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

• Published in: Toxicology and applied pharmacology Vol. 190; no. 1; pp. 72 - 86
• Main Authors: Howard, Angela S, Fitzpatrick, Richard, Pessah, Isaac, Kostyniak, Paul, Lein, Pamela J
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.07.2003; Elsevier
• Subjects: Animals; Antioxidants - pharmacology; Apoptosis; Biological and medical sciences; Calcium Channels - drug effects; Caspases - physiology; Cell Death - drug effects; Cell Nucleus - drug effects; Cell Nucleus - ultrastructure; Cell Survival - drug effects; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - embryology; Chemical and industrial products toxicology. Toxic occupational diseases; Chlorodiphenyl (54% Chlorine) - pharmacology; Chromatin - drug effects; Chromatin - ultrastructure; Developmental neurotoxicity; DNA Fragmentation - drug effects; Enzyme-Linked Immunosorbent Assay; Hippocampal neurons; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - embryology; Inositol 1,4,5-Trisphosphate Receptors; Medical sciences; Neurons - drug effects; PCBs; Polychlorinated Biphenyls - toxicity; Rats; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors, Cytoplasmic and Nuclear - drug effects; Ryanodine receptor; Ryanodine Receptor Calcium Release Channel - drug effects; Toxicology; Various organic compounds; Vitamin E; Vitamin E - pharmacology; PCBs; Hippocampal neurons; Reactive oxygen species; Vitamin E; Ryanodine receptor; Developmental neurotoxicity; Apoptosis; Embryonic development; Nervous system diseases; Rat; Enzyme; Toxicity; Rodentia; Caspase; Polychlorobiphenyl; In vitro; Peptidases; Vertebrata; Mammalia; Neuron; Cell death; Animal; Hydrolases; Mechanism of action
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/S0041-008X(03)00156-X

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 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.