期刊
MOLECULAR NEUROBIOLOGY
卷 53, 期 10, 页码 7078-7088出版社
HUMANA PRESS INC
DOI: 10.1007/s12035-015-9573-8
关键词
PBDE-47; Neurotoxicity; Apoptosis; [Ca2+](i); Delta Psi(m)
资金
- National Natural Science Foundation of China [81072266, 81273021]
- Natural Science Foundation of Hubei Province of China [2013CFB123]
- China Postdoctoral Science Foundation [2015M570643]
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 Delta I-m collapse 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+] (i) elevation, Delta I-m collapse, 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+] (i) overload originates primarily from extracellular Ca2+ component rather than from intracellular calcium storage and that the increase in [Ca2+] (i) is a major contributor to Delta I-m collapse 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.
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