Mechanism of multi-organ compensation under different iodine intake in pregnant rats: results from a repeated-measures study of iodine metabolism.

PURPOSE: This study aimed to explore the differences in iodine metabolism and expression of NIS and Pendrin in pregnant rats under different iodine nutritional status. METHODS: Female Wistar rats were divided into four groups: low iodine (LI), normal iodine (NI), ten fold high iodine (10HI), and fifty fold high iodine (50HI). The intervention began after one week of adaptive feeding. Iodine metabolism experiments were performed beginning on the 15th day of pregnancy. 24-h iodine intake and excretion were calculated. The concentrations of iodine in urine, fecal, thyroid, and placenta were measured by ICP-MS. PCR and Western Blot were used to detect the mRNA levels and cell membrane protein of sodium/iodide symporter (NIS) and Pendrin in the small intestine, thyroid, kidney, and placenta. RESULTS: Fecal iodine excretion (FIE) and urinary iodine excretion (UIE) in the 50HI group were significantly higher than those in the NI group (P < 0.05). The NIS protein and mRNA in the kidney and small intestine have an upward trend in iodine deficiency and a downward trend in iodine excess. Thyroid and placental iodine storage in the 50HI group were significantly higher than those in the NI group (P < 0.05). NIS, Pendrin protein, and mRNA in the thyroid and placenta tend to increase when iodine is deficient and decrease when there is excess. CONCLUSION: Iodine excretion and iodine stores in the placenta and thyroid gland are positively correlated with iodine intake. NIS and Pendrin are also regulated by iodine intake.

The master role of polarized NIS expression in regulating iodine metabolism in the human body.

Objective: The aim of this study was to investigate how polarized sodium iodide symporter (NIS) expression may regulate iodide metabolism in vivo. Materials and methods: Polarized NIS expression was analyzed in tissues that accumulate iodide by the use of immunohistochemistry and polyclonal antibody against the C-terminal end of human NIS (hNIS). Results: Iodide absorption in the human intestine occurs via NIS expressed in the apical membrane. Iodide is secreted into the lumen of the stomach and salivary glands via NIS expressed in the basolateral membrane and then circulates back from the small intestine to the bloodstream via NIS expressed in the apical membrane. Conclusion: Polarized NIS expression in the human body regulates intestinal-bloodstream recirculation of iodide, perhaps prolonging the availability of iodide in the bloodstream. This leads to more efficient iodide trapping by the thyroid gland. Understanding the regulation and manipulating gastrointestinal iodide recirculation could increase radioiodine availability during theranostic NIS applications.

HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression.

Background: The management of aggressive and progressive metastatic papillary thyroid cancer (PTC) is very difficult. An inverse relationship between radioiodine and F-18 fluorodeoxyglucose (FDG) uptake (''flip-flop'' phenomenon) is described for invasive PTC during dedifferentiation. However, no satisfactory biologic explanation for this phenomenon. Hypoxia is an important microenvironmental factor that promotes cancer progression and glycolysis. The Hippo-YAP is a highly conserved tumor suppressor pathway and contributes to cancer metabolic reprogramming. Thus, we investigated the underlying molecular mechanisms of glucose/iodine metabolic reprogramming in PTC, focusing on the tumor hypoxia microenvironment and Hippo-YAP signaling. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of hypoxia-inducible factor 1α (HIF-1α), yes-associated protein (YAP), glucose transporters 1 (GLUT1) and sodium iodine symporter (NIS) in matched PTC and the adjacent noncancerous tissues. PTC cell lines were cultured under normoxic (20% O2) and hypoxic (1% O2) conditions and the glycolysis level and NIS expression were measured. Further, we characterized the molecular mechanism of glucose/iodine metabolic reprogramming in PTC cell. Finally, we validated the results in vivo by establishing subcutaneous xenografts in nude mice. Results: The expression levels of HIF1-α, YAP and GLUT1 were upregulated in PTC tissues and YAP expression was positively associated with HIF-1α, GLUT1 and TNM stages. Meanwhile, the expression of NIS was negatively correlated with YAP. Further, in vitro studies indicated that hypoxia-induced YAP activation was critical for accelerating glycolysis and reducing NIS expression in PTC cells. Inhibition of YAP had the opposite effects in vitro and tumorigenicity in vivo. Hypoxia inhibited the Hippo signaling pathway resulting in the inactivation of YAP phosphorylation, further promoting the nuclear localization of YAP in PTC cells. The mechanism is that hypoxic stress promoted YAP binding to HIF-1α in the nucleus and maintained HIF-1α protein stability. The YAP/HIF-1α complex bound and directly activated the GLUT1 transcription to accelerate glycolysis. Meanwhile, HIF-1α/YAP signaling might indirectly reduce the expression of NIS by promoting the output of MAPK signaling. In vivo studies confirmed the YAP-mediated reprogramming of glucose/iodine metabolism promoted PTC progression. Conclusions: Collectively, our data revealed a novel regulatory mechanism of the glucose/iodine metabolic program rewritten by HIF-1α/YAP signaling in PTC. Inhibition of HIF-1α/YAP signaling alone or in combination with other potential markers may effectively combat aggressive PTC.

