Transcriptional and Epigenetic Mechanisms Underlying Enhanced in Vitro Adipocyte Differentiation by the Brominated Flame Retardant BDE-47

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• 作者：Jorke H. Kamstra ; Eva Hruba ; Bruce Blumberg ; Amanda Janesick ; Susanne Mandrup ; Timo Hamers ; Juliette Legler
• 刊名：Environmental Science & Technology
• 出版年：2014
• 出版时间：April 1, 2014
• 年：2014
• 卷：48
• 期：7
• 页码：4110-4119
• 全文大小：554K
• 年卷期：v.48,no.7(April 1, 2014)
• ISSN：1520-5851

文摘

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鈥?4,4鈥?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 (PPAR纬) in COS7 cells, transiently transfected with a GAL4 reporter construct. Increased gene expression was observed for Ppar纬2, 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 Ppar纬2 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 Ppar纬2 gene induction and promoter demethylation accompanied by activation of PPAR纬, and possible disruption of glucose homeostasis and IGF1 signaling.