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The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System

Chartoumpekis, Dionysios V. and Ziros, Panos G. and Georgakopoulos-Soares, Ilias and Smith, Adam A. T. and Marques, Ana Claudia and Ibberson, Mark and A. Kopp, Peter and Habeos, Ioannis and Trougakos, Ioannis P. and Khoo, Nicholas K. H. and Sykiotis, Gerasimos P. (2020) The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System. Antioxidants, 9 (9). p. 884. ISSN 2076-3921

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Background: Thyroid follicular cells have physiologically high levels of reactive oxygen species because oxidation of iodide is essential for the iodination of thyroglobulin (Tg) during thyroid hormone synthesis. Thyroid follicles (the functional units of the thyroid) also utilize incompletely understood autoregulatory mechanisms to defend against exposure to excess iodide. To date, no transcriptomic studies have investigated these phenomena in vivo. Nuclear erythroid factor 2 like 2 (Nrf2 or Nfe2l2) is a transcription factor that regulates the expression of numerous antioxidant and other cytoprotective genes. We showed previously that the Nrf2 pathway regulates the antioxidant defense of follicular cells, as well as <i>Tg</i> transcription and Tg iodination. We, thus, hypothesized that Nrf2 might be involved in the transcriptional response to iodide overload. Methods: C57BL6/J wild-type (WT) or Nrf2 knockout (KO) male mice were administered regular water or water supplemented with 0.05% sodium iodide for seven days. RNA from their thyroids was prepared for next-generation RNA sequencing (RNA-Seq). Gene expression changes were assessed and pathway analyses were performed on the sets of differentially expressed genes. Results: Analysis of differentially expressed messenger RNAs (mRNAs) indicated that iodide overload upregulates inflammatory-, immune-, fibrosis- and oxidative stress-related pathways, including the Nrf2 pathway. Nrf2 KO mice showed a more pronounced inflammatory–autoimmune transcriptional response to iodide than WT mice. Compared to previously published datasets, the response patterns observed in WT mice had strong similarities with the patterns typical of Graves’ disease and papillary thyroid carcinoma (PTC). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) also responded to iodide overload, with the latter targeting mRNAs that participate mainly in inflammation pathways. Conclusions: Iodide overload induces the Nrf2 cytoprotective response and upregulates inflammatory, immune, and fibrosis pathways similar to autoimmune hyperthyroidism (Graves’ disease) and PTC.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Chartoumpekis, Dionysios V.
Ziros, Panos G.
Georgakopoulos-Soares, Ilias
Smith, Adam A. T.
Marques, Ana Claudia
Ibberson, Mark
A. Kopp, Peter
Habeos, Ioannis
Trougakos, Ioannis P.
Khoo, Nicholas K. H.nkhoo@pitt.edunkhoo
Sykiotis, Gerasimos P.
Date: 18 September 2020
Date Type: Publication
Journal or Publication Title: Antioxidants
Volume: 9
Number: 9
Publisher: MDPI AG
Page Range: p. 884
DOI or Unique Handle: 10.3390/antiox9090884
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
Uncontrolled Keywords: Kelch-like ECH-associated protein 1 (Keap1), Nfe2l2, RNA-Seq, iodine, oxidative stress, inflammation
ISSN: 2076-3921
Official URL:
Funders: Swiss National Science Foundation, Leenaards Foundation, European Cooperation in Science and Technology, Section/Board of Endocrinology of the European Union of Medical Specialists, Exchange in Endocrinology Expertise
Article Type: Research Article
Date Deposited: 19 May 2021 18:07
Last Modified: 19 May 2021 18:07


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