The master role of polarized NIS expression in regulating iodine metabolism in the human body

ABSTRACT Objective: The aim of this study was to investigate how polarized sodium iodide symporter (NIS) expression may regulate iodide metabolism in vivo. Materials and methods: Polarized NIS expression was analyzed in tissues that accumulate iodide by the use of immunohistochemistry and polyclonal antibody against the C-terminal end of human NIS (hNIS). Results: Iodide absorption in the human intestine occurs via NIS expressed in the apical membrane. Iodide is secreted into the lumen of the stomach and salivary glands via NIS expressed in the basolateral membrane and then circulates back from the small intestine to the bloodstream via NIS expressed in the apical membrane. Conclusion: Polarized NIS expression in the human body regulates intestinal-bloodstream recirculation of iodide, perhaps prolonging the availability of iodide in the bloodstream. This leads to more efficient iodide trapping by the thyroid gland. Understanding the regulation and manipulating gastrointestinal iodide recirculation could increase radioiodine availability during theranostic NIS applications.

Characteristics and predictors of breast milk iodine in exclusively breastfed infants: Results from a repeated-measures study of iodine metabolism.

Background: The iodine supply of exclusively breastfed infants entirely depends upon breast milk. Changes in breast milk iodine affect infants' iodine nutritional status. This study aimed to comprehensively assess the characteristics and predictors of breast milk iodine concentration (BMIC). Materials and methods: This 7-day iodine metabolism experiment was conducted in 25 exclusively breastfed mother-infant pairs. The duplicate portion method was used to measure the mother's daily iodine intake from foods and water, and maternal 24-h urine excretion was assessed. We recorded the number of breastfeeds per mother per day and collected breast milk samples before and after each feeding. Results: The median [quartile (Q)1-Q3 range] of BMIC was 115 (86.7, 172) µg/L. The BMIC before breastfeeding was generally higher than that after breastfeeding. Time-sequential analysis found that morning BMIC was most highly correlated with the prior day's iodine intake. Breast milk samples taken in the afternoon or after midnight are closer to the median level of BMIC throughout the day. The number of breast milk samples needed to estimate the iodine level with 95% CI within precision ranges of ± 20% was 83 for a population, 9 for an individual, and 2 for an individual's single day. Maternal total iodine intake (TII) and urine iodine were significantly associated with BMIC. 24-h urinary iodine excretion (24-h UIE) was found to be the best predictive indicator for the BMIC (ß = 0.71, 95% CI: 0.64, 0.79). Conclusion: BMIC is a constantly changing indicator and trended downward during each breastfeeding. Breast milk samples taken in the afternoon or after midnight are most representative. BMIC was significantly associated with recent iodine intake. Maternal 24-h UIE was the best predictor of BMIC.

Studies on urinary excretion and variability of dietary iodine in healthy Japanese adults.

The daily consumption of iodine in Japan is higher than in most countries, and there are few reports on iodine metabolism and variance of habitual iodine ingestion in an iodine-sufficient area. To elucidate the patterns of short-term urinary iodine excretion (UIE) and long-term variability of habitual iodine intake, the urinary iodine excretion process after a high dietary iodine load of 3 mg was observed in eight Japanese adults under strict supervision with complete urine collections for three days. In addition, estimated UIE and dietary iodine intake (DII) were assessed in 24 university students using repeated spot urine samples of ten consecutive days and a food frequency questionnaire in each of the four seasons. Approximately 50, 75 and 90% of orally ingested iodine was excreted into the urine at 8, 13 and 22 hours after ingestion, respectively. Almost an equal amount of ingested iodine in meals was cleared within 33.5 h after eating with a maximum excretion rate at 3-4 h. There was a high fluctuation in the UIE and DII in the university students. The intra- and inter-individual crude coefficients of variation were 123 or 294.7% for UIE, and 58.3 or 88.7% for DII, respectively, indicating a higher variance of habitual iodine intake than in other countries. The frequency of occurrence for UIE above 3 mg was every 43 days. Rapid renal clearance of iodine and high variability as well as low frequency of dietary iodine intake might prevent people from being exposed to an excess iodine intake over the long term in Japan.

