<br>全氟辛酸通过甲状腺细胞中的 TSH-TSHR 信号通路破坏甲状腺特异性基因的表达和调节,Environmental Research

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全氟辛酸通过甲状腺细胞中的 TSH-TSHR 信号通路破坏甲状腺特异性基因的表达和调节
Environmental Research ( IF 7.7 ) Pub Date : 2023-10-11 , DOI: 10.1016/j.envres.2023.117372
Yatao Du ₁ , Chaojie Chen ₂ , Guangdi Zhou ₁ , Zhenzhen Cai ₃ , Qiuhong Man ₄ , Baolin Liu ₅ , Weiye Charles Wang ₁

Affiliation

全氟辛酸（PFOA）是一种在环境中具有高度持久性和广泛分布的化学物质，具有内分泌干扰作用。尽管据报道 PFOA 可以影响甲状腺功能的多个方面，但它降低甲状腺素水平的确切机制尚未阐明。本研究以 FRTL-5 大鼠甲状腺滤泡细胞为模型，研究 PFOA 对甲状腺激素合成相关基因及其调控网络的毒性。我们的结果表明，PFOA 干扰促甲状腺激素（TSH）诱导的环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）的磷酸化，以及配对盒 8 （PAX8）、甲状腺转录因子 1 （TTF1）、钠/碘协同转运蛋白（NIS）、甲状腺球蛋白（TG）和甲状腺过氧化物酶（TPO）的转录水平。然而，上述结果可以通过用毛喉素治疗增强 cAMP 的产生来缓解。进一步的研究表明，PFOA 降低了 TSH 受体（TSHR）的 mRNA 水平并损害了其 N-糖基化，这表明 PFOA 对转录调控和翻译后调控都有破坏作用。此外，PFOA 增加了 FRTL-5 细胞的内质网（ER）应激并降低了 ER 质量。基于这些发现，可以推断 PFOA 通过抑制 TSHR 表达及其 N-糖基化来破坏 TSH 激活的 cAMP 信号通路。我们认为这种机制可能导致 PFOA 引起的甲状腺激素水平降低。我们的研究阐明了 PFOA 破坏甲状腺功能的分子机制，并为抵消 PFOA 破坏性影响的干预措施提供了新的见解和潜在目标。

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Perfluorooctanoic acid disrupts thyroid-specific genes expression and regulation via the TSH-TSHR signaling pathway in thyroid cells

Perfluorooctanoic acid (PFOA) is a highly persistent and widespread chemical in the environment with endocrine disruption effects. Although it has been reported that PFOA can affect multiple aspects of thyroid function, the exact mechanism by which it reduces thyroxine levels has not yet been elucidated. In this study, FRTL-5 rat thyroid follicular cells were used as a model to study the toxicity of PFOA to the genes related to thyroid hormone synthesis and their regulatory network. Our results reveal that PFOA interfered with the phosphorylation of the cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) induced by thyroid-stimulating hormone (TSH), as well as the transcription levels of paired box 8 (PAX8), thyroid transcription factor 1 (TTF1), sodium/iodide cotransporter (NIS), thyroglobulin (TG), and thyroid peroxidase (TPO). However, the above outcomes can be alleviated by enhancing cAMP production with forskolin treatment. Further investigations showed that PFOA reduced the mRNA level of TSH receptor (TSHR) and impaired its N-glycosylation, suggesting that PFOA has disrupting effects on both transcriptional regulation and post-translational regulation. In addition, PFOA increased endoplasmic reticulum (ER) stress and decreased ER mass in FRTL-5 cells. Based on these findings, it can be inferred that PFOA disrupts the TSH-activated cAMP signaling pathway by inhibiting TSHR expression and its N-glycosylation. We propose that this mechanism may contribute to the decrease in thyroid hormone levels caused by PFOA. Our study sheds light on the molecular mechanism by which PFOA can disrupt thyroid function and provides new insights and potential targets for interventions to counteract the disruptive effects of PFOA.

更新日期：2023-10-11

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