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The Pivotal Role of Ca2+ Homeostasis in PBDE-47-Induced Neuronal Apoptosis

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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.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81072266 and 81273021), the Natural Science Foundation of Hubei Province of China (No. 2013CFB123) and China Postdoctoral Science Foundation (No. 2015M570643).

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Authors and Affiliations

  1. 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

    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

  2. Nanjing Entry-Exit Inspection and Quarantine Bureau, 1 Guojian Road, Nanjing, 211106, Jiangsu, People’s Republic of China

    Yihu Chen

  3. Tianjin Center for Disease Control and Prevention, 6 Huayue Road, Tianjin, 300011, Tianjin, People’s Republic of China

    Xue Wu

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  1. Shun Zhang
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  2. Yihu Chen
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  3. Xue Wu
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  4. Hui Gao
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  14. Chunyan Xu
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  15. Aiguo Wang
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Corresponding author

Correspondence to Aiguo Wang.

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The experimental protocol was approved by the Ethics Review Committee for Animal Research at Huazhong University of Science and Technology.

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Zhang, S., Chen, Y., Wu, X. et al. The Pivotal Role of Ca2+ Homeostasis in PBDE-47-Induced Neuronal Apoptosis. Mol Neurobiol 53, 7078–7088 (2016). https://doi.org/10.1007/s12035-015-9573-8

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