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Reactive oxygen species regulated mitochondria-mediated apoptosis in PC12 cells exposed to chlorpyrifos.
Toxicol Appl Pharmacol. 2012 Sep 01; 263(2):148-62.TA

Abstract

Reactive oxidative species (ROS) generated by environmental toxicants including pesticides could be one of the factors underlying the neuronal cell damage in neurodegenerative diseases. In this study we found that chlorpyrifos (CPF) induced apoptosis in dopaminergic neuronal components of PC12 cells as demonstrated by the activation of caspases and nuclear condensation. Furthermore, CPF also reduced the tyrosine hydroxylase-positive immunoreactivity in substantia nigra of the rat. In addition, CPF induced inhibition of mitochondrial complex I activity. Importantly, N-acetyl cysteine (NAC) treatment effectively blocked apoptosis via the caspase-9 and caspase-3 pathways while NAC attenuated the inhibition of mitochondrial complex I activity as well as the oxidative metabolism of dopamine (DA). These results demonstrated that CPF-induced apoptosis was involved in mitochondrial dysfunction through the production of ROS. In the response of cellular antioxidant systems to CPF, we found that CPF treatment increased HO-1 expression while the expression of CuZnSOD and MnSOD was reduced. In addition, we found that CPF treatment activated MAPK pathways, including ERK 1/2, the JNK, and the p38 MAP kinase in a time-dependent manner. NAC treatment abolished MAPK phosphorylation caused by CPF, indicating that ROS are upstream signals of MAPK. Interestingly, MAPK inhibitors abolished cytotoxicity and reduced ROS generation by CPF treatment. Our results demonstrate that CPF induced neuronal cell death in part through MAPK activation via ROS generation, suggesting its potential to generate oxidative stress via mitochondrial damage and its involvement in oxidative stress-related neurodegenerative disease.

Authors+Show Affiliations

Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22714038

Citation

Lee, Jeong Eun, et al. "Reactive Oxygen Species Regulated Mitochondria-mediated Apoptosis in PC12 Cells Exposed to Chlorpyrifos." Toxicology and Applied Pharmacology, vol. 263, no. 2, 2012, pp. 148-62.
Lee JE, Park JH, Shin IC, et al. Reactive oxygen species regulated mitochondria-mediated apoptosis in PC12 cells exposed to chlorpyrifos. Toxicol Appl Pharmacol. 2012;263(2):148-62.
Lee, J. E., Park, J. H., Shin, I. C., & Koh, H. C. (2012). Reactive oxygen species regulated mitochondria-mediated apoptosis in PC12 cells exposed to chlorpyrifos. Toxicology and Applied Pharmacology, 263(2), 148-62. https://doi.org/10.1016/j.taap.2012.06.005
Lee JE, et al. Reactive Oxygen Species Regulated Mitochondria-mediated Apoptosis in PC12 Cells Exposed to Chlorpyrifos. Toxicol Appl Pharmacol. 2012 Sep 1;263(2):148-62. PubMed PMID: 22714038.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reactive oxygen species regulated mitochondria-mediated apoptosis in PC12 cells exposed to chlorpyrifos. AU - Lee,Jeong Eun, AU - Park,Jae Hyeon, AU - Shin,In Chul, AU - Koh,Hyun Chul, Y1 - 2012/06/17/ PY - 2012/02/22/received PY - 2012/06/11/revised PY - 2012/06/11/accepted PY - 2012/6/21/entrez PY - 2012/6/21/pubmed PY - 2012/10/23/medline SP - 148 EP - 62 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 263 IS - 2 N2 - Reactive oxidative species (ROS) generated by environmental toxicants including pesticides could be one of the factors underlying the neuronal cell damage in neurodegenerative diseases. In this study we found that chlorpyrifos (CPF) induced apoptosis in dopaminergic neuronal components of PC12 cells as demonstrated by the activation of caspases and nuclear condensation. Furthermore, CPF also reduced the tyrosine hydroxylase-positive immunoreactivity in substantia nigra of the rat. In addition, CPF induced inhibition of mitochondrial complex I activity. Importantly, N-acetyl cysteine (NAC) treatment effectively blocked apoptosis via the caspase-9 and caspase-3 pathways while NAC attenuated the inhibition of mitochondrial complex I activity as well as the oxidative metabolism of dopamine (DA). These results demonstrated that CPF-induced apoptosis was involved in mitochondrial dysfunction through the production of ROS. In the response of cellular antioxidant systems to CPF, we found that CPF treatment increased HO-1 expression while the expression of CuZnSOD and MnSOD was reduced. In addition, we found that CPF treatment activated MAPK pathways, including ERK 1/2, the JNK, and the p38 MAP kinase in a time-dependent manner. NAC treatment abolished MAPK phosphorylation caused by CPF, indicating that ROS are upstream signals of MAPK. Interestingly, MAPK inhibitors abolished cytotoxicity and reduced ROS generation by CPF treatment. Our results demonstrate that CPF induced neuronal cell death in part through MAPK activation via ROS generation, suggesting its potential to generate oxidative stress via mitochondrial damage and its involvement in oxidative stress-related neurodegenerative disease. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/22714038/Reactive_oxygen_species_regulated_mitochondria_mediated_apoptosis_in_PC12_cells_exposed_to_chlorpyrifos_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(12)00264-5 DB - PRIME DP - Unbound Medicine ER -