title: Characterizing the peroxisome proliferator-activated receptor (PPARγ) ligand binding potential of several major flame retardants, their metabolites, and chemical mixtures in house dust.
abstract: BACKGROUND
  Accumulating evidence has shown that some environmental contaminants can alter adipogenesis and act as obesogens. Many of these contaminants act via the activation of the peroxisome proliferator-activated receptor γ (PPARγ) nuclear receptor.
  
  
  OBJECTIVE
  Our goal was to determine the PPARγ ligand binding potency of several major flame retardants, including polybrominated diphenyl ethers (PBDEs), halogenated phenols and bisphenols, and their metabolites. Ligand binding activity of indoor dust and its bioactivated extracts were also investigated.
  
  
  METHODS
  We used a commercially available fluorescence polarization ligand binding assay to investigate the binding potency of flame retardants and dust extracts to human PPARγ ligand-binding domain. Rosiglitazone was used as a positive control.
  
  
  RESULTS
  Most of the tested compounds exhibited dose-dependent binding to PPARγ. Mono(2-ethylhexyl) tetrabromophthalate, halogenated bisphenols and phenols, and hydroxylated PBDEs were found to be potent PPARγ ligands. The most potent compound was 3-OH-BDE-47, with an IC50 (concentration required to reduce effect by 50%) of 0.24 μM. The extent of halogenation and the position of the hydroxyl group strongly affected binding. In the dust samples, 21 of the 24 samples tested showed significant binding potency at a concentration of 3 mg dust equivalent (DEQ)/mL. A 3-16% increase in PPARγ binding potency was observed following bioactivation of the dust using rat hepatic S9 fractions.
  
  
  CONCLUSIONS
  Our results suggest that several flame retardants are potential PPARγ ligands and that metabolism may lead to increased binding affinity. The PPARγ binding activity of house dust extracts at levels comparable to human exposure warrants further studies into agonistic or antagonistic activities and their potential health effects.
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, North Carolina, USA.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Fang
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Webster
authors.forename: P Lee
authors.initials: PL
authors.lastname: Ferguson
authors.forename: Heather M
authors.initials: HM
authors.lastname: Stapleton
mesh_terms: D000818:Animals; D001681:Biological Assay; D004391:Dust / Q000032:analysis*; D005411:Flame Retardants / Q000032:analysis* / Q000633:toxicity; D055768:Halogenated Diphenyl Ethers / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000378:metabolism / Q000633:toxicity*; D008024:Ligands; D008099:Liver / Q000201:enzymology; D008956:Models, Chemical; D047495:PPAR gamma / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats
chemical_list: D004391:Dust; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D006846:Hydrocarbons, Halogenated; D008024:Ligands; D047495:PPAR gamma