Neurotoxicology Research Group, Institute for Risk Assessment Sciences, Utrecht University, NL-3508 TD Utrecht, The Netherlands.
Toxicol Sci. 2012 Apr;126(2):487-96. doi: 10.1093/toxsci/kfr346. Epub 2012 Jan 4.
Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) are environmental pollutants that are well known for their neurotoxic effects. Numerous in vitro studies reported PCB-induced increases in the basal intracellular calcium concentration (Ca(2+)), and in vivo NDL-PCB neurotoxicity appears at least partly mediated by these disturbances. However, effects of NDL-PCBs on depolarization-evoked calcium influx are poorly investigated, and effects of several congeners, including PCB53, on calcium homeostasis are still unknown. We therefore studied the effects of 20 selected NDL-PCBs on basal and depolarization-evoked Ca(2+) in fura-2-loaded PC12 cells using single-cell fluorescence microscopy. The results demonstrate that hexa- and heptachlorobiphenyls (with the exception of PCB136) were unable to affect basal and depolarization-evoked Ca(2+). However, most tri- and tetrachlorinated as well as some pentachlorinated NDL-PCBs (at 1 and 10μM) increased basal Ca(2+) during a 15-min exposure. The increase in basal Ca(2+), which differed in kinetics for the different congeners, depended partly on influx of extracellular calcium and calcium release from the endoplasmic reticulum. Importantly, all tested tri- and tetrachlorinated biphenyls and some pentachlorinated NDL-PCBs (PCB95, PCB100, and PCB104) reduced depolarization-evoked Ca(2+), with PCB51 and PCB53 being most potent (near complete inhibition at 1μM). The reduction in depolarization-evoked calcium influx depended on the exposure duration but not on the foregoing PCB-induced increase in basal Ca(2+). The inhibition of voltage-gated calcium channels is a novel and sensitive mode of action for NDL-PCBs that contributes to the disturbances in calcium homeostasis and likely is related to NDL-PCB-induced (developmental) neurotoxicity.
非二噁英多氯联苯（NDL-PCBs）是众所周知的神经毒性环境污染物。大量的体外研究报告称，PCBs 会导致细胞内基础钙离子浓度 (Ca(2+)) 升高，而体内 NDL-PCBs 的神经毒性似乎至少部分是由这些干扰介导的。然而，NDL-PCBs 对去极化诱导的钙内流的影响研究甚少，并且包括 PCB53 在内的几种同系物对钙稳态的影响仍不清楚。因此，我们使用单细胞荧光显微镜研究了 20 种选定的 NDL-PCBs 对 PC12 细胞中基础和去极化诱导的 Ca(2+) 的影响。结果表明，六氯和七氯联苯（PCB136 除外）无法影响基础和去极化诱导的 Ca(2+)。然而，大多数三氯和四氯以及一些五氯 NDL-PCBs（在 1 和 10μM 时）在 15 分钟的暴露期间增加了基础 Ca(2+)。不同同系物的动力学不同的基础 Ca(2+) 增加部分取决于细胞外钙的流入和内质网的钙释放。重要的是，所有测试的三氯和四氯联苯以及一些五氯 NDL-PCBs（PCB95、PCB100 和 PCB104）减少了去极化诱导的 Ca(2+)，其中 PCB51 和 PCB53 的作用最强（在 1μM 时几乎完全抑制）。去极化诱导的钙内流减少取决于暴露持续时间，但与前文 PCB 诱导的基础 Ca(2+) 增加无关。电压门控钙通道的抑制是 NDL-PCBs 的一种新的、敏感的作用模式，它导致钙稳态紊乱，可能与 NDL-PCB 诱导的（发育性）神经毒性有关。
