Abstract | BACKGROUND: 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.
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Authors | Milou M L Dingemans, Harm J Heusinkveld, Ake Bergman, Martin van den Berg, Remco H S Westerink |
Journal | Environmental health perspectives
(Environ Health Perspect)
Vol. 118
Issue 4
Pg. 519-25
(Apr 2010)
ISSN: 1552-9924 [Electronic] United States |
PMID | 20368133
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Halogenated Diphenyl Ethers
- Polybrominated Biphenyls
- 2,2',4,4'-tetrabromodiphenyl ether
- Calcium
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Topics |
- Animals
- Calcium
(metabolism)
- Cell Survival
(drug effects)
- Halogenated Diphenyl Ethers
- Halogenation
- PC12 Cells
(drug effects, metabolism)
- Polybrominated Biphenyls
(chemistry, pharmacology)
- Rats
- Structure-Activity Relationship
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