Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor

Angela S. Howard, Richard Fitzpatrick, Isaac N Pessah, Paul Kostyniak, Pamela J Lein

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Perinatal exposure to polychlorinated biphenyls (PCBs) is linked to cognitive deficits in humans and experimental animals; however, the mechanism(s) underlying this effect remain speculative. Apoptosis is essential to normal brain development, and perturbation of normal spatiotemporal patterns of apoptosis can cause persistent neural deficits. We tested the hypothesis that PCBs alter apoptosis in neuronal cell types critical to cognitive function. Primary cultures of rat cortical and hippocampal neurons were treated for 48 h with Aroclor 1254 or the congeners PCB 77 and 47, which represent coplanar and noncoplanar PCBs that bind the arylhydrocarbon receptor (AhR) with high and low affinity, respectively. Using Hoechst dye and an ELISA for DNA oligonucleosomes, we observed that Aroclor 1254 (10 μM) and PCB 47 (1 μM) significantly increased DNA fragmentation in hippocampal but not cortical neurons, and this effect was blocked by the caspase inhibitors, z-VAD-fmk and DEVD-CHO. In contrast, PCB 77 had no effect on apoptosis in either neuronal cell type, suggesting that PCB-induced apoptosis occurs independent of the AhR. The proapoptotic activity of PCBs was inhibited by the ryanodine receptor (RyR) antagonist FLA 365 and by the antioxidant α-tocopherol but not by antagonists of the IP3 receptor (xestospongin C), L-type calcium channel (verapamil), or NMDA receptor (APV). These data indicate that noncoplanar PCBs induce apoptosis in hippocampal neurons subsequent to RyR activation and increased reactive oxygen species and suggest that altered regional profiles of apoptosis may be an important mechanism underlying the developmental neurotoxicity of PCBs.

Original languageEnglish (US)
Pages (from-to)72-86
Number of pages15
JournalToxicology and Applied Pharmacology
Volume190
Issue number1
DOIs
StatePublished - Jul 1 2003

Keywords

  • Apoptosis
  • Developmental neurotoxicity
  • Hippocampal neurons
  • PCBs
  • Reactive oxygen species
  • Ryanodine receptor
  • Vitamin E

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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