Calcium-Related Processes Involved in the Inhibition of Depolarization-Evoked Calcium Increase by Hydroxylated PBDEs in PC12 Cells

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 (100 mM 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 microM), 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.