The Pivotal Role of Ca Homeostasis in PBDE-47-Induced Neuronal Apoptosis.

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 (Ca) homeostasis; however, the underlying mechanisms remain elusive. Thus, we sought to investigate the role of Ca 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 ΔΨ collapse following an early and sustained [Ca] overload, as well as stimulated cytochrome c release from mitochondria into the cytosol in SH-SY5Y cells and rat hippocampal tissue. Interestingly, the extracellular Ca chelator ethylene glycol-bis (2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) blocked PBDE-47-induced [Ca] elevation, ΔΨ collapse, cytochrome c release, and caspase-3 activation in SH-SY5Y cells, whereas the intracellular Ca 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 [Ca] overload originates primarily from extracellular Ca component rather than from intracellular calcium storage and that the increase in [Ca] is a major contributor to ΔΨ collapse and subsequent neuronal apoptosis. Overall, these findings suggest that PBDE-47 affects Ca 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.