Validation of Immunohistochemistry for Canine Proteins Involved in Thyroid Iodine Uptake and Their Expression in Canine Follicular Cell Thyroid Carcinomas (FTCs) and FTC-Derived Organoids.

Thyrotropin receptor (TSHR), sodium iodide symporter (NIS), pendrin, and thyroid peroxidase (TPO) are essential for the uptake of iodine by follicular thyroid cells. The aim of this study was to establish immunohistochemistry (IHC) protocols for TSHR, NIS, pendrin, and TPO in canine tissues and characterize their expression in organoids derived from canine follicular cell thyroid carcinoma (FTC) and in the respective primary tumors. This constitutes a fundamental step to establish organoids as a model to study the uptake of iodine in canine FTC. Commercially available antibodies directed against human proteins were selected. Antibody specificity was confirmed by western blot using lysates of the HTori-3 human thyroid cell line and healthy canine thyroid gland. IHC was validated using HTori-3 cells and a set of canine normal tissues including healthy thyroid gland. The expression of TSHR, NIS, pendrin, and TPO was evaluated in 3 organoid lines derived from FTC and respective primary tumors. All 4 antibodies produced specific bands by western blot and cytoplasmic labeling in follicular cells by IHC in both human HTori-3 cells and canine thyroid gland. NIS also showed basolateral membrane immunolabeling in follicular cells. All 4 proteins were highly expressed in organoids derived from FTC. The expression was similar or higher compared to the primary tumors. The results of this study characterize organoids derived from canine FTC as a suitable in vitro model to investigate iodine uptake, opening new research possibilities in the field of canine thyroid cancer therapy.

Complete response to larotrectinib treatment in a patient with papillary thyroid cancer harboring an ETV6-NTRK3 gene fusion.

Larotrectinib, a highly selective TRK inhibitor, was administered to a patient with rapidly progressing radioactive iodine-refractory papillary NTRK3 fusion-positive thyroid cancer. The patient achieved a durable (sustained for 11 months) complete response after 2 months of treatment and complete intracranial responses in metastatic brain lesions after 7 months of treatment. Larotrectinib may provide a therapeutic route for patients with RAI-R-differentiated thyroid cancer who might otherwise have few treatment options.

Effects of high potassium iodate intake on iodine metabolism and antioxidant capacity in rats.

BACKGROUND: KIO3 and KI are the most common salt iodization agents. Coincidentally, iodine exists naturally in high-iodine drinking water in the form of iodide (I-) or iodate (IO3-). As an oxidizing substance, IO3- should be reduced to I- before it can be effectively used by the thyroid. However, there is a lack of systematic studies on the metabolic process of high dose KIO3in vivo. METHODS: The iodine metabolism processes in the thyroid and serum of rats after high KIO3 intake were determined using high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC/ICP-MS) and arsenic cerium catalytic spectrophotometry. The changes of redox activity in the serum, thyroid, liver, and kidneys were observed by detecting total antioxidative activity (TAA). RESULTS: High doses of IO3- were completely reduced to I-in vivo within 0.5 h. The level of organic bound iodine in the serum was stable, while the organic bound iodine in the thyroid increased to a plateau after intake of high-dose KIO3. The levels of total iodine and I- in serum and thyroid increased quickly, then all decreased after reaching the maximum absorption peak, and I- had two absorption peaks in serum. The thyroid blocking dose of I- was 0.5 mg/kg in rat. Additionally, high KIO3 intake did not influence the TAA in serum and other tissues. CONCLUSION: The body is able to reduce and utilize high doses of KIO3 ingested through the digestive tract. The metabolism of high KIO3in vivo is characterized by two absorption process of I- in serum and the thyroid blocking effect. Moreover, a single intake of high-dose KIO3 does not affect TAA in vivo. The results suggest that such excess IO3- may have be reduced in the digestive tract before I- enters the blood.

Diets supplemented with Saccharina latissima influence the expression of genes related to lipid metabolism and oxidative stress modulating rainbow trout (Oncorhynchus mykiss) fillet composition.

