title: Transcriptional and epigenetic mechanisms underlying enhanced in vitro adipocyte differentiation by the brominated flame retardant BDE-47.
abstract: Recent studies suggest that exposure to endocrine-disrupting compounds (EDCs) may play a role in the development of obesity. EDCs such as the flame retardant 2,2',4,4'-tetrabrominated diphenyl ether (BDE-47) have been shown to enhance adipocyte differentiation in the murine 3T3-L1 model. The mechanisms by which EDCs direct preadipocytes to form adipocytes are poorly understood. Here, we examined transcriptional and epigenetic mechanisms underlying the induction of in vitro adipocyte differentiation by BDE-47. Quantitative high content microscopy revealed concentration-dependent enhanced adipocyte differentiation following exposure to BDE-47 or the antidiabetic drug troglitazone (TROG). BDE-47 modestly activated the key adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) in COS7 cells, transiently transfected with a GAL4 reporter construct. Increased gene expression was observed for Pparγ2, leptin (Lep), and glucose-6-phophatase catalytic subunit (G6pc) in differentiated 3T3-L1 cells after BDE-47 exposure compared to TROG. Methylation-sensitive high resolution melting (MS-HRM) revealed significant demethylation of three CpG sites in the Pparγ2 promoter after exposure to both BDE-47 and TROG in differentiated 3T3-L1 cells. This study shows the potential of BDE-47 to induce adipocyte differentiation through various mechanisms that include Pparγ2 gene induction and promoter demethylation accompanied by activation of PPARγ, and possible disruption of glucose homeostasis and IGF1 signaling.
authors.affiliation: Institute for Environmental Studies, VU University Amsterdam , Amsterdam, 1081HV, The Netherlands.
authors.forename: Jorke H
authors.initials: JH
authors.lastname: Kamstra
authors.forename: Eva
authors.initials: E
authors.lastname: Hruba
authors.forename: Bruce
authors.initials: B
authors.lastname: Blumberg
authors.forename: Amanda
authors.initials: A
authors.lastname: Janesick
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandrup
authors.forename: Timo
authors.initials: T
authors.lastname: Hamers
authors.forename: Juliette
authors.initials: J
authors.lastname: Legler
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002522:Chlorocebus aethiops; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005411:Flame Retardants / Q000633:toxicity*; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D006801:Humans; D051379:Mice; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D047495:PPAR gamma; D012333:RNA, Messenger; D047490:Retinoid X Receptor alpha; C511295:2,2',4,4'-tetrabromodiphenyl ether