Para- and ortho-substitutions are key determinants of polybrominated diphenyl ether activity toward ryanodine receptors and neurotoxicity

Kyung Ho Kim, Diptiman D. Bose, Atefeh Ghogha, Joyce Riehl, Rui Zhang, Christopher D. Barnhart, Pamela J Lein, Isaac N Pessah

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Background: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants that bioaccumulate in human tissues. Their neurotoxicity involves dysregulation of calcium ion (Ca2+) signaling; however, specific mechanisms have yet to be defined. Objective: We aimed to define the structure-activity relationship (SAR) for PBDEs and their metabolites toward ryanodine receptors type 1 (RyR1) and type 2 (RyR2) and to determine whether it predicts neurotoxicity. Methods: We analyzed [3H]ryanodine binding, microsomal Ca2+ fluxes, cellular measurements of Ca2+ homeostasis, and neurotoxicity to define mechanisms and specificity of PBDE-mediated Ca2+ dysregulation. Results: PBDEs possessing two ortho-bromine substituents and lacking at least one para-bromine substituent (e.g., BDE-49) activate RyR1 and RyR2 with greater efficacy than corresponding congeners with two para-bromine substitutions (e.g., BDE-47). Addition of a methoxy group in the free para position reduces the activity of parent PBDEs. The hydroxylated BDEs 6-OH-BDE-47 and 4 ́-OH-BDE-49 are biphasic RyR modulators. Pretreatment of HEK293 cells (derived from human embryonic kidney cells) expressing either RyR1 or RyR2 with BDE-49 (250 nM) sensitized Ca2+ flux triggered by RyR agonists, whereas BDE-47 (250 nM) had negligible activity. The divergent activity of BDE-49, BDE-47, and 6-OH-BDE-47 toward RyRs predicted neurotoxicity in cultures of cortical neurons. Conclusions: We found that PBDEs are potent modulators of RyR1 and RyR2. A stringent SAR at the ortho and para position determined whether a congener enhanced, inhibited, or exerted nonmonotonic actions toward RyRs. These results identify a convergent molecular target of PBDEs previously identified for noncoplanar polychlorinated biphenyls (PCBs) that predicts their cellular neurotoxicity and therefore could be a useful tool in risk assessment of PBDEs and related compounds.

Original languageEnglish (US)
Pages (from-to)519-526
Number of pages8
JournalEnvironmental Health Perspectives
Volume119
Issue number4
DOIs
StatePublished - Apr 2011

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Halogenated Diphenyl Ethers
Ryanodine Receptor Calcium Release Channel
Bromine
Structure-Activity Relationship
Flame Retardants
Ryanodine
HEK293 Cells
Polychlorinated Biphenyls
Homeostasis
Ions
Calcium
Kidney
Neurons
2,2',4,4'-tetrabromodiphenyl ether
2,2',4,5'-tetrabromodiphenyl ether

Keywords

  • Calcium
  • Hydroxylated PBDE
  • Methoxylated PBDE
  • Neurotoxicity
  • Polybrominated biphenyl ether (PBDE)
  • Ryanodine receptor (RyR)

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Public Health, Environmental and Occupational Health

Cite this

Para- and ortho-substitutions are key determinants of polybrominated diphenyl ether activity toward ryanodine receptors and neurotoxicity. / Kim, Kyung Ho; Bose, Diptiman D.; Ghogha, Atefeh; Riehl, Joyce; Zhang, Rui; Barnhart, Christopher D.; Lein, Pamela J; Pessah, Isaac N.

In: Environmental Health Perspectives, Vol. 119, No. 4, 04.2011, p. 519-526.

Research output: Contribution to journalArticle

Kim, Kyung Ho ; Bose, Diptiman D. ; Ghogha, Atefeh ; Riehl, Joyce ; Zhang, Rui ; Barnhart, Christopher D. ; Lein, Pamela J ; Pessah, Isaac N. / Para- and ortho-substitutions are key determinants of polybrominated diphenyl ether activity toward ryanodine receptors and neurotoxicity. In: Environmental Health Perspectives. 2011 ; Vol. 119, No. 4. pp. 519-526.
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AU - Kim, Kyung Ho

AU - Bose, Diptiman D.

