2,3′,4,4′,5-Pentachlorobiphenyl Induces Inflammatory Responses in the Thyroid Through JNK and Aryl Hydrocarbon Receptor-Mediated Pathway

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Abstract

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.

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