The goal of the study is to characterize the systemic pathological effect of pyrrocidine A in mice through (A) intraperitoneal injection with increased exposure time; (B) intravenous administration to obviate the potential for metabolic detoxification in the liver; and (C) oral exposure (gavage).
Approach: Pyrrocidine A is a newly discovered antibiotic produced by the 'protective' maize endophyte Acremonium zeae. This antibiotic exhibits potent activity against kernel rotting fungal pathogens of maize such as the mycotoxin producers Aspergillus flavus (aflatoxin) and Fusarium verticillioides (fumonisin), as well as pathogens of humans including Candida albicans and species of Gram-positive bacteria. Research identified in Objective 5 of the ARS parent CRIS will investigate the epidemiology and biocontrol potential of A. zeae in maize. The Preharvest Mycotoxins Panel reviewing this ARS CRIS project posed the following question: "What safety information is available for pyrrocidines that could convince regulators that its levels could be increased in corn grain and not pose a safety risk for consumers?" The in vivo effect of pyrrocidine A and B to animals or humans is not known. An in vitro study performed by the Department of Pathobiology shows that pyrrocidine A and B are cytotoxic to HepG2 cells (a cell line derived from a human hepatocellular carcinoma) and PK15 cells (a cell line derived from a normal pig kidney) within 24 hours of treatment. This warrants a study of the in vivo toxicity of pyrrocidine A in mice that will include a pilot study to determine toxic dose levels followed by a study of potential target organs and dose response for pyrrocidine A toxicity including comprehensive histopathology and clinical pathology.