The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System
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 under...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-09-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/9/9/884 |
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| author | Dionysios V. Chartoumpekis Panos G. Ziros Ilias Georgakopoulos-Soares Adam A. T. Smith Ana Claudia Marques Mark Ibberson Peter A. Kopp Ioannis Habeos Ioannis P. Trougakos Nicholas K. H. Khoo Gerasimos P. Sykiotis |
| author_facet | Dionysios V. Chartoumpekis Panos G. Ziros Ilias Georgakopoulos-Soares Adam A. T. Smith Ana Claudia Marques Mark Ibberson Peter A. Kopp Ioannis Habeos Ioannis P. Trougakos Nicholas K. H. Khoo Gerasimos P. Sykiotis |
| author_sort | Dionysios V. Chartoumpekis |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T16:14:11Z |
| format | Article |
| id | doaj.art-0957870309ba435c83822ad18103be25 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T16:14:11Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-0957870309ba435c83822ad18103be252023-11-20T14:11:17ZengMDPI AGAntioxidants2076-39212020-09-019988410.3390/antiox9090884The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant SystemDionysios V. Chartoumpekis0Panos G. Ziros1Ilias Georgakopoulos-Soares2Adam A. T. Smith3Ana Claudia Marques4Mark Ibberson5Peter A. Kopp6Ioannis Habeos7Ioannis P. Trougakos8Nicholas K. H. Khoo9Gerasimos P. Sykiotis10Service of Endocrinology and Diabetology, Lausanne University Hospital, and Faculty of Biology and Medicine, University of Lausanne, 1011 Lausanne, SwitzerlandService of Endocrinology and Diabetology, Lausanne University Hospital, and Faculty of Biology and Medicine, University of Lausanne, 1011 Lausanne, SwitzerlandDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USADepartment of Computational Biology, University of Lausanne, 1015 Lausanne, SwitzerlandDepartment of Computational Biology, University of Lausanne, 1015 Lausanne, SwitzerlandVital-IT Group, Swiss Institute of Bioinformatics, 1015 Lausanne, SwitzerlandService of Endocrinology and Diabetology, Lausanne University Hospital, and Faculty of Biology and Medicine, University of Lausanne, 1011 Lausanne, SwitzerlandDivision of Endocrinology, Department of Internal Medicine, University of Patras, 26504 Patras, GreeceDepartment of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, 15784 Athens, GreeceDepartment of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USAService of Endocrinology and Diabetology, Lausanne University Hospital, and Faculty of Biology and Medicine, University of Lausanne, 1011 Lausanne, SwitzerlandBackground: 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.https://www.mdpi.com/2076-3921/9/9/884Kelch-like ECH-associated protein 1 (Keap1)Nfe2l2RNA-Seqiodineoxidative stressinflammation |
| spellingShingle | Dionysios V. Chartoumpekis Panos G. Ziros Ilias Georgakopoulos-Soares Adam A. T. Smith Ana Claudia Marques Mark Ibberson Peter A. Kopp Ioannis Habeos Ioannis P. Trougakos Nicholas K. H. Khoo Gerasimos P. Sykiotis The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System Antioxidants Kelch-like ECH-associated protein 1 (Keap1) Nfe2l2 RNA-Seq iodine oxidative stress inflammation |
| title | The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System |
| title_full | The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System |
| title_fullStr | The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System |
| title_full_unstemmed | The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System |
| title_short | The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System |
| title_sort | transcriptomic response of the murine thyroid gland to iodide overload and the role of the nrf2 antioxidant system |
| topic | Kelch-like ECH-associated protein 1 (Keap1) Nfe2l2 RNA-Seq iodine oxidative stress inflammation |
| url | https://www.mdpi.com/2076-3921/9/9/884 |
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