Abstract
Polychlorinated biphenyls (PCBs) can severely interfere with multiple animals and human systems. To explore the molecular mechanisms underlying 2, 3′, 4, 4′, 5- pentachlorobiphenyl (PCB118)-induced thyroid dysfunction, Fischer rat thyroid cell line-5(FRTL-5) cells were treated with either different concentrations of PCB118 or dimethyl sulfoxide (DMSO). The effects of PCB118 on FRTL-5 cells viability and apoptosis were assessed by using a Cell Counting Kit-8 assay and apoptosis assays, respectively. Quantitative real-time polymerase chain reaction was used to quantify protein kinase B (Akt), Forkhead box protein O3a (FoxO3a), and sodium/iodide symporter (NIS) mRNA expression levels. Western blotting was used to detect Akt, phospho-Akt (p-Akt), FoxO3a, phospho-FoxO3a (p-FoxO3a), and NIS protein levels. Luciferase reporter gene technology was used to detect the transcriptional activities of FoxO3a and NIS promoters. The effects of the constitutively active Akt (CA-Akt) and dominant-negative Akt (DN-Akt) plasmids on p-Akt, p-FoxO3a, and NIS levels were examined in PCB118-treated FRTL-5 cells. The effects of FoxO3a siRNA on FoxO3a, p-FoxO3a, and NIS protein levels were examined in the PCB118-treated FRTL-5 cells. The effects of pcDNA3 (plsmid vectors designed for high-level stable and transient expression in mammalian host)-FoxO3a on NIS promoter activity were examined in the PCB118-treated FRTL-5 cells. Our results indicated that relatively higher PCB118 concentrations can inhibit cell viability in a concentration- and time-dependent manner. Akt, p-Akt, and p-FoxO3a protein or mRNA levels increased significantly in PCB118-treated groups and NIS protein and mRNA levels decreased considerably compared with the control groups. FoxO3a promoter activity increased significantly, whereas NIS promoter activity decreased. These effects on p-FoxO3a and NIS could be decreased by the DN-Akt plasmid, enhanced by the CA-Akt plasmid, and blocked by FoxO3a siRNA. The overexpressed FoxO3a could reduce NIS promoter activity. Our results suggested that PCB118 induces thyroid cell dysfunction through the Akt/FoxO3a/NIS signaling pathway.
Highlights
Polychlorinated biphenyls (PCBs) are a type of typical environmental endocrine disruptors present in persistent organic pollutants
Within 24 h, no evident difference in cell viability was observed between polychlorinated biphenyl 118 (PCB118) (0.025–25000 nM)-treated groups and the dimethyl sulfoxide (DMSO) control group (p > 0.05), and no significant difference was observed between each PCB118-treated group (p > 0.05)
We found that the p-Forkhead box protein O3a (FoxO3a) protein expression level increased (Fig. 4A, B) and FoxO3a promoter activity was enhanced after PCB118 treatment (Fig. 4D)
Summary
Polychlorinated biphenyls (PCBs) are a type of typical environmental endocrine disruptors present in persistent organic pollutants. Because of their stable chemical properties and perfect insulativity, they were widely used in many industries as flame retardants, transformers, capacitors, lubricants, and plasticizers until their production was banned in 1979. Owing to their lipophilic and biological persistence, significant concentrations of PCBs still exist in the environment. Our early findings suggested that low concentrations of 2,30,4,40,5-pentachlorobiphenyl or continuous exposure in animal models to polychlorinated biphenyl 118 (PCB118) induced abnormal thyroid morphology, dramatically decreasing the expression of thyroidal sodium/iodide symporter [NIS or solute carrier family 5, member 5 (SLC5A5)] at the transcriptional level [6]; the underlying mechanism was unknown [7,8,9]
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