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Hydroxylation Increases the Neurotoxic Potential of BDE-47 to Affect Exocytosis and Calcium Homeostasis in PC12 Cells.

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Title: Hydroxylation Increases the Neurotoxic Potential of BDE-47 to Affect Exocytosis and Calcium Homeostasis in PC12 Cells.
Authors: Dingemans, Milou M. L.1 m.dingemans@uu.nl, De Groot, Aart1, Van Kleef, Regina G. D. M.1, Bergman, Åke2, Van Den Berg, Martin1, Vijverberg, Henk P. M.1, Westerink, Remco H. S.1
Source: Environmental Health Perspectives. May2008, Vol. 116 Issue 5, p637-643. 7p. 6 Graphs.
Subject Terms: *Polybrominated diphenyl ethers & the environment, *Homeostasis, Fireproofing agents, Metabolites, Neurotoxicology, Hydroxylation, Oxidative stress, Catecholamines, Exocytosis, Calcium metabolism, Neurotransmitters
Abstract: BACKGROUND: Oxidative metabolism, resulting in the formation of hydroxylated polybrominated diphenyl ether (PBDE) metabolites, may enhance the neurotoxic potential of brominated flame retardants. OBJECTIVE: Our objective was to investigate the effects of a hydroxylated metabolite of 2,2',4,4'-tetra-bromodiphenyl ether (BDE-47; 6-OH-BDE-47) on changes in the intracellular Ca2+ concentration ([Ca2+]i) and vesicular catecholamine release in PC12 cells. METHODS: We measured vesicular catecholamine release and [Ca2+]i using amperometry and imaging of the fluorescent Ca2+-sensitive dye Fura-2, respectively. RESULTS: Acute exposure of PC12 cells to 6-OH-BDE-47 (5 μM) induced vesicular catecholamine release. Catecholamine release coincided with a transient increase in [Ca2+]i, which was observed shortly after the onset of exposure to 6-OH-BDE-47 (120 μM). An additional late increase in [Ca2+]i, was often observed at ≥ 1 μM 6-OH-BDE-47. The initial transient increase was absent in cells exposed to the parent compound BDE-47, whereas the late increase was observed only at 20 μM. Using the mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) and thapsigargin to empty intracellular Ca2+ stores, we found that the initial increase originates from emptying of the endoplasmic reticulum and consequent influx of extracellular Ca2+, whereas the late increase originates primarily from mitochondria. CONCLUSION: The hydroxylated metabolite 6-OH-BDE-47 is more potent in disturbing Ca2+ homeostasis and neurotransmitter release than the parent compound BDE-47. The present findings indicate that bioactivation by oxidative metabolism adds considerably to the neurotoxic potential of PBDES. Additionally, based on the observed mechanism of action, a cumulative neurotoxic effect of PBDES and ortbo-substituted polychlorinated biphenyls on [Ca2+]i cannot be ruled out. [ABSTRACT FROM AUTHOR]
Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Hydroxylation Increases the Neurotoxic Potential of BDE-47 to Affect Exocytosis and Calcium Homeostasis in PC12 Cells.
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  Data: <searchLink fieldCode="AR" term="%22Dingemans%2C+Milou+M%2E+L%2E%22">Dingemans, Milou M. L.</searchLink><relatesTo>1</relatesTo><i> m.dingemans@uu.nl</i><br /><searchLink fieldCode="AR" term="%22De+Groot%2C+Aart%22">De Groot, Aart</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Van+Kleef%2C+Regina+G%2E+D%2E+M%2E%22">Van Kleef, Regina G. D. M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Bergman%2C+Åke%22">Bergman, Åke</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Van+Den+Berg%2C+Martin%22">Van Den Berg, Martin</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Vijverberg%2C+Henk+P%2E+M%2E%22">Vijverberg, Henk P. M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Westerink%2C+Remco+H%2E+S%2E%22">Westerink, Remco H. S.</searchLink><relatesTo>1</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Environmental+Health+Perspectives%22">Environmental Health Perspectives</searchLink>. May2008, Vol. 116 Issue 5, p637-643. 7p. 6 Graphs.