AU - Ghogha, Atefeh

AU - Riehl, Joyce

AU - Zhang, Rui

AU - Barnhart, Christopher D.

AU - Lein, Pamela J

AU - Pessah, Isaac N

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N2 - Background: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants that bioaccumulate in human tissues. Their neurotoxicity involves dysregulation of calcium ion (Ca2+) signaling; however, specific mechanisms have yet to be defined. Objective: We aimed to define the structure-activity relationship (SAR) for PBDEs and their metabolites toward ryanodine receptors type 1 (RyR1) and type 2 (RyR2) and to determine whether it predicts neurotoxicity. Methods: We analyzed [3H]ryanodine binding, microsomal Ca2+ fluxes, cellular measurements of Ca2+ homeostasis, and neurotoxicity to define mechanisms and specificity of PBDE-mediated Ca2+ dysregulation. Results: PBDEs possessing two ortho-bromine substituents and lacking at least one para-bromine substituent (e.g., BDE-49) activate RyR1 and RyR2 with greater efficacy than corresponding congeners with two para-bromine substitutions (e.g., BDE-47). Addition of a methoxy group in the free para position reduces the activity of parent PBDEs. The hydroxylated BDEs 6-OH-BDE-47 and 4 ́-OH-BDE-49 are biphasic RyR modulators. Pretreatment of HEK293 cells (derived from human embryonic kidney cells) expressing either RyR1 or RyR2 with BDE-49 (250 nM) sensitized Ca2+ flux triggered by RyR agonists, whereas BDE-47 (250 nM) had negligible activity. The divergent activity of BDE-49, BDE-47, and 6-OH-BDE-47 toward RyRs predicted neurotoxicity in cultures of cortical neurons. Conclusions: We found that PBDEs are potent modulators of RyR1 and RyR2. A stringent SAR at the ortho and para position determined whether a congener enhanced, inhibited, or exerted nonmonotonic actions toward RyRs. These results identify a convergent molecular target of PBDEs previously identified for noncoplanar polychlorinated biphenyls (PCBs) that predicts their cellular neurotoxicity and therefore could be a useful tool in risk assessment of PBDEs and related compounds.

AB - Background: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants that bioaccumulate in human tissues. Their neurotoxicity involves dysregulation of calcium ion (Ca2+) signaling; however, specific mechanisms have yet to be defined. Objective: We aimed to define the structure-activity relationship (SAR) for PBDEs and their metabolites toward ryanodine receptors type 1 (RyR1) and type 2 (RyR2) and to determine whether it predicts neurotoxicity. Methods: We analyzed [3H]ryanodine binding, microsomal Ca2+ fluxes, cellular measurements of Ca2+ homeostasis, and neurotoxicity to define mechanisms and specificity of PBDE-mediated Ca2+ dysregulation. Results: PBDEs possessing two ortho-bromine substituents and lacking at least one para-bromine substituent (e.g., BDE-49) activate RyR1 and RyR2 with greater efficacy than corresponding congeners with two para-bromine substitutions (e.g., BDE-47). Addition of a methoxy group in the free para position reduces the activity of parent PBDEs. The hydroxylated BDEs 6-OH-BDE-47 and 4 ́-OH-BDE-49 are biphasic RyR modulators. Pretreatment of HEK293 cells (derived from human embryonic kidney cells) expressing either RyR1 or RyR2 with BDE-49 (250 nM) sensitized Ca2+ flux triggered by RyR agonists, whereas BDE-47 (250 nM) had negligible activity. The divergent activity of BDE-49, BDE-47, and 6-OH-BDE-47 toward RyRs predicted neurotoxicity in cultures of cortical neurons. Conclusions: We found that PBDEs are potent modulators of RyR1 and RyR2. A stringent SAR at the ortho and para position determined whether a congener enhanced, inhibited, or exerted nonmonotonic actions toward RyRs. These results identify a convergent molecular target of PBDEs previously identified for noncoplanar polychlorinated biphenyls (PCBs) that predicts their cellular neurotoxicity and therefore could be a useful tool in risk assessment of PBDEs and related compounds.

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KW - Hydroxylated PBDE

KW - Methoxylated PBDE

KW - Neurotoxicity

KW - Polybrominated biphenyl ether (PBDE)

KW - Ryanodine receptor (RyR)

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