title: The Pivotal Role of Ca2+Homeostasis in PBDE-47-Induced Neuronal Apoptosis.
abstract: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants and are ubiquitous in the environment and human tissues. Recent evidence has demonstrated that PBDE-induced neurotoxicity is associated with neuronal apoptosis via interfering with the calcium ion (Ca2+) homeostasis; however, the underlying mechanisms remain elusive. Thus, we sought to investigate the role of Ca2+homeostasis in PBDE-47-induced neuronal apoptosis. Here, we showed that PBDE-47 significantly decreased neuronal number while increased neuronal apoptosis in vitro and in vivo, as manifested by an increased percentage of Annexin V-positive staining cells and caspase-3 activation in human neuroblastoma SH-SY5Y cells and hippocampal neurons of rats. Further study identified that PBDE-47 elicited ΔΨmcollapse following an early and sustained [Ca2+]i,overload, as well as stimulated cytochrome c release from mitochondria into the cytosol in SH-SY5Y cells and rat hippocampal tissue. Interestingly, the extracellular Ca2+chelator ethylene glycol-bis (2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) blocked PBDE-47-induced [Ca2+]ielevation, ΔΨmcollapse, cytochrome c release, and caspase-3 activation in SH-SY5Y cells, whereas the intracellular Ca2+chelator 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM) had no influences on them, indicating that the [Ca2+]ioverload originates primarily from extracellular Ca2+component rather than from intracellular calcium storage and that the increase in [Ca2+]iis a major contributor to ΔΨmcollapse and subsequent neuronal apoptosis. Overall, these findings suggest that PBDE-47 affects Ca2+homeostasis as a crucial event in activation of neuronal death associated with mitochondria and provide novel insight into the mechanism of action underlying PBDE neurotoxicity.
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.|Nanjing Entry-Exit Inspection and Quarantine Bureau, 1 Guojian Road, Nanjing, 211106, Jiangsu, People's Republic of China.
authors.forename: Yihu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.|Tianjin Center for Disease Control and Prevention, 6 Huayue Road, Tianjin, 300011, Tianjin, People's Republic of China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Rulin
authors.initials: R
authors.lastname: Ma
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Kuang
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xia
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Lei
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Pei
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, People's Republic of China. wangaiguo@mails.tjmu.edu.cn.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Wang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D006624:Hippocampus / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D017207:Rats, Sprague-Dawley
chemical_list: D055768:Halogenated Diphenyl Ethers; C511295:2,2',4,4'-tetrabromodiphenyl ether; D004533:Egtazic Acid; D045304:Cytochromes c; D053148:Caspase 3; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium
keywords: Apoptosis; Neurotoxicity; PBDE-47; [Ca2+] i; ΔΨm