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Subchronic microcystin‐lr exposure increased hepatic apoptosis and induced compensatory mechanisms in mice

Acute lethal cytotoxicity of microcystin‐LR (MC‐LR), a toxin produced by fresh‐water cyanobacteria, has been attributed to protein phosphatases type 1 and type 2A (PP1/PP2A) inhibition and reactive oxygen species (ROS) generation. However, the effects and molecular mechanisms of prolonged, sublethal MC‐LR exposure are less known. We studied mice intraperitonealy injected with saline or 25 μg MC‐LR/kg for 28 days (every 2 days). MC‐LR induced apoptosis in liver and not in kidneys or heart of treated animals. Liver also showed decreased α‐tubulin levels (45.56% ± 7.65% of controls) and activation of p38‐MAPK and CaMKII pathways (137.93% ± 11.64% and 419.35% ± 67.83% of the control group, respectively). PP1/PP2A activity decreased from 1.82 ± 0.23 (controls) to 0.91 ± 0.98 mU/mg (MC‐LR–treated mice); however, no difference in total Ser/Thr phosphatase activity was found between both the groups. The results demonstrated that apoptosis and cytoskeleton disruption contributed to the hepatic cytotoxic effects of subchronic MC‐LR administration. These effects occurred in association with sustained activation of signaling cascades and development of compensatory mechanisms to maintain total Ser/Thr phosphatase activity. © 2012 Wiley Periodicals, Inc. J Biochem Mol Toxicol 26:131–138, 2012; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.20419