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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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

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

Published In Environ Health Perspect, (2011 Apr)

Abstract: 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.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.We analyzed [3H]ryanodine binding, microsomal Ca(2+) fluxes, cellular measurements of Ca(2+) homeostasis, and neurotoxicity to define mechanisms and specificity of PBDE-mediated Ca(2+) dysregulation.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.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.

PubMed ID: 21106467 Exiting the NIEHS site

MeSH Terms: Animals; Calcium Signaling/drug effects; Calcium/metabolism; Cell Line; Environmental Pollutants/chemistry; Environmental Pollutants/metabolism; Environmental Pollutants/toxicity*; Halogenated Diphenyl Ethers/chemistry; Halogenated Diphenyl Ethers/metabolism; Halogenated Diphenyl Ethers/toxicity*; Humans; Nervous System/drug effects*; Nervous System/metabolism; Rats; Rats, Sprague-Dawley; Ryanodine Receptor Calcium Release Channel/metabolism*; Structure-Activity Relationship

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