2. Academic Validation
  3. Perfluorooctanoic acid disrupts thyroid-specific genes expression and regulation via the TSH-TSHR signaling pathway in thyroid cells

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

  • Environ Res. 2023 Oct 11;239(Pt 1):117372. 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 6
Affiliations

Affiliations

  • 1 Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200292, China.
  • 2 Institute of Biothermal Science and Technology, University of Shanghai for Science and Technology, Shanghai, 200093, China; The Base of Achievement Transformation, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, 200438, China.
  • 3 Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200292, China; Department of Clinical Laboratory, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China.
  • 4 Department of Clinical Laboratory, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China. Electronic address: manqiuhong307@163.com.
  • 5 Institute of Biothermal Science and Technology, University of Shanghai for Science and Technology, Shanghai, 200093, China; Shanghai Co-innovation Center for Energy Therapy of Tumors, Shanghai, 200093, China. Electronic address: blliuk@163.com.
  • 6 Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200292, China. Electronic address: wangweiye@xinhuamed.com.cn.
PMID: 37827365 DOI: 10.1016/j.envres.2023.117372
Abstract

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.

Keywords

ER stress; Glycosylation; Hypothyroidism; Perfluorooctanoic acid; TSH receptor.

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