Bromination Pattern of Hydroxylated Metabolites of BDE-47 Affects Their Potency to Release Calcium from Intracellular Stores in PC12 Cells
2010 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 118, no 4, 519-525 p.Article in journal (Refereed) Published
BACKGROUND: Brominated flame retardants, including the widely used polybrominated diphenyl ethers (PBDEs), have been detected in humans, raising concern about possible neurotoxicity. Recent research demonstrated that the hydroxylated metabolite 6-OH-BDE-47 increases neurotransmitter release by releasing calcium ions (Ca2+) from intracellular stores at much lower concentrations than its environmentally relevant parent congener BDE-47. Recently, several other hydroxylated BDE-47 metabolites, besides 6-OH-BDE-47, have been detected in human serum and cord blood. OBJECTIVE AND METHODS: To investigate the neurotoxic potential of other environmentally relevant PBDEs and their metabolites, we examined and compared the acute effects of BDE-47, BDE-49, BDE-99, BDE-100, BDE-153, and several metabolites of BDE-47-6-OH-BDE-47 (and its methoxylated analog 6-MeO-BDE-47), 6'-OH-BDE-49, 5-OH-BDE-47, 3-OH-BDE-47, and 4'-OH-BDE-49 on intracellular Ca2+ concentration ([Ca2+](i)), measured using the Ca2+-responsive dye Fura-2 in neuroendocrine pheochromocytoma (PC12) cells. RESULTS: In contrast to the parent PBDEs and 6-MeO-BDE-47, all hydroxylated metabolites induced Ca2+ release from intracellular stores, although with different lowest observed effect concentrations (LOECs). The major intracellular Ca2+ sources were either endoplasmic reticulum (ER; 5-OH-BDE-47 and 6'-OH-BDE-49) or both ER and mitochondria (6-OH-BDE-47, 3-OH-BDE-47, and 4'-OH-BDE-49). When investigating fluctuations in [Ca2+](i), which is a more subtle end point, we observed lower LOECs for 6-OH-BDE-47 and 4'-OH-BDE-49, as well as for BDE-47. CONCLUSIONS: The present findings demonstrate that hydroxylated metabolites of BDE-47 cause disturbance of the [Ca2+](i). Importantly, shielding of the OH group on both sides with bromine atoms and/or the ether bond to the other phenyl ring lowers the potency of hydroxylated PBDE metabolites.
Place, publisher, year, edition, pages
2010. Vol. 118, no 4, 519-525 p.
brominated flame retardant, calcium, calcium fluctuations, Fura-2, intracellular calcium stores, neurotoxicity, PC12, persistent organic pollutant, polybrominated diphenyl ether, structure-activity relationship
Research subject Materials Chemistry
IdentifiersURN: urn:nbn:se:su:diva-50136DOI: 10.1289/ehp.0901339ISI: 000276454800025OAI: oai:DiVA.org:su-50136DiVA: diva2:380577
authorCount :52010-12-212010-12-212010-12-21Bibliographically approved