Iodotyrosines Are Biomarkers for Preclinical Stages of Iodine-Deficient Hypothyroidism in Dehal1 -Knockout Mice.

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. -knockout (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 KO and wild-type () 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. Dehal1 is highly expressed in the thyroid and is also present in the kidneys, liver, and, unexpectedly, the choroid plexus. transcription of was induced by iodine deficiency only in the thyroid tissue. Under normal iodine intake, KO mice were euthyroid, but they showed negative iodine balance due to a continuous loss of iodotyrosines in the urine. Counterintuitively, the UIC of KO mice is twofold higher than that of mice, indicating that S-K measures both inorganic and organic iodine. Under iodine restriction, KO mice rapidly develop profound hypothyroidism, while mice remain euthyroid, suggesting reduced retention of iodine in the thyroids of KO mice. Urinary and plasma iodotyrosines were continually elevated throughout the life cycles of KO mice, including the neonatal period, when pups were still euthyroid. 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 KO mice have low iodine reserves in their thyroid glands, pointing to defective capacity for iodine storage.