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Heterozygous p53 knockout mouse model for dehydropyrrolizidine alkaloid-induced carcinogenesis

Ammon W. Brown, Bryan L. Stegelmeier, Steven M. Colegate, Kip E. Panter, Edward L. Knoppel, Jeffery Q. Hall
Journal of applied toxicology 2015 v.35 no.12 pp. 1557-1563
animal models, body weight, carcinogenesis, carcinogens, dose response, food availability, hemangiosarcoma, heterozygosity, humans, knockout mutants, liver neoplasms, males, odds ratio, pelleted feeds, riddelliine, rodents, toxicology
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.