Transcriptomic profiling of the response to excess iodide in Keap1 hypomorphic mice reveals new gene-environment interactions in thyroid homeostasis

• Published in: Redox biology 2024-02, Vol.69, p.102978, Article 102978
• Main Authors: Ziros, Panos G., Chartoumpekis, Dionysios V., Georgakopoulos-Soares, Ilias, Psarias, Georgios, Sykiotis, Gerasimos P.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidant; Antioxidants - metabolism; Gene Expression Profiling; Gene-Environment Interaction; Goiter; Homeostasis; Humans; Iodides - metabolism; Iodine; Kelch-Like ECH-Associated Protein 1 - genetics; Kelch-Like ECH-Associated Protein 1 - metabolism; Mice; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative Stress; Proliferation; Thyroid; Thyroid Gland - metabolism
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2023.102978

Iodide plays a pivotal role in thyroid homeostasis due to its crucial involvement in thyroid hormone biosynthesis. Exposure to pharmacological doses of iodide elicits in the thyroid an autoregulatory response to preserve thyroid function, as well as an antioxidant response that is mediated by the Keap1/Nrf2 signaling pathway. The objective of the present study was to investigate the transcriptional response of the thyroid to excess iodide in a background of enhanced Nrf2 signaling. Keap1 knockdown (Keap1KD) mice that have activated Nrf2 signaling were exposed or not to excess iodide in their drinking water for seven days and compared to respective wild-type mice. RNA-sequencing of individual mouse thyroids identified distinct transcriptomic patterns in response to iodide, with Keap1KD mice showing an attenuated inflammatory response, altered thyroidal autoregulation, and enhanced cell growth/proliferative signaling, as confirmed also by Western blotting for key proteins involved in antioxidant, autoregulatory and proliferative responses. These findings underscore novel gene-environment interactions between the activation status of the Keap1/Nrf2 antioxidant response system and the dietary iodide intake, which may have implications not only for the goiter phenotype of Keap1KD mice but also for humans harboring genetic variations in KEAP1 or NFE2L2 or treated with Nrf2-modulating drugs. [Display omitted] •Genetic activation of antioxidant signaling alters the thyroidal response to iodide overload.•Mice with genetically activated Nrf2 showed an attenuated iodide-induced inflammatory response.•They also showed altered thyroidal autoregulation and enhanced growth/proliferative signaling.