Calcium-Related Processes Involved in the Inhibition of Depolarization-Evoked Calcium Increase by Hydroxylated PBDEs in PC12 Cells
Calcium-Related Processes Involved in the Inhibition of Depolarization-Evoked Calcium Increase by Hydroxylated PBDEs in PC12 Cells
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DOI：
10.1093/toxsci/kfp310
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发表时间：
2010-04-01
影响因子：
3.8
通讯作者：
Westerink, Remco H. S.
中科院分区：
文献类型：
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作者：
Dingemans, Milou M. L.;van den Berg, Martin;Westerink, Remco H. S.
体外研究表明，羟基化多溴联苯醚（OH-PBDEs）与其母体同系物相比具有更高的潜在毒性。一个例子是OH-多溴二苯醚通过内质网和线粒体释放Ca（2+）和/或细胞外Ca（2+）内流，诱导细胞内基础Ca（2+）浓度（[Ca（2+）]（i））增加。ER和线粒体调节Ca（2+）稳态与电压门控Ca（2+）通道（VGCC）密切相关。因此，在神经内分泌嗜铬细胞瘤细胞中，使用Ca（2+）响应染料Fura-2测量了（OH-）PBDEs对去极化（100 mM K（+））诱发的[Ca（2+）]（i）净增加的影响（去极化诱发的[Ca（2+）]（i））。OH-PBDEs剂量依赖性地抑制去极化诱发的[Ca（2+）]（i）。基础[Ca（2+）]（i）的预先增加增强了这种抑制作用。特别是在较高浓度的羟基多溴二苯醚（5-20 μ M）下，基础[Ca（2+）]（i）的大幅增加强烈抑制了去极化诱发的[Ca（2+）]（i）。与细胞外Ca（2+）流入（6-OH-BDE-47或5-OH-BDE-47）相比，细胞内储存的Ca（2+）释放（3-OH-BDE-47或6 '-OH-BDE-49）导致的基础[Ca（2+）]（i）增加似乎对抑制作用更敏感。接近膜的预期[Ca（2+）]（i）差异表明涉及接近VGCC的Ca（2+）依赖性调节过程。当与去极化同时应用时，一些OH-多溴二苯醚也诱导了对去极化诱发的[Ca（2+）]（i）的中度直接抑制。多溴二苯醚和甲氧基化BDE-47既不影响基础钙离子浓度，也不影响去极化诱发的钙离子浓度，但BDE-47会适度增加基础钙离子浓度和去极化诱发的钙离子浓度的波动。这些发现表明，羟基多溴二苯醚抑制去极化诱发的[Ca（2+）]（i）取决于先前的基础[Ca（2+）]（i）。影响Ca（2+）稳态的相关环境污染物（例如，因此，多氯联苯）也可能抑制去极化诱发的[Ca（2+）]（i），证明进一步研究环境污染物对Ca（2+）稳态的可能混合效应是合理的。
In vitro studies indicated that hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have an increased toxic potential compared to their parent congeners. An example is the OH-PBDE induced increase of basal intracellular Ca(2+) concentration ([Ca(2+)](i)) by release of Ca(2+) from endoplasmic reticulum (ER) and mitochondria and/or influx of extracellular Ca(2+). ER and mitochondria regulate Ca(2+) homeostasis in close association with voltage-gated Ca(2+) channels (VGCCs). Therefore, effects of (OH-)PBDEs on the depolarization-evoked (100mM K(+)) net increase in [Ca(2+)](i) (depolarization-evoked [Ca(2+)](i)) were measured in neuroendocrine pheochromocytoma cells using the Ca(2+)-responsive dye Fura-2. OH-PBDEs dose dependently inhibited depolarization-evoked [Ca(2+)](i). This inhibition was potentiated by a preceding increase in basal [Ca(2+)](i). Especially at higher concentrations of OH-PBDEs (5-20 mu M), large increases in basal [Ca(2+)](i) strongly inhibited depolarization-evoked [Ca(2+)](i). The inhibition appeared more sensitive to increases in basal [Ca(2+)](i) by Ca(2+) release from intracellular stores (by 3-OH-BDE-47 or 6'-OH-BDE-49) compared to those by influx of extracellular Ca(2+) (by 6-OH-BDE-47 or 5-OH-BDE-47). The expected [Ca(2+)](i) difference close to the membrane suggests involvement of Ca(2+)-dependent regulatory processes close to VGCCs. When coapplied with depolarization, some OH-PBDEs induced also moderate direct inhibition of depolarization-evoked [Ca(2+)](i). Polybrominated diphenyl ethers and methoxylated BDE-47 affected neither basal nor depolarization-evoked [Ca(2+)](i), except for BDE-47, which moderately increased fluctuations in basal [Ca(2+)](i) and depolarization-evoked [Ca(2+)](i). These findings demonstrate that OH-PBDEs inhibit depolarization-evoked [Ca(2+)](i) depending on preceding basal [Ca(2+)](i). Related environmental pollutants that affect Ca(2+) homeostasis (e.g., polychlorinated biphenyls) may thus also inhibit depolarization-evoked [Ca(2+)](i), justifying further investigation of possible mixture effects of environmental pollutants on Ca(2+) homeostasis.