title: Para- and ortho-substitutions are key determinants of polybrominated diphenyl ether activity toward ryanodine receptors and neurotoxicity.
abstract: BACKGROUND
  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.
  
  
  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 Ca(2+) fluxes, cellular measurements of Ca(2+) homeostasis, and neurotoxicity to define mechanisms and specificity of PBDE-mediated Ca(2+) 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.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, California 95616, USA. npessah@ucdavis.edu
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Kim
authors.forename: Diptiman D
authors.initials: DD
authors.lastname: Bose
authors.forename: Atefeh
authors.initials: A
authors.lastname: Ghogha
authors.forename: Joyce
authors.initials: J
authors.lastname: Riehl
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Barnhart
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Lein
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D004785:Environmental Pollutants / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D055768:Halogenated Diphenyl Ethers / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D009420:Nervous System / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D004785:Environmental Pollutants; D055768:Halogenated Diphenyl Ethers; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium