title: Ligand binding and activation of PPARγ by Firemaster® 550: effects on adipogenesis and osteogenesis in vitro.
abstract: BACKGROUND
  The use of alternative flame retardants has increased since the phase out of pentabromodiphenyl ethers (pentaBDEs). One alternative, Firemaster® 550 (FM550), induces obesity in rats. Triphenyl phosphate (TPP), a component of FM550, has a structure similar to that of organotins, which are obesogenic in rodents.
  
  
  OBJECTIVE
  We tested the hypothesis that components of FM550 are biologically active peroxisome proliferator-activated receptor γ (PPARγ) ligands and estimated indoor exposure to TPP.
  
  
  METHODS
  FM550 and its components were assessed for ligand binding to and activation of human PPARγ. Solvent mapping was used to model TPP in the PPARγ binding site. Adipocyte and osteoblast differentiation were assessed in bone marrow multipotent mesenchymal stromal cell models. We estimated exposure of children to TPP using a screening-level indoor exposure model and house dust concentrations determined previously.
  
  
  RESULTS
  FM550 bound human PPARγ, and binding appeared to be driven primarily by TPP. Solvent mapping revealed that TPP interacted with binding hot spots within the PPARγ ligand binding domain. FM550 and its organophosphate components increased human PPARγ1 transcriptional activity in a Cos7 reporter assay and induced lipid accumulation and perilipin protein expression in BMS2 cells. FM550 and TPP diverted osteogenic differentiation toward adipogenesis in primary mouse bone marrow cultures. Our estimates suggest that dust ingestion is the major route of exposure of children to TPP.
  
  
  CONCLUSIONS
  Our findings suggest that FM550 components bind and activate PPARγ. In addition, in vitro exposure initiated adipocyte differentiation and antagonized osteogenesis. TPP likely is a major contributor to these biological actions. Given that TPP is ubiquitous in house dust, further studies are warranted to investigate the health effects of FM550.
authors: Department of Environmental Health, Boston University, Boston, Massachusetts, USA.
authors: Hari K
authors: HK
authors: Pillai
authors: Mingliang
authors: M
authors: Fang
authors: Dmitri
authors: D
authors: Beglov
authors: Dima
authors: D
authors: Kozakov
authors: Sandor
authors: S
authors: Vajda
authors: Heather M
authors: HM
authors: Stapleton
authors: Thomas F
authors: TF
authors: Webster
authors: Jennifer J
authors: JJ
authors: Schlezinger
mesh_terms: D017667:Adipocytes; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002648:Child; D004391:Dust / Q000032:analysis; D004781:Environmental Exposure / Q000032:analysis; D005411:Flame Retardants / Q000633:toxicity*; D006801:Humans; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017154:Stromal Cells / Q000187:drug effects*
chemical_list: D004391:Dust; D005411:Flame Retardants; D047495:PPAR gamma