Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China; Haidian Maternal&Child Health Hospital, Health Care Department for Women, Beijing 100080, China.
Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
Sci Total Environ. 2021 Apr 1;763:142936. doi: 10.1016/j.scitotenv.2020.142936. Epub 2020 Oct 14.
Decabromodiphenyl ether (BDE-209) is a persistent environmental pollutant that poses great risks to human health and has been associated with glucose and lipid metabolism. However, the mechanisms by which BDE-209 disturbs glycolipid metabolism in the liver remain unclear. Therefore, this study sought to confirm the effects of BDE-209 on glycolipid metabolism in mice livers and L02 cells to elucidate potential mechanisms of action. In vivo BDE-209 exposure caused histological damage and lipid accumulation, elevated glucose, low-density lipoprotein, total cholesterol, and triglyceride levels, and decreased glycogen and high-density lipoprotein levels in mice livers. Moreover, in vitro BDE-209 exposure not only induced L02 cells cytotoxicity (i.e., reduced cell viability and increased LDH leakage and ROS generation) but also increased glucose and triglyceride concentrations in L02 cells. Furthermore, IGF-1, an activator of the PI3K-AKT pathway, markedly inhibited BDE-209-induced glucose concentration increase in L02 cells and antagonized the inhibitory effect of BDE-209 on the PI3K/AKT/GLUT4 pathway by counteracting the changes in the expression levels of p-IRS, AKT, PI3K, p-AKT, and GLUT4. Moreover, GW9662, a PPARγ inhibitor, blocked lipid accumulation and the upregulation of the mTOR/PPARγ/RXRα pathway in L02 cells induced by BDE-209 by relieving the increases in p-mTOR, PPARγ, and RXRα protein expression levels. In summary, this study revealed that BDE-209 disrupted glycolipid metabolism by inhibiting the PI3K/AKT/GLUT4 pathway and activating the mTOR/PPARγ/RXRα pathway.
十溴二苯醚（BDE-209）是一种持久性的环境污染物，对人类健康构成巨大威胁，并与葡萄糖和脂质代谢有关。然而，BDE-209 干扰肝脏糖脂代谢的机制尚不清楚。因此，本研究旨在确认 BDE-209 对小鼠肝脏和 L02 细胞糖脂代谢的影响，以阐明其潜在的作用机制。体内 BDE-209 暴露导致小鼠肝脏组织损伤和脂质积累，血糖、低密度脂蛋白、总胆固醇和甘油三酯水平升高，肝糖原和高密度脂蛋白水平降低。此外，体外 BDE-209 暴露不仅诱导 L02 细胞毒性（即降低细胞活力、增加 LDH 漏出和 ROS 生成），还增加 L02 细胞中的葡萄糖和甘油三酯浓度。此外，IGF-1 是 PI3K-AKT 通路的激活剂，显著抑制 BDE-209 诱导的 L02 细胞葡萄糖浓度升高，并通过拮抗 BDE-209 对 PI3K/AKT/GLUT4 通路的抑制作用，抵消 p-IRS、AKT、PI3K、p-AKT 和 GLUT4 表达水平的变化，拮抗 BDE-209 对 PI3K-AKT/GLUT4 通路的抑制作用。此外，PPARγ 抑制剂 GW9662 通过减轻 p-mTOR、PPARγ 和 RXRα 蛋白表达水平的增加，阻断 BDE-209 诱导的 L02 细胞脂质积累和 mTOR/PPARγ/RXRα 通路的上调。综上所述，本研究表明 BDE-209 通过抑制 PI3K/AKT/GLUT4 通路和激活 mTOR/PPARγ/RXRα 通路破坏糖脂代谢。
