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Cylindrospermopsin toxicity in mice following a 90-d oral exposure
Citation:
Chernoff, N., D. Hill, I. Chorus, D. Diggs, H. Huang, D. King, J. Lang, T. Le, Judy Schmid, G. Travlos, E. Whitley, R. Wilson, AND C. Wood. Cylindrospermopsin toxicity in mice following a 90-d oral exposure. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH - PART A: CURRENT ISSUES. Taylor & Francis, Inc., Philadelphia, PA, 81(13):549-566, (2018).
Impact/Purpose:
Cylindrospermopsin (CYN) is a cyanobacterial toxin that is commonly found in United States freshwaters. CYN is thought to have caused an episode of serious illness in a town in Australia through treated drinking water exposure as well as lethal effects in livestock that were exposed in water from farm ponds. There is global concern regarding the potential of environmental levels of CYN to adversely affect humans coming in contact with it through recreational or drinking water. Most toxicology studies on CYN have utilized the intraperitoneal route, and it is extremely difficult, or impossible, to use these data to set exposure guideline values for environmental exposures. This study exposed mice to daily gavages containing any of three different doses of CYN for 90 days and looked at a variety of endpoints dealing with biological function and/or health. These data may assist in setting exposure guidelines for both recreational or drinking water exposures.
Description:
Cylindrospermopsin (CYN) is a toxin associated with numerous species of freshwater cyanobacteria throughout the world. It is thought to have caused an episode of serious illness in Australia through treated drinking water, as well as lethal effects in livestock exposed to water from farm ponds. Toxicity included effects indicative of both hepatic and renal dysfunction and in humans progressed from initial hepatomegaly, vomiting, and malaise to acidosis and hypokalemia, bloody diarrhea, and hyperemia in mucous membranes. Laboratory animal studies have mostly involved the intraperitoneal route of administration and have largely confirmed this pattern of toxicity with changes in liver enzymes and histopathology consistent with hepatic injury, and indications of adverse renal effects. The study reported here was designed to assess subchronic exposure (90 days) of purified CYN administered orally. The doses used ranged from 75 to 300 µg/kg/day. At the end of the dosing period, examinations of the animals indicated elevated kidney and liver body weight ratios at all dose levels; dose related increased levels of ALT, and decreased BUN and cholesterol levels in males; increased monocyte counts. Histopathological changes including enlarged hepatocytes and cord disruption in livers; cellular hypertrophy, tubule dilation, and lesions in cortical tubules that were more predominant in males. A series of genes were differentially expressed including up-regulated Bax (apoptosis), down-regulated Fabp4 (fatty acid metabolism), up-related Rpl6 (liver tissue regeneration), and down-regulated Proc and Klkb1 (blood anticoagulants). There was a sex-related difference in responses to CYN with males appearing to be more sensitive for many endpoints. Changes in many parameters occurred at all dose levels and a No Observed Effect Level was not identified.
