EVALUATION OF THE POTENTIAL FOR IN VIVO TOXICITY OF PYRROCIDINE A IN MICE
Location: Bacterial Foodborne Pathogens & Mycology Research Unit
Title: Toxicity of the Fungal Metabolite Pyrrocidine A to Mice
Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: November 17, 2010
Publication Date: November 17, 2010
Citation: Burcham, G.N., Haschek, W.M., Wicklow, D.T., Wilson, C.R., Hooser, S.B. 2010. Toxicity of the Fungal Metabolite Pyrrocidine A to Mice. Meeting Abstract.
Pyrrocidines A and B are polyketide-amino acid-derived antibiotics produced by the fungus Acremonium zeae, a common seedborne endophyte of corn. Pyrrocidine A exhibits potent activity against Gram-positive bacteria, including drug resistant strains, and displayed significant activity against Candida albicans, as well as major stalk and ear rot pathogens of corn. A. zeae isolates from corn grown in warmer regions consistently produce pyrrocidines while corn isolates from regions with cold winters seldom produce pyrrocidines. Pyrrocidines have been detected in visibly molded (unmarketable) corn subjected to drought and temperature stress. A. zeae is being evaluated for its potential application as a biocontrol agent in protecting corn plants from virulent pathogens, thus inviting the 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 to consumers?" There are no reports of A. zeae toxicity to livestock or humans, nor have pyrrocidines been detected in corn based food products. Patented drug candidates, oteromycin, GKK 1032A2, and hirsutellones A,B, and C, exhibit the closest known structural resemblance to pyrrocidines A and B, but there are no reports of mammalian toxicity in the Dictionary of Natural Products database.
In 2007 the Haschek laboratory reported that the cytotoxicity of pyrrocidine A to human HepG2 cells was more potent than known Fusarium mycotoxins, deoxynivalenol, fumonisin B1, moniliformin, and zearalenone. However, pyrrocidine A toxicity was not identified in mice at doses up to 10 mg/kg body weight based on clinical signs, organ weights, and gross and microscopic lesions.
To evaluate higher doses, adult, male, Swiss-Webster mice were administered pyrrocidine A at 0 (DMSO control), 10, 100, or 250 mg/kg by intraperitoneal injection (n = 5/group). Pyrrocidine A at 10 mg/kg, was not lethal and did not cause clinical signs, while 100 mg/kg and 250 mg/kg resulted in death within 24 hours. Pyrrocidine A at 25 mg/kg and at 50 mg/kg caused death in a single mouse tested at each concentration within 12 hours. No significant gross or histological lesions were seen.
Pyrrocidine A is cytotoxic to mammalian cells in culture. In mice, doses of 10 mg/kg (i.p.) do not cause acute toxicity, while doses of 25 mg/kg or greater can be rapidly fatal. Future studies will attempt to more accurately identify the toxic dose and characterize target organ toxicity.