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Published on: October 21, 2017
Subchronic microcystin-LR exposure increased hepatic apoptosis and induced compensatory mechanisms in mice
Noelia Lezcano1, Daniela Sedán, Ignacio Lucotti
1Centro de Investigaciones Cardiovasculares, CCT-La Plata CONICET, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 1900 La Plata, Argentina.
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.
Insights
Subchronic exposure to microcystin-LR (MC-LR) causes liver cell death and cytoskeleton damage in mice. These effects are linked to activated signaling pathways and compensatory mechanisms maintaining phosphatase activity.
Area of Science:
- Toxicology
- Cell Biology
- Biochemistry
Background:
- Microcystin-LR (MC-LR) is a cyanobacterial toxin known for acute lethal effects via protein phosphatase inhibition and ROS generation.
- The molecular mechanisms of prolonged, sublethal MC-LR exposure remain less understood, particularly concerning chronic toxicity.
- Investigating subchronic effects is crucial for understanding environmental and occupational health risks associated with cyanotoxins.
Purpose of the Study:
- To elucidate the molecular mechanisms and cellular effects of prolonged, sublethal microcystin-LR (MC-LR) exposure in vivo.
- To determine the impact of subchronic MC-LR administration on specific organs, focusing on liver, kidney, and heart.
- To investigate the involvement of apoptosis, cytoskeleton integrity, and specific signaling pathways in MC-LR-induced hepatotoxicity.
Main Methods:
- Subchronic administration of MC-LR (25 μg/kg) or saline to mice via intraperitoneal injection every two days for 28 days.
- Assessment of apoptosis, α-tubulin levels, and activation of p38-MAPK and CaMKII pathways in liver, kidney, and heart tissues.
- Measurement of protein phosphatases type 1 and type 2A (PP1/PP2A) activity and total Ser/Thr phosphatase activity.
Main Results:
- MC-LR induced significant apoptosis specifically in the liver, with no observed apoptosis in kidneys or heart.
- Decreased α-tubulin levels and sustained activation of p38-MAPK and CaMKII signaling pathways were noted in the livers of MC-LR treated mice.
- PP1/PP2A activity was significantly reduced, yet total Ser/Thr phosphatase activity remained unchanged, indicating compensatory mechanisms.
Conclusions:
- Subchronic MC-LR exposure leads to hepatic cytotoxicity through apoptosis and cytoskeleton disruption.
- Sustained activation of signaling cascades, including p38-MAPK and CaMKII, plays a key role in MC-LR-induced liver damage.
- The liver employs compensatory mechanisms to maintain total Ser/Thr phosphatase activity despite PP1/PP2A inhibition, highlighting complex adaptive responses to toxicological insult.
