Xu Bojin, Yang Hui, Sun Minne, Chen Huanhuan, Jiang Lin, Zheng Xuqin, Ding Guoxian, Liu Yun, Sheng Yunlu, Cui Dai, Duan Yu
*Department of Endocrinology and.
Department of Gerontology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Toxicol Sci. 2016 Feb;149(2):300-11. doi: 10.1093/toxsci/kfv235. Epub 2015 Oct 31.
Polychlorinated biphenyls (PCBs) are durable and widely distributed environmental contaminants that can compromise the normal functions of multiple organs and systems; one important mechanism is the induction of inflammatory disorders. In this study, we explored the influences of 2,3',4,4',5-pentachlorobiphenyl (PCB118) on inflammatory responses and its underlying mechanisms in the thyroid. Wistar rats were administered PCB118 intraperitoneally at 0, 10, 100, and 1000 μg/kg/d, 5 days a week for 13 weeks; rat thyroid FRTL-5 cells were treated with PCB118 (0, 0.25, 2.5, and 25 nM) for indicated time. Results revealed that PCB118 promoted the generation of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) in a time- and dose-related manner and decreased sodium/iodide symporter (NIS) protein expression. Moreover, stimulation with PCB118 resulted in the upregulation of the aryl hydrocarbon receptor (AhR)-responsive gene cytochrome P450 1A1 in FRTL-5 cells; whereas pretreatment with the AhR inhibitor α-naphthoflavone or AhR small interfering RNA (siRNA) suppressed AhR, CYP1A1, IL-6, and ICAM-1 and restored NIS expression. In vivo and in vitro studies also suggested that the c-Jun N-terminal kinase (JNK) pathway was activated on PCB118 exposure, and the experiments using siRNA for JNK partially blocked PCB118-induced upregulation of IL-6 and ICAM-1 and downregulation of NIS. Altogether, PCB118 stimulates production of IL-6, TNF-α, and ICAM-1 in the thyroid through AhR and JNK activations and subsequently interferes with NIS expression, resulting in the disruption of thyroid structure and function.
多氯联苯（PCBs）是持久性且广泛分布的环境污染物，可损害多个器官和系统的正常功能；一个重要机制是引发炎症紊乱。在本研究中，我们探究了2,3',4,4',5-五氯联苯（PCB118）对甲状腺炎症反应及其潜在机制的影响。将Wistar大鼠按0、10、100和1000μg/kg/d的剂量腹腔注射PCB118，每周5天，共13周；用PCB118（0、0.25、2.5和25 nM）处理大鼠甲状腺FRTL-5细胞指定时间。结果显示，PCB118以时间和剂量相关的方式促进白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和细胞间黏附分子-1（ICAM-1）的生成，并降低钠/碘同向转运体（NIS）蛋白表达。此外，PCB118刺激导致FRTL-5细胞中芳烃受体（AhR）反应性基因细胞色素P450 1A1上调；而用AhR抑制剂α-萘黄酮或AhR小干扰RNA（siRNA）预处理可抑制AhR、CYP1A1、IL-6和ICAM-1，并恢复NIS表达。体内和体外研究还表明，暴露于PCB118时c-Jun氨基末端激酶（JNK）途径被激活，使用JNK的siRNA进行的实验部分阻断了PCB118诱导的IL-6和ICAM-1上调以及NIS下调。总之，PCB118通过激活AhR和JNK刺激甲状腺中IL-6、TNF-α和ICAM-1的产生，随后干扰NIS表达从而导致甲状腺结构和功能破坏。
