EPA Science Inventory

Toxicity and recovery in the pregnant mouse after gestational exposure to the cyanobacterial toxin, cylindrospermopsin.


ROGERS, E H., R ZEHR, M I. GAGE, D. E. Malarkey, C. E. Bradfield, Y. Liu, R H. JASKOT, J E. RICHARDS, C R. WOOD, M B. ROSEN, N CHERNOFF, AND J. E. Schmid. Toxicity and recovery in the pregnant mouse after gestational exposure to the cyanobacterial toxin, cylindrospermopsin. . JOURNAL OF APPLIED TOXICOLOGY. John Wiley & Sons, Ltd., Indianapolis, IN, 31(3):242-54, (2011).


Cylindrospermopsin (CYN) is a tricyclic alkaloid toxin produced by fresh water cyanobacterial species worldwide. CYN has been responsible for both livestock and human poisoning after oral exposure. This study investigated the toxicity of CYN to pregnant mice exposed during different segments of gestation. The course of recovery and individual responses to the toxin were evaluated. Adverse effects of CYN were monitored up to 7 weeks post-dosing by clinical examination, histopathology, biochemistry and gene expression. Exposure on gestational days (GD) 8-12 induced significantly more lethality than GD13-17 exposure. Periorbital, gastrointestinal and distal tail hemorrhages were seen in both groups. Serum markers indicative of hepatic injury (alanine amino transferase, aspartate amino transferase and sorbitol dehydrogenase) were increased in both groups; markers of renal dysfunction (blood urea nitrogen and creatinine) were elevated in the GD8-12 animals. Histopathology was observed in the liver (centrilobular necrosis) and kidney (interstitial inflammation) in groups exhibiting abnormal serum markers. The expression profiles of genes involved in ribosomal biogenesis, xenobiotic and lipid metabolism, inflammatory response and oxidative stress were altered 24 h after the final dose. One week after dosing, gross, histological and serum parameters had returned to normal, although increased liver/body weight ratio and one instance of gastrointestinal bleeding was found in the GD13-17 group. Gene expression changes persisted up to 2 weeks post-dosing and returned to normal by 4 weeks. Responses of individual animals to CYN exposure indicated highly significant inter-animal variability within the treated groups. Copyright © 2010 John Wiley & Sons, Ltd.


1. We wished to characterize the toxicity of cylindrospermopsin (cyn) in adult animals using a variety of endpoints: gross observations, clinical chemistry markers of hepatic and renal function, histopathology, and analysis of gene expression in liver tissue. All of these endpoints had been previously described with the exception of the gene array data but continued work with this toxin made this characterization in our laboratory essential.. 2. One extremely important, and almost always neglected, aspect of the toxicity of any agent is the course of recovery after exposure to toxic levels. In the incident that occurred in Australia, people returned home from hospital but there was no information on the degree and timing of the recovery. This was especially critical given that most of the affected people were children under the age of 16. 3. There has been a great deal of interest in the utilization of gene arrays to describe agent-induced adverse effects. Very few of these studies have made within-experiment attempts to compare the sensitivity of the different endpoints. This is the first study to look at these different approaches to evaluate toxicity within a single experiment. 4. Individual differences are well-known to affect responses to any given toxic agent. The extraordinary variability of response to cyn has been noted by several workers and we have also documented the high degree of individual variability in our laboratory. The data generated in this study described individual animals' responses over all of the endpoints mentioned above. Further analyses will enable us to evaluate the degree of individual variability for the different endpoints, the constancy of the degree of toxicity across different endpoints in individual animals, and the possibility of using selective breeding as a method of determining initial causes of toxicity as well as methods of detoxification.


Record Details:

Start Date: 04/01/2011
Completion Date: 04/01/2011
Record Last Revised: 02/27/2014
Record Created: 02/10/2009
Record Released: 02/10/2009
OMB Category: Other
Record ID: 203864