Ma Yue, Yang Jie, Wan Yanjian, Peng Yang, Ding Shuai, Li Yuanyuan, Xu Bing, Chen Xi, Xia Wei, Ke Yuebin, Xu Shunqing
Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Key Laboratory of Molecular Biology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
J Appl Toxicol. 2018 Mar;38(3):398-407. doi: 10.1002/jat.3549. Epub 2017 Nov 2.
Recent studies suggest that perfluorooctanoic acid (PFOA) can play a role in the development of obesity; however, the associated mechanisms are poorly understood. We investigated how PFOA exposure affected the differentiation of 3 T3-L1 preadipocytes and the associated transcriptional and epigenetic mechanisms. Cells treated with different doses of PFOA (ranging from 0.01 to 100 μg ml ) were assessed for proliferation, differentiation and triglyceride accumulation. The gene expression levels of peroxisome proliferator activated receptor gamma (PPARγ) and its target genes were measured. DNA methylation levels of PPARγ promoter and global DNA methylation levels were also tested. We found a concentration-dependent enhancement of adipocyte proliferation and differentiation following PFOA exposure. PFOA also induced a significant concentration-dependent increase in the accumulation of lipid and triglyceride. Increased gene expression was also observed for PPARγ, CCAAT/enhancer binding proteins α, fatty acid binding protein 2 and lipoprotein lipase in differentiated cells after PFOA exposure. The ability of PFOA to induce adipogenesis was blocked by GW9662, a known PPARγ antagonist. In addition, significant demethylation of the cytosine-phosphate-guanine sites in the PPARγ promoter was observed after exposure to PFOA. In addition, PFOA exposure resulted in decreased global DNA methylation and increased expression levels of DNA methyltransferases genes. We found that treatment with low levels of PFOA can induce adipogenic differentiation in preadipocytes, and the underlying mechanisms probably involve the activation of PPARγ transcription and demethylation of PPARγ promoter.
近期研究表明，全氟辛酸（PFOA）可能在肥胖症的发生发展中起作用；然而，相关机制尚不清楚。我们研究了PFOA暴露如何影响3T3-L1前脂肪细胞的分化以及相关的转录和表观遗传机制。对用不同剂量PFOA（范围为0.01至100μg/ml）处理的细胞进行增殖、分化和甘油三酯积累评估。检测过氧化物酶体增殖物激活受体γ（PPARγ）及其靶基因的基因表达水平。还检测了PPARγ启动子的DNA甲基化水平和整体DNA甲基化水平。我们发现PFOA暴露后脂肪细胞增殖和分化呈浓度依赖性增强。PFOA还诱导脂质和甘油三酯积累显著增加且呈浓度依赖性。PFOA暴露后，分化细胞中PPARγ、CCAAT/增强子结合蛋白α、脂肪酸结合蛋白2和脂蛋白脂肪酶的基因表达也增加。PFOA诱导脂肪生成的能力被已知的PPARγ拮抗剂GW9662阻断。此外，暴露于PFOA后，观察到PPARγ启动子中胞嘧啶-磷酸-鸟嘌呤位点显著去甲基化。此外，PFOA暴露导致整体DNA甲基化降低和DNA甲基转移酶基因表达水平增加。我们发现，低水平PFOA处理可诱导前脂肪细胞发生脂肪生成分化，其潜在机制可能涉及PPARγ转录激活和PPARγ启动子去甲基化。
