Toxic response indicators of microcystin-LR in F344 rats following a single-dose treatment
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Madhavi Billam1, Sandeep Mukhi, Lili Tang
1Department of Environmental Toxicology, The Institute of Environmental and Human Health, Texas Tech University, Box 41163, Lubbock, TX 79409-1163, USA.
Abstract:
Microcystin-LR (MCLR) is the most common hepatotoxic cyanotoxin produced primarily by Microcystis aeruginosa. In this study, young F344 rats were intraperitoneally injected with a single dose (25, 50, 100, and 150 microg/kg) of MCLR to explore possible toxic effect and toxic response indicators. Acute toxic symptoms, including body weight loss and death, were monitored for 7 days. Mortality reached 100% (9/9) in rats treated with a single MCLR dose of 150 microg/kg. Histopathological examination showed spot necrosis in the liver of animals treated at low doses, while massive hemorrhage and widespread necrotic foci occurred at higher doses, indicating extensive liver damage. Protein phosphatase 2A (PP2A) expression showed a dose-dependent decrease in the liver. Immunohistochemical localization indicated that nuclear PP2A was affected first, followed by cytoplasmic PP2A. In addition, there was a significant increase in sphingolipid levels at higher doses, indicating the involvement of a ceramide-mediated apoptotic pathway. Expression of apoptosis and cell cycle regulatory proteins like Bax, Bcl2, and Bad showed a dose-dependent decrease. This study demonstrated that treatment with a single dose of MCLR caused liver damage, increased sphingolipid levels, and decreased PP2A expression, which ultimately down-regulated the expression of Bcl2 family proteins.
Insights
A single dose of microcystin-LR (MCLR) caused significant liver damage in rats, indicated by necrosis and hemorrhage. This cyanotoxin exposure led to decreased protein phosphatase 2A (PP2A) expression and altered apoptotic protein levels.
Area of Science:
- Toxicology
- Hepatotoxicity
- Cyanotoxin Research
Background:
- Microcystin-LR (MCLR) is a prevalent hepatotoxin produced by Microcystis aeruginosa.
- Understanding MCLR's toxic effects and identifying reliable biomarkers are crucial for public health.
Purpose of the Study:
- To investigate the toxic effects of single-dose MCLR exposure in young F344 rats.
- To identify potential toxic response indicators following MCLR administration.
Main Methods:
- Intraperitoneal injection of F344 rats with varying doses of MCLR (25-150 microg/kg).
- Monitoring of acute toxic symptoms, mortality, and body weight changes over 7 days.
- Histopathological examination of liver tissues, assessment of protein phosphatase 2A (PP2A) expression, and analysis of sphingolipid and apoptosis-related protein levels.
Main Results:
- 100% mortality observed at the highest MCLR dose (150 microg/kg).
- Dose-dependent liver damage, ranging from spot necrosis to massive hemorrhage and necrotic foci.
- Significant decrease in PP2A expression (nuclear first, then cytoplasmic) and increased sphingolipid levels.
- Down-regulation of apoptosis regulatory proteins (Bax, Bcl2, Bad) in a dose-dependent manner.
Conclusions:
- Single-dose MCLR exposure induces severe liver damage and mortality in rats.
- Decreased PP2A expression and elevated sphingolipids are key indicators of MCLR toxicity.
- MCLR disrupts apoptotic pathways, contributing to liver cell death.
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