Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor
Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor
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DOI：
10.1016/s0041-008x(03)00156-x
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发表时间：
2003-07-01
影响因子：
3.8
通讯作者：
Lein, PJ
中科院分区：
文献类型：
--
作者：
Howard, AS;Fitzpatrick, R;Lein, PJ
围产期接触多氯联苯 (PCB) 与人类和实验动物的认知缺陷有关；然而，这种效应背后的机制仍然是推测性的。细胞凋亡对于正常的大脑发育至关重要，细胞凋亡的正常时空模式的扰动可能会导致持续的神经缺陷。我们测试了 PCB 会改变对认知功能至关重要的神经元细胞类型的凋亡的假设。大鼠皮质和海马神经元的原代培养物用 Aroclor 1254 或同源物 PCB 77 和 47 处理 48 It，它们分别代表以高亲和力和低亲和力结合芳基烃受体 (AhR) 的共面和非共面 PCB。使用 Hoechst 染料和 DNA 寡核小体 ELISA，我们观察到 Aroclor 1254 (10 muM) 和 PCB 47 (1 muM) 显着增加海马而非皮层神经元中的 DNA 断裂，并且这种效应被 caspase 抑制剂 z-VAD-fmk 和 DEVD-CHO 阻断。相比之下，PCB 77 对任一神经元细胞类型的细胞凋亡均没有影响，这表明 PCB 诱导的细胞凋亡的发生独立于 AhR。 PCB 的促凋亡活性可被兰尼碱受体 (RyR) 拮抗剂 FLA 365 和抗氧化剂 α-生育酚抑制，但不会被 IP3 受体 (xestospongin C)、L 型钙通道 (维拉帕米) 或 NMDA 受体 (APV) 拮抗剂抑制。这些数据表明，非共面 PCB 在 RyR 激活和活性氧增加后诱导海马神经元凋亡，并表明细胞凋亡区域分布的改变可能是 PCB 发育神经毒性的重要机制。 (C) 2003 年爱思唯尔科学（美国）。版权所有。
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 It 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 muM) and PCB 47 (1 muM) 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 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. (C) 2003 Elsevier Science (USA). All rights reserved.