Calcium-related processes involved in the inhibition of depolarization-evoked calcium increase by hydroxylated PBDEs in PC12 cells

Abstract

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 OHPBDE-induced increase of basal intracellular Ca2+ concentration ([Ca2+]i) by release of Ca2+ from endoplasmic reticulum (ER) and mitochondria and/or influx of extracellular Ca2+. ER and mitochondria regulate Ca2+ homeostasis in close association with voltage-gated Ca21 channels (VGCCs). Therefore, effects of (OH-)PBDEs on the depolarization-evoked (100mM K+) net increase in [Ca2+]i (depolarization-evoked [Ca21]i) were measured in neuroendocrine pheochromocytoma cells using the Ca2+-responsive dye Fura-2. OH-PBDEs dose dependently inhibited depolarization-evoked [Ca2+]i. This inhibition was potentiated by a preceding increase in basal [Ca2+]i. Especially at higher concentrations of OH-PBDEs (5-20mM), large increases in basal [Ca2+]i strongly inhibited depolarization-evoked [Ca2+]i. The inhibition appeared more sensitive to increases in basal [Ca21]i by Ca21 release from intracellular stores (by 3-OH-BDE-47 or 6#-OH-BDE-49) compared to those by influx of extracellular Ca2+ (by 6-OH-BDE-47 or 5-OH-BDE-47). The expected [Ca2+]i difference close to the membrane suggests involvement of Ca2+-dependent regulatory processes close to VGCCs. When coapplied with depolarization, some OH-PBDEs induced also moderate direct inhibition of depolarization-evoked [Ca2+]i. Polybrominated diphenyl ethers and methoxylated BDE-47 affected neither basal nor depolarization-evoked [Ca2+]i, except for BDE-47, which moderately increased fluctuations in basal [Ca2+]i and depolarization-evoked [Ca2+]i. These findings demonstrate that OH-PBDEs inhibit depolarization-evoked [Ca2+]i depending on preceding basal [Ca2+]i. Related environmental pollutants that affect Ca2+ homeostasis (e.g., polychlorinated biphenyls) may thus also inhibit depolarization-evoked [Ca2+]i, justifying further investigation of possible mixture effects of environmental pollutants on Ca2+ homeostasis. © The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.