Cylindrospermopsin toxicity in mice following a 90-d oral exposure

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.

Global scanning of cylindrospermopsin: Critical review and analysis of aquatic occurrence, bioaccumulation, toxicity and health hazards

“…Though several papers have focused on mammalian toxicity due to its direct relevance to humans (Antal et al, 2011;Baker et al, 2001;Basu et al, 2018;Bazin et al, 2010;Chernoff et al, 2018;Fastner et al, 2003;Fonseca et al, 2014;Gacsi et al, 2009;Kittler et al, 2016), limited in vivo mechanistic toxicity work with aquatic species has been performed. Based on our literature review, eleven studies have reported mechanistic toxicity information for CYN exposure in aquatic organisms (Table 2 of Supplemental Materials).…”

Cylindrospermopsin-Microcystin-LR Combinations May Induce Genotoxic and Histopathological Damage in Rats

“…exposure [62], male mice were more sensitive than females to CYN administered i.p. [63]. CYN exposure doses (75, 23.7, and 7.5 µg/kg b.w.)…”

“…These in vivo results are in accord with other in vivo and in vitro studies where MC-LR induced liver injury through the production of ROS among other mechanisms [ 74 , 79 , 80 ]. Hepatocyte injury was also observed after CYN exposure in rats [ 42 , 43 , 81 ] and mice [ 41 , 63 , 82 , 83 ], with its severity increasing with the dose [ 37 , 63 , 82 , 83 , 84 ]. On the other hand, a variable number of multinucleated hepatocytes was observed in the high and medium-dosed groups (23.7 + 237 or 75 + 750 μg/kg b.w.…”

“…Sections of 4 µm were stained with hematoxylin and eosin and examined microscopically, with a Modular Microscopy BX43 (Olympus, Shinjuku, Tokyo, Japan). For the histopathological study, males and females were evaluated and both presented similar lesions, but the lesion score was performed only in males as they have been reported to be more sensitive to cylindrospermopsin effects [43,63]. A semiquantitative evaluation of the severity of lesions was scored.…”

Pathology in Ecological Research With Implications for One Health: Session Summary

“…Lesions also occurred in the renal medulla and include thinning of the outer stripe and the presence of intraluminal protein in the inner stripe and inner medulla. 16…”