This study aimed to evaluate the impact of diets including increasing amounts (1, 2 and 4%) of an iodine-rich macroalgae, Saccharina latissima, on gene expression and fillet composition of commercial-sized rainbow trout. Liver and muscle expression of genes related to growth, iodine, oxidative stress, and lipid metabolism, and the fillet content of fatty acids, cholesterol, and vitamin D3 were assessed. The highest kelp inclusion led to lower final body weight and HSI, without significant differences in mRNA transcription of genes involved in growth (ghr1, ghr2 and igf1) or iodine metabolism (dio1, thra, and thrb). A significant downregulation of an oxidative stress marker, gpx1b2, was observed in fish fed 2% S. latissima, which might suggest the need for less endogenous antioxidants. Dietary inclusion of kelp impacted lipid metabolism, with a downregulation of fatty acid synthase, accompanied by a general decrease of fatty acids in fillet. The present study demonstrated that supplementation of diets with 1 or 2% S. latissima can be achieved without detrimental effects on rainbow trout final weight. Evidence suggest a lipid-lowering effect of diets that did not compromise fillet EPA and DHA concentrations, being 3.7 times above the recommended levels for human consumption.

Iodine biofortification through expression of HMT, SAMT and S3H genes in Solanum lycopersicum L.

The uptake process and physiological reaction of plants to aromatic iodine compounds have not yet been documented. The aim of this research was to compare uptake by tomato plants of KI and KIO3, as well as of organic iodine compounds - 5-ISA (5-iodosalicylic acid), 3,5-diISA (3,5-diiodosalicylic acid), 2-IBeA (2-iodobenzoic acid), 4-IBeA (4-iodobenzoic acid) and 2,3,5-triIBeA (2,3,5-triiodobenzoic acid). Only 2,3,5-triIBeA had a negative influence on plant development. All organic iodine compounds were taken up by roots and transported to leaves and fruits. Among all the compounds applied, the most efficiently transferred iodine was 2-IBeA - to fruits, and 4-IBeA - to leaves. The order of iodine accumulation in fruit cell compartments was as follows: organelles > cell walls > soluble portions of cells; for leaf and root cells, it was: organelles > cell walls or soluble portions, depending on the compound applied. The compounds studied influence iodine metabolism through expression of the HMT gene which encodes halide ion methyltransferase in leaves and roots. Also, their influence on modification of the activity of the SAMT and S3H genes that encode salicylic acid carboxyl methyltransferase and salicylic acid 3-hydroxylase was established. It was discovered that exogenously applied 5-ISA, 3,5-diISA, 2-IBeA and 4-IBeA are genuinely (endogenously) synthesised in tomato plants; to date, this has not been described for the tomato, nor for any other species of higher plant.

Ocean acidification increases iodine accumulation in kelp-based coastal food webs.

Kelp are main iodine accumulators in the ocean, and their growth and photosynthesis are likely to benefit from elevated seawater CO2 levels due to ocean acidification. However, there are currently no data on the effects of ocean acidification on iodine metabolism in kelp. As key primary producers in coastal ecosystems worldwide, any change in their iodine metabolism caused by climate change will potentially have important consequences for global geochemical cycles of iodine, including iodine levels of coastal food webs that underpin the nutrition of billions of humans around the world. Here, we found that elevated pCO2 enhanced growth and increased iodine accumulation not only in the model kelp Saccharina japonica using both short-term laboratory experiment and long-term in situ mesocosms, but also in several other edible and ecologically significant seaweeds using long-term in situ mesocosms. Transcriptomic and proteomic analysis of S. japonica revealed that most vanadium-dependent haloperoxidase genes involved in iodine efflux during oxidative stress are down-regulated under increasing pCO2 , suggesting that ocean acidification alleviates oxidative stress in kelp, which might contribute to their enhanced growth. When consumed by abalone (Haliotis discus), elevated iodine concentrations in S. japonica caused increased iodine accumulation in abalone, accompanied by reduced synthesis of thyroid hormones. Thus, our results suggest that kelp will benefit from ocean acidification by a reduction in environmental stress however; iodine levels, in kelp-based coastal food webs will increase, with potential impacts on biogeochemical cycles of iodine in coastal ecosystems.

Role of iodide metabolism in physiology and cancer.

Iodide (I-) metabolism is crucial for the synthesis of thyroid hormones (THs) in the thyroid and the subsequent action of these hormones in the organism. I- is principally transported by the sodium iodide symporter (NIS) and by the anion exchanger PENDRIN, and recent studies have demonstrated the direct participation of new transporters including anoctamin 1 (ANO1), cystic fibrosis transmembrane conductance regulator (CFTR) and sodium multivitamin transporter (SMVT). Several of these transporters have been found expressed in various tissues, implicating them in I- recycling. New research supports the exciting idea that I- participates as a protective antioxidant and can be oxidized to hypoiodite, a potent oxidant involved in the host defense against microorganisms. This was possibly the original role of I- in biological systems, before the appearance of TH in evolution. I- per se participates in its own regulation, and new evidence indicates that it may be antineoplastic, anti-proliferative and cytotoxic in human cancer. Alterations in the expression of I- transporters are associated with tumor development in a cancer-type-dependent manner and, accordingly, NIS, CFTR and ANO1 have been proposed as tumor markers. Radioactive iodide has been the mainstay adjuvant treatment for thyroid cancer for the last seven decades by virtue of its active transport by NIS. The rapid advancement of techniques that detect radioisotopes, in particular I-, has made NIS a preferred target-specific theranostic agent.

