Archives of Toxicology

, Volume 88, Issue 8, pp 1537–1548

BDE-47 and 6-OH-BDE-47 modulate calcium homeostasis in primary fetal human neural progenitor cells via ryanodine receptor-independent mechanisms

  • Kathrin Gassmann
  • Timm Schreiber
  • Milou M. L. Dingemans
  • Guido Krause
  • Claudia Roderigo
  • Susanne Giersiefer
  • Janette Schuwald
  • Michaela Moors
  • Klaus Unfried
  • Åke Bergman
  • Remco H. S. Westerink
  • Christine R. Rose
  • Ellen Fritsche
Molecular Toxicology

DOI: 10.1007/s00204-014-1217-7

Cite this article as:
Gassmann, K., Schreiber, T., Dingemans, M.M.L. et al. Arch Toxicol (2014) 88: 1537. doi:10.1007/s00204-014-1217-7

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 ([Ca2+]i) may underlie PBDE-induced DNT. To test this hypothesis, we investigated acute effects of BDE-47 and 6-OH-BDE-47 on [Ca2+]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 [Ca2+]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 [Ca2+]i transients. This increase in [Ca2+]i is due to extracellular Ca2+ influx and intracellular release of Ca2+, mainly from the endoplasmic reticulum (ER). While extracellular Ca2+ seems to enter the cytoplasm upon 6-OH-BDE-47 by interfering with the cell membrane and independent of Ca2+ ion channels, ER-derived Ca2+ 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 [Ca2+]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.

Keywords

Brominated flame retardant Calcium Human neural progenitor cell Neurotoxicity Polybrominated diphenyl ether Ryanodine receptor 

Supplementary material

204_2014_1217_MOESM1_ESM.docx (438 kb)
Supplementary material 1 (DOCX 437 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Kathrin Gassmann
    • 1
  • Timm Schreiber
    • 1
  • Milou M. L. Dingemans
    • 2
  • Guido Krause
    • 3
  • Claudia Roderigo
    • 3
  • Susanne Giersiefer
    • 1
  • Janette Schuwald
    • 1
  • Michaela Moors
    • 1
  • Klaus Unfried
    • 1
  • Åke Bergman
    • 4
  • Remco H. S. Westerink
    • 2
  • Christine R. Rose
    • 3
  • Ellen Fritsche
    • 1
    • 5
  1. 1.Leibniz Research Institute for Environmental MedicineDuesseldorfGermany
  2. 2.Neurotoxicology Research Group, Toxicology Division, Faculty of Veterinary Medicine, Institute for Risk Assessment SciencesUtrecht UniversityUtrechtThe Netherlands
  3. 3.Institute of NeurobiologyHeinrich-Heine-UniversityDuesseldorfGermany
  4. 4.Department of Environmental ChemistryStockholm UniversityStockholmSweden
  5. 5.Heinrich-Heine-UniversityDuesseldorfGermany

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