Ligand binding and activation of PPARgamma by Firemaster(R) 550: effects on adipogenesis and osteogenesis in vitro.

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Pillai HK, Fang M, Beglov D, Kozakov D, Vajda S, Stapleton HM, Webster TF, Schlezinger JJ

Ligand binding and activation of PPARgamma by Firemaster(R) 550: effects on adipogenesis and osteogenesis in vitro.

Environ Health Perspect. 2014 Nov;122(11):1225-32. doi: 10.1289/ehp.1408111. Epub 2014 Jul 25.

PubMed ID

25062436 [ View in PubMed

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Abstract

BACKGROUND: The use of alternative flame retardants has increased since the phase out of pentabromodiphenyl ethers (pentaBDEs). One alternative, Firemaster(R) 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. OBJECTIVES: We tested the hypothesis that components of FM550 are biologically active peroxisome proliferator-activated receptor gamma (PPARgamma) ligands and estimated indoor exposure to TPP. METHODS: FM550 and its components were assessed for ligand binding to and activation of human PPARgamma. Solvent mapping was used to model TPP in the PPARgamma 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 PPARgamma, and binding appeared to be driven primarily by TPP. Solvent mapping revealed that TPP interacted with binding hot spots within the PPARgamma ligand binding domain. FM550 and its organophosphate components increased human PPARgamma1 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 PPARgamma. 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.