Date of Award:
Doctor of Philosophy (PhD)
Animal, Dairy, and Veterinary Sciences
Arnaud Van Wettere (Committee Chair), Bryan L Stegelmeier (Committee Co-Chair)
Arnaud Van Wettere
Bryan L Stegelmeier
Jeffery O. Hall
Dehydropyrrolizidine alkaloids are arguably the most important plant derived toxins in terms of impact on human and animal health. Dehydropyrrolizidine alkaloids are a large group of chemically related compounds found in 3% of flowering plants worldwide. Human exposure occurs from ingestion of herbal products including teas supplements or contaminated grain. Animals are exposed through contaminated feed or grazing. There are at least 350 identified toxic PAs, from more than 6,000 plants. The toxins primarily cause liver damage, but some are proven to cause cancer. Indidvidual dehydropyrrolizidine alkaloids vary in their toxic effects. Riddelliine is the only dehydropyrrolizidine alkaloid with extensive evidence of its cancer-causing effects. The purpose of the research presented herein is to characterize and compare the relative toxic and cancer-causing effects of select dehydropyrrolizidine alkaloids. In the first experiment, seven compounds are administered to C57BL6/j mice by oral gavage for ten days at varying doses. Microscopic liver damage, liver enzymes, and liver concentrations of the toxic metabolite were compared. There was variation in the characteristics and severity of liver damage between compounds. Liver enzymes indicative of liver damage were observed. Riddelliine caused the greatest concentration of the toxic metabolite in the liver. In the second experiment, five dehydropyrrolizidine alkaloids were administered to genetically modified mice for ten days at the same dose. These mice are designed to develop cancer more readily. There was no statistically significant difference in the development of cancer between the mice exposed to any of the five compounds compared to the control group, in. This indicates that short-duration exposure to dehydropyrrolizidine alkaloids at high doses may be less likely to cause cancer than long term low-dose exposure. In the third experiment, three dehydropyrrolizidine alkaloids were administered to mice at a common dose for 8 days. Whole genome RNA expression was compared for each compound at two time-points. Two of the compounds, riddelliine and senecionine, caused liver damage and similar gene expression changes. The dysregulated genes were related to cancer development and metabolism, indicating that senecionine may also cause cancer. Dysregulated genes tended to return to normal expression levels after 28 days, indicating recovery.
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Clayton, Michael J., "Relative Hepatotoxocity, Carcinogenicity, and Toxicogenomics of Select Dehydropyrrolizidine Alkaloids in Mice" (2023). All Graduate Theses and Dissertations, Fall 2023 to Present. 71.
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