Endocrine Abstracts

Introduction: Nrf2 (Nfe2l2) is a transcription factor that regulates a series of cytoprotective and antioxidant enzymes. Upon exposure to oxidative or electrophilic stress, Nrf2 enters the nucleus and induces its target genes expression. Follicular thyroid cells have physiologically high levels of reactive oxygen species as oxidation of iodine is essential for iodination of thyroglobulin and thyroid hormones synthesis. We have shown previously that Nrf2 pathway is active in thyroid and regulates the transcription of thyroglobulin.

Hypothesis: We thus hypothesized that the response of thyroid to iodine excess should comprise Nrf2-dependent and independent pathways.

Methods: To this end, 3 months-old male C57Bl6J wild-type (WT) or Nrf2 knockout (Nrf2KO) mice were exposed to 0.05% sodium iodide in their water for 7 days. Thyroids were used for RNA extraction; RNA-seq was performed by Exiqon, with a fold-change cutoff set at 2. Representative genes of the enriched pathways were quantified by qPCR to validate RNA-seq results. Pathway analysis of the differentially expressed genes was performed using the Ingenuity Pathway Analysis (IPA) software. Pathways that were enriched with a p-value <0.05 were considered significant.

Results: 828 genes were differentially expressed in response to iodine exposure; 66% were upregulated, as were most of the highly enriched pathways (related to inflammatory-immune response, antioxidant response, xenobiotic metabolism, platelet activation and calcium signaling). About 300 genes were differentially expressed between WT and Nrf2KO mice; highly enriched pathways were related to glutathione and xenobiotic metabolism, Ahr signaling and Nrf2 signaling and were all downregulated in Nrf2KO mice. Analysis of the potential upstream regulators of these highly enriched pathways revealed that Nrf2 and NfkB are main regulators of the antioxidant and inflammatory response induction upon iodine exposure and that fibrosis signaling is downstream to Tgfβ-Smad cascade. Last, we performed an analysis limited to already known thyroid pathways. A few genes were enriched following this method. Specifically, Duoxa1 (hydrogen peroxide generator) and Nis (sodium iodide symporter) were upregulated upon iodine exposure, which are expected responses. Thyroglobulin was decreased and Duoxa1 was increased in Nrf2KO mice confirming our previous findings.

Conclusions: In conclusion, Nrf2-driven cytoprotective response and inflammatory pathways are upregulated after iodine overload. Nrf2 regulates transcriptomic responses in the thyroid, including a small but significant part of the response to iodine challenge. Hence, Nrf2 can be considered a novel player bridging thyroid antioxidant response and thyroid economy.