Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor
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 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…
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PCB-induced impairment of mitochondrial and endoplasmic reticulum calcium handling, together with ryanodine receptor activation, can lead to sustained intracellular calcium elevation, excitotoxic stress, and neuronal injury.
“More generally, PCB-induced impairment of mitochondrial and endoplasmic reticulum calcium handling, together with ryanodine receptor activation, can lead to sustained intracellular calcium elevation, excitotoxic stress, and neuronal injury (Howard et al., 2003; Wong et al., 1997).”
From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Howard et al., 2003
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“More generally, PCB-induced impairment of mitochondrial and endoplasmic reticulum calcium handling, together with ryanodine receptor activation, can lead to sustained intracellular calcium elevation, excitotoxic stress, and neuronal injury (Howard et al., 2003; Wong et al., 1997).”
- Authors
- Howard, A.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Howard, A
- Venue
- Toxicology and Applied Pharmacology
- Publisher
- Elsevier BV
- Published
- 2003-07-01
- Volume
- 190
- Issue
- 1
- Pages
- 72-86
- ISSN
- 0041-008X (ISSN-L)
- OpenAlex
- W1979505439
- Cited by
- 112
- References
- 3
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 8 · 2021: 5 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 5 · 2016: 1 · 2015: 5 · 2014: 5 · 2013: 5 · 2012: 4
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicology and Applied Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of California, Davis
- National Institute of Environmental Health Sciences (2 P30 ES03819-14, P01ES011269, P30ES003819, T32ES007141)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R03HD040936)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- polychlorinated biphenyls, PCB 77, PCB 47, Aroclor 1254, ryanodine receptor, caspase-dependent apoptosis, hippocampal neurons, cortical neurons, developmental neurotoxicity, aryl hydrocarbon receptor, reactive oxygen species, alpha-tocopherol, DNA fragmentation, perinatal exposure, cognitive impairment
- MeSH terms
- Animals, Antioxidants, Cell Nucleus, Cell Survival, Cells, Cultured, Cerebral Cortex, Chromatin, Enzyme-Linked Immunosorbent Assay, Hippocampus, Neurons, Polychlorinated Biphenyls, Vitamin E, Calcium Channels, Cell Death, Apoptosis, Reactive Oxygen Species, Receptors, Cytoplasmic and Nuclear, Ryanodine Receptor Calcium Release Channel, Chlorodiphenyl (54% Chlorine), Caspases, Rats, Inositol 1,4,5-Trisphosphate Receptors, DNA Fragmentation
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