title: BDE-47 and 6-OH-BDE-47 modulate calcium homeostasis in primary fetal human neural progenitor cells via ryanodine receptor-independent mechanisms.
abstract: Polybrominated diphenyl ethers (PBDEs) are bioaccumulating flame retardants found in rising concentrations in human tissue. Epidemiological and animal studies have raised concern for their potential to induce developmental neurotoxicity (DNT). Considering the essential role of calcium homeostasis in neurodevelopment, PBDE-induced disturbance of intracellular calcium concentration ([Ca(2+)]i) may underlie PBDE-induced DNT. To test this hypothesis, we investigated acute effects of BDE-47 and 6-OH-BDE-47 on [Ca(2+)]i in human neural progenitor cells (hNPCs) and unraveled involved signaling pathways. Short-time differentiated hNPCs were exposed to BDE-47, 6-OH-BDE-47, and multiple inhibitors/stimulators of presumably involved signaling pathways to determine possible effects on [Ca(2+)]i by single-cell microscopy with the fluorescent dye Fura-2. Initial characterization of calcium signaling pathways confirmed the early developmental stage of hNPCs. In these cells, BDE-47 (2 μM) and 6-OH-BDE-47 (0.2 μM) induce [Ca(2+)]i transients. This increase in [Ca(2+)]i is due to extracellular Ca(2+) influx and intracellular release of Ca(2+), mainly from the endoplasmic reticulum (ER). While extracellular Ca(2+) seems to enter the cytoplasm upon 6-OH-BDE-47 by interfering with the cell membrane and independent of Ca(2+) ion channels, ER-derived Ca(2+) is released following activation of protein lipase C and inositol 1,4,5-trisphosphate receptor, but independently of ryanodine receptors. These findings illustrate that immature developing hNPCs respond to low concentrations of 6-OH-BDE-47 by an increase in [Ca(2+)]i and provide new mechanistic explanations for such BDE-induced calcium disruption. Thus, these data support the possibility of a critical window of PBDE exposure, i.e., early human brain development, which has to be acknowledged in risk assessment.
authors.affiliation: Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, 40225, Duesseldorf, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Gassmann
authors.forename: Timm
authors.initials: T
authors.lastname: Schreiber
authors.forename: Milou M L
authors.initials: MM
authors.lastname: Dingemans
authors.forename: Guido
authors.initials: G
authors.lastname: Krause
authors.forename: Claudia
authors.initials: C
authors.lastname: Roderigo
authors.forename: Susanne
authors.initials: S
authors.lastname: Giersiefer
authors.forename: Janette
authors.initials: J
authors.lastname: Schuwald
authors.forename: Michaela
authors.initials: M
authors.lastname: Moors
authors.forename: Klaus
authors.initials: K
authors.lastname: Unfried
authors.forename: Åke
authors.initials: Å
authors.lastname: Bergman
authors.forename: Remco H S
authors.initials: RH
authors.lastname: Westerink
authors.forename: Christine R
authors.initials: CR
authors.lastname: Rose
authors.forename: Ellen
authors.initials: E
authors.lastname: Fritsche
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D053686:Fetal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D005865:Gestational Age; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011075:Polybrominated Biphenyls / Q000633:toxicity*; D061251:Primary Cell Culture; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: C580599:6-OH-BDE-47; D055768:Halogenated Diphenyl Ethers; D011075:Polybrominated Biphenyls; D019837:Ryanodine Receptor Calcium Release Channel; C511295:2,2',4,4'-tetrabromodiphenyl ether; D002118:Calcium