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Induction of apoptosis in mouse liver by microcystin-LR: a combined transcriptomic, proteomic, and simulation
Ting Chen1, Qingsong Wang, Jun Cui
1State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, Nanjing University, Nanjing 210093, China.
Abstract:
Microcystins (MCs) are a family of cyclic heptapeptide hepatotoxins produced by freshwater species of cyanobacteria that have been implicated in the development of liver cancer, necrosis, and even deadly intrahepatic bleeding. MC-LR, the most toxic MC variant, is also the most commonly encountered in a contaminated aquatic system. This study presents the first data in the toxicological research of MCs that combines the use of standard apoptotic assays with transcriptomics, proteomic technologies, and computer simulations. By using histochemistry, DNA fragmentation assays, and flow cytometry analysis, we determined that MC-LR causes rapid, dose-dependent apoptosis in mouse liver when BALB/c mice are treated with MC-LR for 24 h at doses of either 50, 60, or 70 microg/kg of body weight. We then used gene expression profiling to demonstrate differential expressions (>2-fold) of 61 apoptosis-related genes in cells treated with MC-LR. Further proteomic analysis identified a total of 383 proteins of which 35 proteins were up-regulated and 30 proteins were down-regulated more than 2.5-fold when compared with controls. Combining computer simulations with the transcriptomic and proteomic data, we found that low doses (50 microg/kg) of MC-LR lead to apoptosis primarily through the BID-BAX-BCL-2 pathway, whereas high doses of MC-LR (70 microg/kg) caused apoptosis via a reactive oxygen species pathway. These results indicated that MC-LR exposure can cause apoptosis in mouse liver and revealed two independent pathways playing a major regulatory role in MC-LR-induced apoptosis, thereby contributing to a better understanding of the hepatotoxicity and the tumor-promoting mechanisms of MCs.
Insights
Microcystin-LR (MC-LR) induces liver apoptosis in mice through distinct pathways. Low doses activate the BID-BAX-BCL-2 pathway, while high doses trigger a reactive oxygen species pathway, clarifying MC-LR hepatotoxicity.
Area of Science:
- Environmental Toxicology
- Molecular Biology
- Biochemistry
Background:
- Microcystins (MCs), cyclic heptapeptide hepatotoxins from cyanobacteria, are linked to liver disease and cancer.
- MC-LR is the most prevalent and toxic MC variant, posing risks in contaminated aquatic environments.
Purpose of the Study:
- To elucidate the molecular mechanisms of MC-LR-induced liver apoptosis.
- To investigate the dose-dependent effects of MC-LR on apoptotic pathways in mouse liver.
Main Methods:
- Standard apoptotic assays (histochemistry, DNA fragmentation, flow cytometry) were employed.
- Transcriptomic and proteomic analyses identified differentially expressed genes and proteins.
- Computer simulations integrated multi-omics data to model apoptotic pathways.
Main Results:
- MC-LR induced rapid, dose-dependent apoptosis in mouse liver at doses of 50-70 microg/kg.
- Transcriptomics revealed differential expression of 61 apoptosis-related genes.
- Proteomics identified 35 up-regulated and 30 down-regulated proteins.
- Low-dose MC-LR induced apoptosis via the BID-BAX-BCL-2 pathway; high-dose MC-LR induced apoptosis via a reactive oxygen species pathway.
Conclusions:
- MC-LR exposure causes apoptosis in mouse liver through distinct molecular pathways.
- Understanding these pathways is crucial for comprehending MC-LR hepatotoxicity and tumor promotion.
