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Research Para- and Ortho-Substitutions Are Key Determinants of Polybrominated Diphenyl Ether Activity toward Ryanodine Receptors and Neurotoxicity

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


Bac k g r o u n d: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants that bioaccumulate in human tissues. Their neurotoxicity involves dysregulation of calcium ion (Ca 2+) signaling; however, specific mechanisms have yet to be defined. Obj e c t i v e: 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. Me t h o d s: 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. Re s u l t s: 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 culture

Year: 2011
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