title: Mitochondrion-Mediated Apoptosis Induced by Acrylamide is Regulated by a Balance Between Nrf2 Antioxidant and MAPK Signaling Pathways in PC12 Cells.
abstract: Acrylamide (ACR) is a potent toxin that affects the human nervous system. However, the underlying mechanism of ACR neurotoxicity remains poorly understood. In the present study, we investigated whether ACR induces mitochondrion-dependent apoptosis and the involved signaling pathways in PC12 cells. ACR exposure activated the mitochondrial apoptotic pathway in PC12 cells and triggered the up-regulation of Bax/Bcl-2 ratio, excessive release of cytochrome c, cleavage of capase-9 and caspase-3, depolarization of the mitochondrial membrane, structural damages to the mitochondria, and compaction of nuclear heterochromatin. ACR-induced oxidative stress was also observed based on distinct increase in cellular reactive oxygen species (ROS) and malondialdehyde (MDA), and significant decrease in glutathione (GSH). Mitogen-activated protein kinases (MAPK) signaling including extracellular signal-regulated protein kinases (ERK), c-Jun N-terminal kinases (JNK), and p38 were phosphorylated by ROS overproduction in PC12 cells in a time-and dose-dependent manner. ACR promoted the translocation of nuclear factor E2-related factor 2 (Nrf2) from the cytosol to the nucleus, thereby enhancing the expression of downstream γ-glutamyl-cysteine synthetase (γ-GCS). The regulation of Nrf2 activation by MAPK pathways was confirmed by the blockade of MAPK pathways. The suppression of JNK and p38 pathways showed a protective effect on ACR-induced mitochondrial dysfunction and apoptosis. Nrf2 knockdown further enhanced MDA production and reduced GSH generation induced by ACR. These results suggest that MAPK and Nrf2 signaling pathways contribute to mitochondrion-mediated apoptosis induced by ACR in PC12 cells.
authors: Department of Health Toxicology, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong-Road, Wuhan, Hubei, 430030, People's Republic of China.|School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, China.
authors: Xiaoqi
authors: X
authors: Pan
authors: Department of Health Toxicology, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong-Road, Wuhan, Hubei, 430030, People's Republic of China.
authors: Dandan
authors: D
authors: Yan
authors: Department of Health Toxicology, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong-Road, Wuhan, Hubei, 430030, People's Republic of China.
authors: Dun
authors: D
authors: Wang
authors: Department of Health Toxicology, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong-Road, Wuhan, Hubei, 430030, People's Republic of China.
authors: Xu
authors: X
authors: Wu
authors: Department of Health Toxicology, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong-Road, Wuhan, Hubei, 430030, People's Republic of China.
authors: Wanyun
authors: W
authors: Zhao
authors: Department of Health Toxicology, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong-Road, Wuhan, Hubei, 430030, People's Republic of China.
authors: Qing
authors: Q
authors: Lu
authors: Department of Health Toxicology, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong-Road, Wuhan, Hubei, 430030, People's Republic of China. yanhong@mails.tjmu.edu.cn.
authors: Hong
authors: H
authors: Yan
mesh_terms: D020106:Acrylamide / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D020868:Gene Silencing; D005978:Glutathione / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008315:Malondialdehyde / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D020106:Acrylamide; D008315:Malondialdehyde; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione
keywords: Acrylamide; Apoptosis; MAPK; Nrf2; Oxidative stress