Heterozygous P53 knockout mouse model for dehydropyrrolizidine alkaloid-induced carcinogenesis

Authors: BROWN, AMMON - Us Army Research; Stegelmeier, Bryan; Colegate, Steven; Panter, Kip; Knoppel, Edward; HALL, JEFFERY - Utah State University

Submitted to: Journal of Applied Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/18/2014
Publication Date: 12/1/2015
Publication URL: http://handle.nal.usda.gov/10113/62768
Citation: Brown, A.W., Stegelmeier, B.L., Colegate, S.M., Panter, K.E., Knoppel, E.L., Hall, J.O. 2015. Heterozygous P53 knockout mouse model for dehydropyrrolizidine alkaloid-induced carcinogenesis. Journal of Applied Toxicology. 35(12):1557-1563.

Interpretive Summary: Dehydropyrrolizidine alkaloids (PAs) are plant toxins that can cause cancer. They poison wildlife, livestock and humans as they can contaminate feeds and food. A small animal model is needed to compare the cancer producing or carcinogenic potential of PAs. In this study heterozygous p53 knockout mice were administered 5, 15, or 45 mg/kg bodyweight per day of a purified PA, riddelliine for 14 days. Another group was fed rat food containing riddelliine at a dose of 1 mg/kg bodyweight per day in pelleted feed for 12 months. All groups were monitored for cancer for 12 months. Exposure to riddelliine increased the odds of tumor development in a dose responsive manner (odds ratio 2.05 and Walds 95% confidence limits between 1.2 and 3.4). The most common neoplastic process was hepatic hemangiosarcoma, which is consistent with published life time rodent riddelliine carcinogenesis studies. Peliosis hepatis and other previously unreported lesions were also identified. The observations indicated that heterozygous p53 knockout mice are susceptible to riddelliine-induced carcinogenesis, and are potentially a useful model for further investigation of comparative carcinogenesis of structurally and toxicologically different dehydropyrrolizidine alkaloids and their N-oxides.

Technical Abstract: Dehydropyrrolizidine alkaloids 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 dehydropyrrolizidine alkaloids, heterozygous p53 knockout mice were administered 5, 15, or 45 mg/kg bodyweight per day of riddelliine by oral gavage for 14 days or dosed 1 mg riddelliine/kg bodyweight per day 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 Walds 95% confidence limits between 1.2 and 3.4). The most common neoplastic process was hepatic hemangiosarcoma, which is consistent with published life time rodent riddelliine carcinogenesis studies. Peliosis hepatis and other previously unreported lesions were also identified. The observations indicated that heterozygous p53 knockout mice are susceptible to riddelliine-induced carcinogenesis, and are potentially a useful model for further investigation of comparative carcinogenesis of structurally and toxicologically different dehydropyrrolizidine alkaloids and their N-oxides.