The Pivotal Role of Ca2+ 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 (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.