title: Subchronic microcystin-LR exposure increased hepatic apoptosis and induced compensatory mechanisms in mice.
abstract: 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.
authors.affiliation: Centro de Investigaciones Cardiovasculares, CCT-La Plata CONICET, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 1900 La Plata, Argentina.
authors.forename: Noelia
authors.initials: N
authors.lastname: Lezcano
authors.forename: Daniela
authors.initials: D
authors.lastname: Sedán
authors.forename: Ignacio
authors.initials: I
authors.lastname: Lucotti
authors.forename: Leda
authors.initials: L
authors.lastname: Giannuzzi
authors.forename: Leticia
authors.initials: L
authors.lastname: Vittone
authors.forename: Darío
authors.initials: D
authors.lastname: Andrinolo
authors.forename: Cecilia
authors.initials: C
authors.lastname: Mundiña-Weilenmann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008387:Marine Toxins; D051379:Mice; D052998:Microcystins / Q000008:administration & dosage / Q000302:isolation & purification / Q000633:toxicity*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D008387:Marine Toxins; D052998:Microcystins; D017382:Reactive Oxygen Species; D014404:Tubulin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048051:p38 Mitogen-Activated Protein Kinases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; C057862:cyanoginosin LR