Molecular mechanisms of human thyrocyte dysfunction induced by low concentrations of polychlorinated biphenyl 118 through the Akt/FoxO3a/NIS pathway
Molecular mechanisms of human thyrocyte dysfunction induced by low concentrations of polychlorinated biphenyl 118 through the Akt/FoxO3a/NIS pathway
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DOI：
10.1002/jat.3032
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发表时间：
2015-09-01
影响因子：
3.3
通讯作者：
Duan, Yu
中科院分区：
文献类型：
--
作者：
Guo, Hongwei;Yang, Hui;Duan, Yu
多氯联苯（PCBs）是一种典型的持久性有机污染物，对人体多个器官系统都有一定的干扰作用。长期暴露于低剂量PCB 118可严重损害甲状腺结构，显著降低血清甲状腺激素水平，抑制钠/碘同向转运体（NIS）和甲状腺球蛋白（Tg）等关键基因的表达。为探讨2，3，4，4，5-五氯联苯（PCB 118）诱导甲状腺细胞功能障碍的分子机制，以2，3，4，4，5-五氯联苯（PCB 118）和二甲基亚砜（DMSO）为对照，对单层培养的人甲状腺上皮细胞（HTECs）进行处理。我们的研究结果表明，相对较高浓度的PCB 118可以诱导HTEC的活力损失。在文化与PCB 118的浓度从0.025到25纳米，这并不影响细胞活力或凋亡，Tg和甲状腺素（T-4）的浓度显着降低与那些在控制。此外，Akt的mRNA和蛋白水平在PCB 118处理组中显著增加，而FoxO 3a的表达没有显示出特别的变化。此外，暴露于PCB 118与p-Akt和p-FoxO 3a蛋白水平的显着增加，这些影响被LY 294002阻断。与此相反，NIS的mRNA和蛋白表达水平显着降低，这种作用被LY 294002阻断。与对照细胞不同，在PCB 118处理组中观察到FoxO 3a的细胞质移位。我们的研究表明，PCB 118可能通过Akt/FoxO 3a/NIS信号通路诱导甲状腺细胞功能障碍，这为寻找对抗PCBs对人体损害的干预措施提供了潜在的新见解。版权所有（c）2015约翰威利父子有限公司
Polychlorinated biphenyls (PCBs) are typical persistent organic pollutants that can interfere with multiple organ systems of humans. Previously, we concluded that persistent exposure to low doses of PCB118 could severely damage the thyroidal structure, dramatically decrease the concentration of serum thyroid hormones and inhibit the pivotal gene expressions such as sodium/iodide symporter (NIS) and thyroglobulin (Tg). To explore the molecular mechanisms of thyrocyte dysfunction induced by 2,3,4,4,5-pentachlorobiphenyl (PCB118), monolayer cultured human thyroid epithelial cells (HTECs) were treated with PCB118 or dimethyl sulfoxide (DMSO) as a control. Our results indicated that relatively higher concentrations of PCB118 could induce a loss in the viability of HTEC. In cultures with concentrations of PCB118 from 0.025 to 25 nM, which did not affect cell viability or apoptosis, concentrations of Tg and thyroxine (T-4) were significantly decreased compared with those in the controls. In addition, mRNA and protein levels of Akt were increased significantly in the PCB118-treated groups, whereas FoxO3a expression did not show particular variation. Furthermore, exposure to PCB118 was associated with a significant increase of the protein levels of p-Akt and p-FoxO3a, and these effects were blocked by LY294002. In contrast, mRNA and protein expression levels of NIS were decreased significantly, and this effect was blocked by LY294002. Unlike control cells, a cytoplasmic shift of FoxO3a was observed in the PCB118-treated group. Our research suggests that PCB118 may induce thyrocyte dysfunction through the Akt/FoxO3a/NIS signalling pathway, which provides potential new insights for finding interventions to counteract the damage to the human body caused by PCBs. Copyright (c) 2015 John Wiley & Sons, Ltd.