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.
Dingemans
Milou M L
MM
Neurotoxicology Research Group, Toxicology Division, Institute for Risk Assessment Sciences, Utrecht University, NL-3508 TD Utrecht, The Netherlands. m.dingemans@uu.nl
van den Berg
Martin
M
Bergman
Ake
A
Westerink
Remco H S
RH
D000818:Animals; D002118:Calcium / Q000032:analysis / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D005411:Flame Retardants / Q000378:metabolism / Q000633:toxicity*; D016257:Fura-2 / Q000378:metabolism; D055768:Halogenated Diphenyl Ethers / Q000378:metabolism / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006900:Hydroxylation / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats
D020746:Calcium Channels, L-Type; D004785:Environmental Pollutants; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D002118:Calcium; D016257:Fura-2