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- Title
Para- and Ortho-Substitutions Are Key Determinants of Polybrominated Diphenyl Ether Activity toward Ryanodine Receptors and Neurotoxicity.
- Authors
Kyung Ho Kim; Bose, Diptiman D.; Ghogha, Atefeh; Riehl, Joyce; Zhang, Rui; Barnhart, Christopher D.; Lein, Pamelaÿ J.; Pessah, Isaac N.
- 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.
- Publication
Environmental Health Perspectives, 2011, Vol 119, Issue 4, p519
- ISSN
0091-6765
- Publication type
Academic Journal
- DOI
10.1289/ehp.1002728