Transcriptional and epigenetic mechanisms underlying enhanced in vitro adipocyte differentiation by the brominated flame retardant BDE-47.
Transcriptional and epigenetic mechanisms underlying enhanced in vitro adipocyte differentiation by the brominated flame retardant BDE-47.
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DOI：
10.1021/es405524b
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发表时间：
2014-04-01
影响因子：
11.4
通讯作者：
Legler, Juliette
中科院分区：
文献类型：
--
作者：
Kamstra, Jorke H.;Hruba, Eva;Blumberg, Bruce;Janesick, Amanda;Mandrup, Susanne;Hamers, Timo;Legler, Juliette
最近的研究表明，暴露于内分泌干扰化合物（EDCs）可能在肥胖的发展中发挥作用。在小鼠3 T3-L1模型中，内分泌干扰物（如阻燃剂2，2 ′，4，4 ′-四溴二苯醚（BDE-47））已被证明可增强脂肪细胞分化。内分泌干扰物引导前脂肪细胞形成脂肪细胞的机制知之甚少。在这里，我们研究了BDE-47诱导体外脂肪细胞分化的转录和表观遗传机制。定量高含量显微镜检查显示，接触BDE-47或抗糖尿病药物曲格列酮（TROG）后，脂肪细胞分化呈浓度依赖性增强。BDE-47适度激活了COS 7细胞中关键的脂肪形成转录因子过氧化物酶体增殖物激活受体γ（PPARγ），该细胞用GAL 4报告基因构建体瞬时转染。与TROG相比，BDE-47暴露后，在分化的3 T3-L1细胞中观察到Pparγ2、瘦素（Lep）和葡萄糖-6-磷酸酶催化亚基（G6 pc）的基因表达增加。甲基化敏感高分辨率熔解（MS-HRM）显示，在分化的3 T3-L1细胞中，暴露于BDE-47和TROG后，Pparγ2启动子中的三个CpG位点发生了显著的去甲基化。该研究显示，BDE-47有可能通过各种机制诱导脂肪细胞分化，包括Pparγ2基因诱导和启动子去甲基化，同时激活PPARγ，并可能破坏葡萄糖稳态和IGF 1信号传导。
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.
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影响因子：
8.8
作者：
Legler, Juliette
通讯作者：
Legler, Juliette
影响因子：
10.4
作者：
Athanasiadou M;Cuadra SN;Marsh G;Bergman A;Jakobsson K
通讯作者：
Jakobsson K
影响因子：
4.1
作者：
Saal, Frederick S. vom;Nagel, Susan C.;Coe, Benjamin L.;Angle, Brittany M.;Taylor, Julia A.
通讯作者：
Taylor, Julia A.
影响因子：
3.8
作者：
Alworth, LC;Howdeshell, KL;vom Saal, FS
通讯作者：
vom Saal, FS
DOI：
10.1073/pnas.0703739104
发表时间：
2007-08-07
影响因子：
11.1
作者：
Dolinoy, Dana C.;Huang, Dale;Jirtle, Randy L.
通讯作者：
Jirtle, Randy L.