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 language | English (US) |
|---|---|
| Pages (from-to) | 519-526 |
| Number of pages | 8 |
| Journal | Environmental Health Perspectives |
| Volume | 119 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2011 |
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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 journal › Article
}
TY - JOUR
T1 - Para- and ortho-substitutions are key determinants of polybrominated diphenyl ether activity toward ryanodine receptors and neurotoxicity
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
PY - 2011/4
Y1 - 2011/4
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.
KW - Calcium
KW - Hydroxylated PBDE
KW - Methoxylated PBDE
KW - Neurotoxicity
KW - Polybrominated biphenyl ether (PBDE)
KW - Ryanodine receptor (RyR)
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UR - http://www.scopus.com/inward/citedby.url?scp=79955560083&partnerID=8YFLogxK
U2 - 10.1289/ehp.1002728
DO - 10.1289/ehp.1002728
M3 - Article
C2 - 21106467
AN - SCOPUS:79955560083
VL - 119
SP - 519
EP - 526
JO - Environmental Health Perspectives
JF - Environmental Health Perspectives
SN - 0091-6765
IS - 4
ER -