Differential effects of 20 non-dioxin-like PCBs on basal and depolarization-evoked intracellular calcium levels in PC12 cells

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+)](i)), 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+)](i) 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+)](i). However, most tri- and tetrachlorinated as well as some pentachlorinated NDL-PCBs (at 1 and 10μM) increased basal [Ca(2+)](i) during a 15-min exposure. The increase in basal [Ca(2+)](i), 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+)](i), 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+)](i). 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.