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Research Article Advance Publication

Environ Health Perspect; DOI:10.1289/ehp.1408111

Ligand Binding and Activation of PPARγ by Firemaster® 550: Effects on Adipogenesis and Osteogenesis in Vitro

Hari K. Pillai,1 Mingliang Fang,2 Dmitri Beglov,3 Dima Kozakov,3 Sandor Vajda,3 Heather M. Stapleton,2 Thomas F. Webster,1 and Jennifer J. Schlezinger1
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1Department of Environmental Health, Boston University, Boston, Massachusetts, USA; 2Nicholas School of the Environment, Duke University, Durham, North Carolina, USA; 3Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA
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This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. EHP Advance Publication articles are completely citable using the DOI number assigned to the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.

Citation: Pillai HK, Fang M, Beglov D, Kozakov D, Vajda S, Stapleton HM, Webster TF, Schlezinger JJ. Ligand Binding and Activation of PPARγ by Firemaster® 550: Effects on Adipogenesis and Osteogenesis in VitroEnviron Health Perspect; http://dx.doi.org/10.1289/ehp.1408111.

Received: 10 January 2014
Accepted: 24 July 2014
Advance Publication: 25 July 2014

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Abstract

Background: Alternative flame retardant use has increased since the phase out of pentabromodiphenyl ethers. One alternative, Firemaster® 550 (FM550), induces obesity in rats. Triphenyl phosphate (TPP), a component of FM550, has a structure similar to organotins, which are obesogenic in rodents.

Objectives: We tested the hypothesis that FM550 components 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 house dust concentrations determined in a previously published study and a screening-level indoor exposure model.

Results: FM550 bound human PPARγ and binding appeared to be driven primarily by TPP. Solvent mapping revealed that TPP interacts with binding hotspots 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 health effects of FM550.


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