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

• Published in: Environmental health perspectives 2011-04, Vol.119 (4), p.519-526
• Main Authors: Kim, Kyung Ho, Bose, Diptiman D., Ghogha, Atefeh, Riehl, Joyce, Zhang, Rui, Barnhart, Christopher D., Lein, Pamela J., Pessah, Isaac N.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Calcium; Calcium - metabolism; Calcium Signaling - drug effects; Cell Line; Cellular; Congeners; Diagnosis; Environment. Living conditions; Environmental health; Environmental Pollutants - chemistry; Environmental Pollutants - metabolism; Environmental Pollutants - toxicity; Ethers; Fluxes; Halogenated diphenyl ethers; Halogenated Diphenyl Ethers - chemistry; Halogenated Diphenyl Ethers - metabolism; Halogenated Diphenyl Ethers - toxicity; Health aspects; Humans; Medical sciences; Metabolites; Modulators; Nervous System - drug effects; Nervous System - metabolism; Nervous system diseases; Neurons; Neurotoxicity; Physiological aspects; Polybrominated biphenyls; Polychlorinated biphenyls; Public health. Hygiene; Public health. Hygiene-occupational medicine; Rats; Rats, Sprague-Dawley; Receptors; Risk factors; Ryanodine Receptor Calcium Release Channel - metabolism; Structure-Activity Relationship; Synthetic aperture radar; Toxicology; Vehicles
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.1002728

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-btommt substituents and lacking at least one para-htomine substituent (e.g., BDE-49) activate RyR1 and RyR2 with greater efficacy than corresponding congeners with two para-hrommz 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.