Organophosphorus Flame Retardants Impair Intracellular Lipid Metabolic Function in Human Hepatocellular Cells
Organophosphorus Flame Retardants Impair Intracellular Lipid Metabolic Function in Human Hepatocellular Cells
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DOI：
10.1021/acs.chemrestox.9b00058
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发表时间：
2019-06-01
影响因子：
4.1
通讯作者：
Wang, Cui
中科院分区：
文献类型：
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作者：
Hao, Zhengliang;Zhang, Zhijie;Wang, Cui
有机磷阻燃剂（OPFRs）作为溴系阻燃剂的替代品，作为内分泌干扰物（EDCs）已逐渐被人们所接受。最近，有证据表明，这些内分泌干扰物可能导致慢性健康问题，如肥胖，并被称为代谢干扰物。然而，OPFRs引起的脂质代谢紊乱仍然知之甚少，特别是在生物分子水平上。在此，我们使用人肝细胞（HepG 2），以研究所造成的9个OPFR（卤代，芳基，烷基）的脂质代谢中断。除长碳链烷基OPFR外，所有受试OPFR均可引起细胞内甘油三酯（TG）和/或总胆固醇（TC）蓄积。详细地说，芳基OPFR（TPhP和TCP）诱导TC和TG沉积。卤代OPFR（TCEP、TBPP、TDCPP和TCPP）诱导细胞内TG蓄积，只有TDCPP也诱导TC蓄积。此外，TPhP诱导脂质积累，通过调节基因编码的蛋白质参与脂肪酸β-氧化，脂质和脂肪酸合成。所有卤代OPFR仅通过β-氧化而非脂质合成引起TG蓄积。TPhP和TDCPP通过PPARgamma和srebp 2信号通路诱导TC蓄积。线粒体功能障碍，包括降低的耗氧率和ATP含量也可能导致脂质代谢的破坏测试OPFR。我们的数据表明，卤代和芳基OPFR可能不是安全的候选人，并应提供进一步的信息作为潜在的，以及代谢中断的机制。长碳链烷基OPFR可能比其他两组更安全。
Organophosphorus flame retardants (OPFRs), a replacement for brominated flame retardants, have gradually been accepted as endocrine disrupting chemicals (EDCs). Recently, evidence has shown that these EDCs could cause chronic health problems, such as obesity, and referred to as metabolic disruptors. However, the disturbance to lipid metabolism caused by OPFRs remains poorly understood, especially at biological molecular levels. Herein, we used the human hepatocellular cells (HepG2) to study the lipid metabolism disruption caused by nine OPFRs (halogenated-, aryl-, and alkyl-containing). All the tested OPFRs, excluding the long carbon chain alkyl-OPFRs, could cause intracellular triglyceride (TG) and/or total cholesterol (TC) accumulation. In detail, aryl-OPFRs (TPhP and TCP) induced both TC and TG deposition. Halogenated-OPFRs (TCEP, TBPP, TDCPP, and TCPP) induced intracellular TG accumulation, and only TDCPP also induced TC accumulation. Furthermore, TPhP induced lipid accumulation through regulation genes encoding proteins involved in fatty acid beta-oxidation, lipid, and fatty acid synthesis. All the halogenated-OPFRs cause TG accumulation only, enacted through beta-oxidation rather than lipid synthesis. TPhP and TDCPP induced TC accumulation through both PPAR gamma and srebp2 signaling. Mitochondrial dysfunction including decreased oxygen consumption rate and ATP content may also contribute to lipid metabolic disruption by the tested OPFRs. Our data indicated that halogenated-and aryl-OPFRs may not be safe candidates, and further information should be made available as potential for, as well as the mechanism of, metabolic disruption. And long carbon chain alkyl-OPFRs may be safer than the other two groups.