title: Heterozygous p53 knockout mouse model for dehydropyrrolizidine alkaloid-induced carcinogenesis.
abstract: Dehydropyrrolizidine alkaloids (DHPA) are a large, structurally diverse group of plant-derived protoxins that are potentially carcinogenic. With worldwide significance, these alkaloids can contaminate or be naturally present in the human food supply. To develop a small animal model that may be used to compare the carcinogenic potential of the various DHPAs, male heterozygous p53 knockout mice were administered a short-term treatment of riddelliine 5, 15 or 45 mg kg(-1) bodyweight day(-1) by oral gavage for 14 days, or dosed a long-term treatment of riddelliine 1 mg kg(-1) bodyweight day(-1) in pelleted feed for 12 months. Exposure to riddelliine increased the odds of tumor development in a dose-responsive manner (odds ratio 2.05 and Wald 95% confidence limits between 1.2 and 3.4). The most common neoplastic process was hepatic hemangiosarcoma, which is consistent with published lifetime rodent riddelliine carcinogenesis studies. Angiectasis (peliosis hepatis) and other previously unreported lesions were also identified. The results of this research demonstrate the utility of the heterozygous p53 knockout mouse model for further investigation of comparative carcinogenesis of structurally and toxicologically different DHPAs and their N-oxides.
authors.affiliation: USDA/ARS Poisonous Plant Research Laboratory, Logan, UT, USA.
authors.forename: Ammon W
authors.initials: AW
authors.lastname: Brown
authors.affiliation: USDA/ARS Poisonous Plant Research Laboratory, Logan, UT, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Stegelmeier
authors.affiliation: USDA/ARS Poisonous Plant Research Laboratory, Logan, UT, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Colegate
authors.affiliation: USDA/ARS Poisonous Plant Research Laboratory, Logan, UT, USA.
authors.forename: Kip E
authors.initials: KE
authors.lastname: Panter
authors.affiliation: USDA/ARS Poisonous Plant Research Laboratory, Logan, UT, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Knoppel
authors.affiliation: Utah Veterinary Diagnostic Laboratory, Utah State University, Logan, UT, USA.
authors.forename: Jeffery O
authors.initials: JO
authors.lastname: Hall
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015197:Carcinogenicity Tests; D004305:Dose-Response Relationship, Drug; D006394:Hemangiosarcoma / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D006579:Heterozygote; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D011763:Pyrrolizidine Alkaloids / Q000302:isolation & purification / Q000633:toxicity*; D012674:Senecio / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D011763:Pyrrolizidine Alkaloids; D016159:Tumor Suppressor Protein p53; C013672:riddelliine
keywords: angiectasis; carcinogenesis; hemangiosarcoma; p53 knockout; pyrrolizidine alkaloid; riddelliine; rodent model