| Autor: |
González-Guerrero C; Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital Research Institute (IdiPAZ), Autonomous University of Madrid, Madrid, Spain., Borsò M; Department of Pathology, Laboratory of Biochemistry, University of Pisa, Pisa, Italy., Alikhani P; Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital Research Institute (IdiPAZ), Autonomous University of Madrid, Madrid, Spain., Alcaina Y; Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital Research Institute (IdiPAZ), Autonomous University of Madrid, Madrid, Spain.; Cell Engineering Laboratory, La Paz Hospital Research Institute, Madrid, Spain., Salas-Lucia F; Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital Research Institute (IdiPAZ), Autonomous University of Madrid, Madrid, Spain.; Department of Medicine, The University of Chicago, Chicago, Illinois, USA., Liao XH; Department of Medicine, The University of Chicago, Chicago, Illinois, USA., García-Giménez J; Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital Research Institute (IdiPAZ), Autonomous University of Madrid, Madrid, Spain., Bertolini A; Department of Pathology, Laboratory of Biochemistry, University of Pisa, Pisa, Italy., Martin D; Cell Engineering Laboratory, La Paz Hospital Research Institute, Madrid, Spain., Moratilla A; Cell Engineering Laboratory, La Paz Hospital Research Institute, Madrid, Spain., Mora R; Department of Analytical Chemistry, La Paz University Hospital, Madrid, Spain., Buño-Soto A; Department of Analytical Chemistry, La Paz University Hospital, Madrid, Spain., Mani AR; Division of Medicine, University College London, London, United Kingdom., Bernal J; Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain., Saba A; Department of Pathology, Laboratory of Biochemistry, University of Pisa, Pisa, Italy., de Miguel MP; Cell Engineering Laboratory, La Paz Hospital Research Institute, Madrid, Spain., Refetoff S; Department of Medicine, The University of Chicago, Chicago, Illinois, USA.; Department of Pediatrics and Committee on Genetics, The University of Chicago, Chicago, Illinois, USA., Zucchi R; Department of Pathology, Laboratory of Biochemistry, University of Pisa, Pisa, Italy., Moreno JC; Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital Research Institute (IdiPAZ), Autonomous University of Madrid, Madrid, Spain.; Rare Diseases Networking Biomedical Research Centre (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. |
| Abstrakt: |
Background: Iodine is required for the synthesis of thyroid hormone (TH), but its natural availability is limited. Dehalogenase1 (Dehal1) recycles iodine from mono- and diiodotyrosines (MIT, DIT) to sustain TH synthesis when iodine supplies are scarce, but its role in the dynamics of storage and conservation of iodine is unknown. Methods: Dehal1 -knockout ( Dehal1 KO) mice were generated by gene trapping. The timing of expression and distribution was investigated by X-Gal staining and immunofluorescence using recombinant Dehal1-beta-galactosidase protein produced in fetuses and adult mice. Adult Dehal1 KO and wild-type ( Wt ) animals were fed normal and iodine-deficient diets for 1 month, and plasma, urine, and tissues were isolated for analyses. TH status was monitored, including thyroxine, triiodothyronine, MIT, DIT, and urinary iodine concentration (UIC) using a novel liquid chromatography with tandem mass spectrometry method and the Sandell-Kolthoff (S-K) technique throughout the experimental period. Results: Dehal1 is highly expressed in the thyroid and is also present in the kidneys, liver, and, unexpectedly, the choroid plexus. In vivo transcription of Dehal1 was induced by iodine deficiency only in the thyroid tissue. Under normal iodine intake, Dehal1 KO mice were euthyroid, but they showed negative iodine balance due to a continuous loss of iodotyrosines in the urine. Counterintuitively, the UIC of Dehal1 KO mice is twofold higher than that of Wt mice, indicating that S-K measures both inorganic and organic iodine. Under iodine restriction, Dehal1 KO mice rapidly develop profound hypothyroidism, while Wt mice remain euthyroid, suggesting reduced retention of iodine in the thyroids of Dehal1 KO mice. Urinary and plasma iodotyrosines were continually elevated throughout the life cycles of Dehal1 KO mice, including the neonatal period, when pups were still euthyroid. Conclusions: Plasma and urine iodotyrosine elevation occurs in Dehal1-deficient mice throughout life. Therefore, measurement of iodotyrosines predicts an eventual iodine shortage and development of hypothyroidism in the preclinical phase. The prompt establishment of hypothyroidism upon the start of iodine restriction suggests that Dehal1 KO mice have low iodine reserves in their thyroid glands, pointing to defective capacity for iodine storage. |
