Page 810 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Cyanobacterial (Blue-Green Algae) Toxins Chapter | 57 769

VetBooks.ir 1 and 2A (Falconer and Yeung, 1992; Runnegar et al., 1996; Zhou et al., 2002). In mice, subchronic exposure i.
p. of microcystin-LR (20 μg/kg) causes the appearance of
1993). The disruption of the cytoskeletal components and
hepatic nodules, a characteristic not observed after oral
the associated rearrangement of filamentous actin within
hepatocytes account for the morphological changes, subchronic administration (Ito et al., 1997).
although other mechanisms play a role in the development
of liver lesions. Microcystins induce apoptosis of hepato-
Toxicity
cytes via induction of free radical formation and mito-
chondrial alterations (Ding and Ong, 2003). A single-dose The lethal doses 50 (LD 50 s) for microcystins vary
i.v. in rats demonstrated an increase in liver sphingolipid between 50 μg/kg and 11 mg/kg, depending on the micro-
levels at higher doses (implicating ceramide-mediated cystin analog, the species affected, and the route of
apoptosis), a dose-dependent decreased PP2A expression, administration. In mice, the oral LD 50 value for
and ultimately a dose-dependent decreased expression of microcystin-LR is 10.9 mg/kg, whereas the i.p. LD 50 is
Bcl2 family proteins, involved in cell cycle/apoptosis reg- 50 μg/kg. Because most blooms contain a number of
ulation (Billam et al., 2008). The role of oxidative stress structural variants of microcystins, it is difficult to
has become increasingly apparent, and the ultimate toxic estimate the toxicity potential of a bloom. The no-
effect may depend on the ability of antioxidant pathways observed-adverse-effect level for orally administered
to counter the stressors (Ding and Ong, 2003; Jayaraj microcystin-LR to mice is 40 μg/kg/day (Fawell et al.,
et al., 2006; Xiong et al., 2010). In addition, microcystins 1994). In pigs, the lowest-observed-adverse-effect level
are classified as tumor-promoting compounds (Humpage for microcystin-LR is 100 μg/kg/day (Falconer et al.,
and Falconer, 1999). Investigations have indicated the 1994), and in rat it is 50 μg/kg/day (Heinze, 1999). WHO
role of protooncogenes in this tumorigenesis, hypothe- set the tolerable daily intake (TDI) for human ingestion of
sized to be a sequelae of dysregulation of phosphorylation microcystin-LR at 0.04 μg/kg/day (Kuiper-Goodman
(Li et al., 2009). Several studies have demonstrated the et al., 1999). The potential risk to humans by ingesting
ability of microcystins to induce DNA damage in liver food products derived from animals exposed to microcys-
cells (Zegura et al., 2011). tins was evaluated in beef (Orr et al., 2003) and dairy cat-
Clinical signs of microcystin poisoning have been tle (Orr et al., 2001). Based on these studies, it is unlikely
described in a number of reports in livestock, humans, that consumption of milk, meat, or liver poses a signifi-
and wildlife in the United States (DeVries et al., 1993; cant health risk to humans. It might be prudent to estab-
Galey et al., 1987; Puschner et al., 1998) and other coun- lish specific guidelines for nonlethal, chronic microcystin
tries (Done and Bain, 1993; Van Halderen et al., 1995; exposure in livestock.
Mez et al., 1997; Naegeli et al., 1997; Azevedo et al.,
2002; Ballot et al., 2004; Ndetei and Muhandiki, 2005; Treatment
Handeland and Østensvik, 2010; Wood et al., 2010).
Interestingly, laboratory animals select water with No specific antidote for microcystins exists. The rapid
microcystin-producing strains of cyanobacteria over a onset of acute hepatotoxicosis renders therapeutic inter-
water source with nontoxic strains (Lopez Rodas and vention quite difficult, and mortality rates are very high.
Costas, 1999), suggesting an increased risk for toxicosis In addition, despite the evaluation of numerous treatment
in animals due to behavioral preferences. Microcystin options, no specific therapy has been proven to be effec-
intoxication should be suspected in cases of acute hepato- tive. The most promising strategy appears to be preven-
toxicosis with clinical signs of diarrhea, vomiting, weak- tion of uptake into hepatocytes through the administration
ness, pale mucous membranes, and shock. Although most of compounds that may compete for the specific transpor-
animals die within a few hours of exposure, some animals ters associated with microcystin uptake; administration of
may live for several hours and develop hyperkalemia, the antibiotic rifampin (i.p.) in mice effectively reduced
hypoglycemia, nervousness, recumbency, and convul- mortality after exposure (i.p.) to microcystin-LR
sions. Animals that survive the acute intoxication may (Hermansky et al., 1991). By contrast, other compounds,
develop hepatogenous photosensitization. Nephrotoxic such as glutathione, silymarin, and cyclosporine A, were
effects have been described in laboratory animals after only beneficial if administered as a prophylactic
chronic microcystin exposure (Milutinovic et al., 2003). (Hermansky et al., 1991; Rao et al., 2004). These com-
Evidence suggests potential suppression of immune func- pounds may help reduce microcystin toxicity in chronic
tion at sublethal exposures (Shi et al., 2004). Evidence exposure scenarios. Due to the role of oxidative stress,
also suggests MC-LR causing thyroid dysfunction in mice antioxidants such as vitamin E, selenium, and green tea
(Zhao et al., 2015). In humans, primary liver cancer as polyphenols also appear to be beneficial prophylactically
well as colorectal cancer have been associated with (Gehringer et al., 2003a,b; Jayaraj et al., 2007; Xu et al.,
microcystin-contaminated drinking water (Ueno et al., 2007). Although the adsorption of microcystins by