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 ΔΨm 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, ΔΨm 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 ΔΨm 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.

• Authors: Shun Zhang, Yihu Chen, Xue Wu, Hui Gao, Rulin Ma, Chunyang Jiang, Gang Kuang, Guodong Zhao, Tao Xia, Xiaofei Zhang, Rongrong Lei, Cheng Zhang, Pei Li, Chunyan Xu, Aiguo Wang
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 53 Issue 10 Pg. 7078-7088 (12 2016) ISSN: 1559-1182 [Electronic] United States
• PMID: 26676572 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Halogenated Diphenyl Ethers
• 2,2',4,4'-tetrabromodiphenyl ether
• Egtazic Acid
• Cytochromes c
• Caspase 3
• 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cytochromes c (metabolism)
• Egtazic Acid (analogs & derivatives, metabolism, pharmacology)
• Enzyme Activation (drug effects)
• Female
• Halogenated Diphenyl Ethers (toxicity)
• Hippocampus (pathology)
• Homeostasis (drug effects)
• Humans
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Neurons (drug effects, enzymology, pathology)
• Rats, Sprague-Dawley