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Cylindrospermopsin Toxicity in Mice following a 90-d Oral Exposure

N. Chernoff, D.J. Hill, I. Chorus, D.L. Diggs, H. Huang, D. King, J.R. Lang, T.-T. Le, J.E. Schmid, G.S. Travlos, E.M. Whitley, R.E. Wilson & C.R. Wood.
Journal of Toxicology and Environmental Health, Part A (2018) DOI: https://doi.org/10.1080/15287394.2018.1460787 PMID: 29693504

Publication

Abstract

Cylindrospermopsin (CYN) is a toxin associated with numerous species of freshwater cyanobacteria throughout the world. It is postulated to have caused an episode of serious illnesses 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. In humans, symptoms progressed from initial hepatomegaly, vomiting, and malaise to acidosis and hypokalemia, bloody diarrhea, and hyperemia in mucous membranes. Laboratory animal studies predominantly involved the intraperitoneal (i.p.) route of administration and confirmed this pattern of toxicity with changes in liver enzyme activities and histopathology consistent with hepatic injury and adverse renal effects. The aim of this study was designed to assess subchronic oral exposure (90 d) of purified CYN from 75 to 300 µg/kg/d in mouse. At the end of the dosing period, examinations of animals noted (1) elevated organ to body weight ratios of liver and kidney at all dose levels, (2) treatment-related increases in serum alanine aminotransferase (ALT) activity, (3) decreased blood urea nitrogen (BUN) and cholesterol concentrations in males, and (4) elevated monocyte counts in both genders. Histopathological alterations included hepatocellular hypertrophy and cord disruption in the liver, as well as renal cellular hypertrophy, tubule dilation, and cortical tubule lesions that were more prominent in males. A series of genes were differentially expressed including Bax (apoptosis), Rpl6 (tissue regeneration), Fabp4 (fatty acid metabolism), and Proc (blood coagulation). Males were more sensitive to many renal end points suggestive of toxicity. At the end of exposure, toxicity was noted at all dose levels, and the 75 µg/kg group exhibited significant effects in liver and kidney/body weight ratios, reduced BUN, increased serum monocytes, and multiple signs of histopathology indicating that a no-observed-adverse-effect level could not be determined for any dose level.

Figures

Figure 1. Photomicrographs of the liver tissue of female mice.

Photomicrographs of the liver tissue of female mice (controls A and B; CYN 300 µg/kg C and D). Liver lesions included distortion of hepatic architecture, hepatocellular hypertrophy, cytoplasmic alteration and degeneration, and/or necrosis of centrilobular hepatocytes often infiltrated by inflammatory cells. Hematoxylin and eosin stain used. Size bars = 100 µm.

Figure 2. CYN induces a reduction in the outer stripe of the outer medulla of the kidney in male animals.

CYN induces a reduction in the outer stripe of the outer medulla of the kidney in male animals (control A; CYN 300 µg/kg C), and in sagittal sections (10×), demarcation of the outer stripe is less pronounced in the CYN-exposed (300 µg/kg) than control kidneys (arrows). Tubular epithelial cells (1000×) in the S3 region (control B; CYN 300 µg/kg D) exhibit epithelial atrophy, loss of luminal microvilli, cytoplasmic swelling or glycogen accumulation (colorless areas), and mild anisokaryosis. Hematoxylin and eosin stain used. Size bars, 1000 µm in 10×; 100 µm in 1000×.

Tables

Table 1. Selected Organ Weight and Organ Weight to Body Weight Ratios in Mice in the 90-d Gavage Study of CYN.

Table 2. Clinical Chemistry Data for Mice in the 90-d Gavage Study of CYN.

Table 3. Selected Hematology Data for Mice in the 90-d Gavage Study of CYN.

Table 4. Incidence and Severity of Histopathologic Liver Lesions in Mice in the 90-d Gavage Study of CYN.

Table 5. Incidence and Severity of Histopathologic Kidney Lesions in Mice in the 90-d Gavage Study of CYN.

Table 6. Gene Expression.

Supplemental Materials

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Supplemental Material

Cylindrospermopsin toxicity in mice following a 90-d oral exposure