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  Data: *<searchLink fieldCode="DE" term="%22Polybrominated+diphenyl+ethers+%26+the+environment%22">Polybrominated diphenyl ethers & the environment</searchLink><br />*<searchLink fieldCode="DE" term="%22Homeostasis%22">Homeostasis</searchLink><br /><searchLink fieldCode="DE" term="%22Fireproofing+agents%22">Fireproofing agents</searchLink><br /><searchLink fieldCode="DE" term="%22Metabolites%22">Metabolites</searchLink><br /><searchLink fieldCode="DE" term="%22Neurotoxicology%22">Neurotoxicology</searchLink><br /><searchLink fieldCode="DE" term="%22Hydroxylation%22">Hydroxylation</searchLink><br /><searchLink fieldCode="DE" term="%22Oxidative+stress%22">Oxidative stress</searchLink><br /><searchLink fieldCode="DE" term="%22Catecholamines%22">Catecholamines</searchLink><br /><searchLink fieldCode="DE" term="%22Exocytosis%22">Exocytosis</searchLink><br /><searchLink fieldCode="DE" term="%22Calcium+metabolism%22">Calcium metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22Neurotransmitters%22">Neurotransmitters</searchLink>
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  Data: BACKGROUND: Oxidative metabolism, resulting in the formation of hydroxylated polybrominated diphenyl ether (PBDE) metabolites, may enhance the neurotoxic potential of brominated flame retardants. OBJECTIVE: Our objective was to investigate the effects of a hydroxylated metabolite of 2,2',4,4'-tetra-bromodiphenyl ether (BDE-47; 6-OH-BDE-47) on changes in the intracellular Ca2+ concentration ([Ca2+]i) and vesicular catecholamine release in PC12 cells. METHODS: We measured vesicular catecholamine release and [Ca2+]i using amperometry and imaging of the fluorescent Ca2+-sensitive dye Fura-2, respectively. RESULTS: Acute exposure of PC12 cells to 6-OH-BDE-47 (5 μM) induced vesicular catecholamine release. Catecholamine release coincided with a transient increase in [Ca2+]i, which was observed shortly after the onset of exposure to 6-OH-BDE-47 (120 μM). An additional late increase in [Ca2+]i, was often observed at ≥ 1 μM 6-OH-BDE-47. The initial transient increase was absent in cells exposed to the parent compound BDE-47, whereas the late increase was observed only at 20 μM. Using the mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) and thapsigargin to empty intracellular Ca2+ stores, we found that the initial increase originates from emptying of the endoplasmic reticulum and consequent influx of extracellular Ca2+, whereas the late increase originates primarily from mitochondria. CONCLUSION: The hydroxylated metabolite 6-OH-BDE-47 is more potent in disturbing Ca2+ homeostasis and neurotransmitter release than the parent compound BDE-47. The present findings indicate that bioactivation by oxidative metabolism adds considerably to the neurotoxic potential of PBDES. Additionally, based on the observed mechanism of action, a cumulative neurotoxic effect of PBDES and ortbo-substituted polychlorinated biphenyls on [Ca2+]i cannot be ruled out. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1289/ehp.11059
    Languages:
      – Code: eng
        Text: English
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      Pagination:
        PageCount: 7
        StartPage: 637
    Subjects:
      – SubjectFull: Polybrominated diphenyl ethers & the environment
        Type: general
      – SubjectFull: Homeostasis
        Type: general
      – SubjectFull: Fireproofing agents
        Type: general
      – SubjectFull: Metabolites
        Type: general
      – SubjectFull: Neurotoxicology
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      – SubjectFull: Hydroxylation
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      – SubjectFull: Oxidative stress
        Type: general
      – SubjectFull: Catecholamines
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      – SubjectFull: Exocytosis
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      – SubjectFull: Calcium metabolism
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      – SubjectFull: Neurotransmitters
        Type: general
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      – TitleFull: Hydroxylation Increases the Neurotoxic Potential of BDE-47 to Affect Exocytosis and Calcium Homeostasis in PC12 Cells.
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              Text: May2008
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              Y: 2008
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