Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor.
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 microM) and PCB 47 (1 microM) 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 alpha-tocopherol but not by antagonists of the IP(3) 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.
Howard
Angela S
AS
Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Fitzpatrick
Richard
R
Pessah
Isaac
I
Kostyniak
Paul
P
Lein
Pamela J
PJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D015220:Calcium Channels / Q000187:drug effects; D020169:Caspases / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects / Q000196:embryology; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D053938:DNA Fragmentation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000196:embryology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009474:Neurons / Q000187:drug effects*; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects*; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D015220:Calcium Channels; D002843:Chromatin; D053496:Inositol 1,4,5-Trisphosphate Receptors; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; D020111:Chlorodiphenyl (54% Chlorine); D014810:Vitamin E; D011078:Polychlorinated Biphenyls; D020169:Caspases