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Iodine deficiency leads to differential thyroid-specific gene expression and tissue microstructure in dehal1 knockout mice

AuthorsGarcía Giménez, Jorge; González-Guerrero, Cristian; Salas-Lucia, Federico; Pulido, Elisa; Grijota Martínez, María del Carmen; Guadaño-Ferraz, Ana CSIC ORCID ; Miguel, Maria De; Moreno, José C.
Issue Date7-Sep-2019
Citation42nd Annual Meeting of the ETA (2019)
Abstract[Introduction]: Thyroid hormone (TH) synthesis is influenced by the intracellular iodide content in the thyrocytes, which regulates key steps such as the iodination and coupling of the thyroglobulins´s tyrosines. DEHAL1 is an enzyme that recycles iodide in the thyrocytes. However, the effect of a DEHAL1 deletion on the thyroid´s regulatory mechanisms against iodine deficiency has not yet been described. We studied in the effects of iodine restriction in Dehal1 knockout (Dehal1(-/-)) and wildtype (WT) mice on thyroid-specific gene expression and thyroid microstructural changes.
[Methods]: Dehal1(-/-) and WT mice underwent normal (NID), low (LID) and very low iodine diets (VLID) containing 5.6, 1 and 0.25 µg I/day, respectively, for 90 days. T4 concentration was determined by radioimmunoassay. Urinary iodide concentration (UIC) was monitored by Sandell-Kolthoff reaction. qPCR gene expression in genes involved in iodide and TH transport (Slc5A5, Slc16A2, Slc26A4) and; hormonosynthesis (Tshr, Tg, Tpo, Duox2, Duoxa2) or transcription (Pax8, Nkx 2-1, Foxe1, Glis3) at 0, 15 and 28 days. Morphometric studies were performed at d90.
[Results]: At basal conditions (NID, d0), both WT and Dehal1(-/-) mice are euthyroid (T4: 58.5 ng/ml vs 59.9 ng/ml; p>0.05), however Dehal(-/-) mice loses significantly more iodide in the urine (12.12 µg/L vs 35.50 µg/L; p<0.05). This difference is sustained in time and progressive iodine deficiency (LID, VLID). Dehal1 expression was undetectable in Dehal1(-/-) mice but increased 2.3-fold (p < 0.05) in WT mice under VLID at d28. In WT mice, average thyroid-specific gene expression was maximally upregulated (5-fold) at LID conditions, but it suffers downregulation under VLID (2-fold). In contrast, in KO mice, maximal gene overexpression occurs at VLID conditions (10-fold) suggesting the loss of a transcriptional counter-regulatory mechanism in Dehal1(-/-) mice under severe iodine restriction. Notably, Slc5a5 and Tpo show the most prominent upregulation (40-fold and 16-fold, respectively). Regarding transcription factors, Pax8, Nkx2.1 and Foxe1 are maximally expressed at LID but selfdownregulate at VLID in WT. However, Glis3 persists upregulated at VLID conditiins, escaping from such auto-regulatory mechanism. Morphometrically, LID induced a 3-fold increase in the thyroid area in both genotypes. However, only in Dehal1(-/-) average thyrocyte height was higher (p<0.001) and the follicular lumen smaller (p<0.001) compared to WT.
[Conclusions]: Dehal1(-/-) mice present a basal thyroid specific gene overexpression, even under euthyroid and iodine sufficiency conditions. Such overexpression increases along with the severity of iodine restriction, and escapes a transcriptional down-regulation probably involving a Glis3-related pathway. The specific overexpression pattern of Dehal1(-/-) mice is consistent with the large size of thyrocytes, translating an intrincic metabolically hyperactive thyroid gland.
DescriptionTrabajo presentado en el 42nd Annual Meeting of the European Thyroid Association, celebrado en Budapest (Hungría) del 7 al 10 de septiembre de 2019.
Appears in Collections:(IIBM) Comunicaciones congresos

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