract: Exposure to the mycotoxin ochratoxin A (OTA) causes nephropathy in domestic animals and rodents and renal tumors in rodents and poultry. Humans are exposed to OTA by consuming foods made with contaminated cereal grains and other commodities. Management of human health risks due to OTA exposure depends, in part, on establishing a mode of action (MOA) for OTA carcinogenesis. To further investigate OTA's MOA, p53 heterozygous (p53+/-) and p53 homozygous (p53+/+) mice were exposed to OTA in diet for 26 weeks. The former are susceptible to tumorigenesis upon chronic exposure to genotoxic carcinogens. OTA-induced renal damage but no tumors were observed in either strain, indicating that p53 heterozygosity conferred little additional sensitivity to OTA. Renal changes included dose-dependent increases in cellular proliferation, apoptosis, karyomegaly, and tubular degeneration in proximal tubules, which were consistent with ochratoxicosis. The lowest observed effect level for renal changes in p53+/- and p53+/+ mice was 200 μg OTA/kg bw/day. Based on the lack of tumors and the severity of renal and body weight changes at a maximum tolerated dose, the results were interpreted as suggestive of a primarily nongenotoxic (epigenetic) MOA for OTA carcinogenesis in this mouse model.
authors.affiliation: Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada genevieve.bondy@hc-sc.gc.ca.
authors.forename: Genevieve S
authors.initials: GS
authors.lastname: Bondy
authors.affiliation: Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Caldwell
authors.affiliation: Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Aziz
authors.affiliation: Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada.
authors.forename: Laurie C
authors.initials: LC
authors.lastname: Coady
authors.affiliation: Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Armstrong
authors.affiliation: Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada.
authors.forename: Ivan H A
authors.initials: IH
authors.lastname: Curran
authors.affiliation: Regions and Programs Bureau, Health Canada, Burnaby, BC, Canada.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Koffman
authors.affiliation: Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada.
authors.forename: Kamla
authors.initials: K
authors.lastname: Kapal
authors.affiliation: Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada.
authors.forename: David E
authors.initials: DE
authors.lastname: Lefebvre
authors.affiliation: Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada.
authors.forename: Rekha
authors.initials: R
authors.lastname: Mehta
mesh_terms: D000818:Animals; D004435:Eating / Q000187:drug effects; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009793:Ochratoxins / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D036401:Toxicity Tests, Chronic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D009793:Ochratoxins; D016159:Tumor Suppressor Protein p53; C025589:ochratoxin A
keywords: carcinogenicity; chronic toxicity.; mouse; ochratoxin; p53