Caspase Cascade Regulated Mitochondria Mediated Apoptosis in Monocrotophos Exposed PC12 Cells

Monocrotophos (MCP) is a commonly used organophosphorus (OP) pesticide. We studied apoptotic changes in PC12 cells exposed to MCP. A significant induction in reactive oxygen species (ROS), lipid peroxide (LPO), and the ratio of glutathione disulfide (GSSG)/reduced glutathione (GSH) was observed in c...

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Bibliographic Details
Published in:Chemical research in toxicology 2010-11, Vol.23 (11), p.1663-1672
Main Authors: Kashyap, M. P, Singh, A. K, Siddiqui, M. A, Kumar, V, Tripathi, V. K, Khanna, V. K, Yadav, S, Jain, S. K, Pant, A. B
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis Regulatory Proteins - metabolism
bcl-2-Associated X Protein - metabolism
Caspases - genetics
Caspases - metabolism
Cell Membrane Permeability - drug effects
Cytochromes c - metabolism
Insecticides - toxicity
Lipid Peroxidation - drug effects
Mitochondria - metabolism
Monocrotophos - toxicity
PC12 Cells
Rats
Reactive Oxygen Species - metabolism
Tumor Suppressor Protein p53 - metabolism
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Summary:Monocrotophos (MCP) is a commonly used organophosphorus (OP) pesticide. We studied apoptotic changes in PC12 cells exposed to MCP. A significant induction in reactive oxygen species (ROS), lipid peroxide (LPO), and the ratio of glutathione disulfide (GSSG)/reduced glutathione (GSH) was observed in cells exposed to selected doses of MCP. Following the exposure of PC12 cells to MCP, the levels of protein and mRNA expressions of Caspase-3, Caspase-9, Bax, p53, P21, Puma, and cytochrome-c were significantly upregulated, whereas the levels of Bcl2, Bclw, and Mcl1 were downregulated. TUNEL assay, DNA laddering, and micronuclei induction show that long-term exposure of PC12 cells to MCP at higher concentration (10−5 M) decreases the number of apoptotic events due to an increase in the number of necrotic cells. MCP-induced translocation of Bax and cytochrome-c proteins between the cytoplasm and mitochondria confirmed the role of p53 and Puma in mitochondrial membrane permeability. Mitochondria mediated apoptosis induction was confirmed by the increased activity of caspase cascade. We believe that this is the first report showing MCP-induced apoptosis in PC12 cells, which is mitochondria mediated and regulated through the caspase cascade. Our data demonstrates that MCP induced the apoptotic cell death in neuronal cells and identifies the possible cellular and molecular mechanisms of organophosphate pesticide-induced apoptosis in neuronal cells.
ISSN:0893-228X
1520-5010
DOI:10.1021/tx100234m