MicroRNAs in thyroid development, function and tumorigenesis.

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that modulate the vast majority of cellular processes. During development, the correct timing and expression of miRNAs in the tissue differentiation is essential for organogenesis and functionality. In thyroid gland, DICER and miRNAs are necessary for accurately establishing thyroid follicles and hormone synthesis. Moreover, DICER1 mutations and miRNA deregulation observed in human goiter influence thyroid tumorigenesis. The thyroid malignant transformation by MAPK oncogenes is accompanied by global miRNA changes, with a marked reduction of "tumor-suppressor" miRNAs and activation of oncogenic miRNAs. Loss of thyroid cell differentiation/function, and consequently iodine trapping impairment, is an important clinical characteristic of radioiodine-refractory thyroid cancer. However, few studies have addressed the direct role of miRNAs in thyroid gland physiology. Here, we focus on what we have learned in the thyroid follicular cell differentiation and function as revealed by cell and animal models and miRNA modulation in thyroid tumorigenesis.

Thyroid diseases in pregnancy: a current and controversial topic on diagnosis and treatment over the past 20 years.

BACKGROUND: Management of thyroid diseases during pregnancy requires special considerations because maternal thyroid diseases can have adverse effects on both pregnancy and fetus. Universal screening for thyroid diseases in pregnant women is not currently supported by studies with high evidence whereas guidelines have been released for individuals at high risk, although controversies are still in debate. Iodine prophylaxis should be performed systematically to women during pregnancy. MATERIALS AND METHODS: An electronic search of PubMed/Medline and EMBASE concerning thyroid diseases and pregnancy have been conducted over the past 20 years and summarized. RESULTS: Data regarding prevention and treatment of thyroid diseases during pregnancy are reported from analysis of the literature. CONCLUSIONS: As thyroid dysfunction may cause profound impact on mother's and fetus's health, implementation by strict application of clinico-diagnostic flowchart and recommendations is of paramount importance when dealing with thyroid diseases during pregnant state.

Iodine, Iodine metabolism and Iodine deficiency disorders revisited.

Iodine is a vital micronutrient required at all stages of life; fetal life and early childhood being the most critical phases of requirement. Diet is the sole source of iodine, which in turn is dependent upon the iodine content of water and soil. Iodine is metabolized in the human body through a series of stages involving the hypothalamus, pituitary, thyroid gland and blood. Recent advances in physiology and molecular science have revolutionized our understanding of iodine metabolism at the cellular and sub-cellular level. This in turn has improved our knowledge of Iodine Deficiency Disorders (IDD), their prevention, management and control. This article makes an attempt to revisit this important topic in light of recent advances and provides a comprehensive account of the subject.

Clinical prognosis in BRAF-mutated PTC

BRAF mutation has recently emerged as a potential prognostic marker for papillary thyroid carcinoma (PTC) due to several studies suggesting that it may condition the development of tumors with aggressive behavior. A study of the phenotypes of thyroid follicular cell lines and transgenic mice characterized by targeted expression of BRAF mutation indicates that, at variance with RET/PTC rearrangement, it induces or facilitates genomic instability and higher invasiveness and eventually deeper tumor de-differentiation and more significant suppression of apoptosis. An analysis of differential gene expression of PTCs harboring BRAF mutation versus PTCs characterized by other genetic alterations shows an important impairment of the expression of genes related to intra-thyroidal iodine metabolism machinery, up-regulation of Glut-1 mRNA, methylation-induced gene silencing of tumor suppressor genes and up-regulation of pro-angiogenetic proteins such as VEGF. Correlation of BRAF mutation with PTC clinico-pathological features yields controversial results, with several studies showing the association with unfavourable clinico-pathological qualities, while others do not confirm the findings. This review will summarize the studies in favor of or in contrast with a role of BRAF mutation as a prognostic marker in PTC. We will also indicate what information we still need in order to routinely introduce this indicator in clinical practice.

Mutações no BRAF surgiram recentemente como potenciais marcadores prognósticos do carcinoma papílifero de tiróide (CPT) graças a vários estudos que sugerem que ele possa condicionar o desenvolvimento de tumores com comportamento agressivo. Um estudo do fenótipo das células de linhagem folicular de tiróide em camundongos transgênicos caracterizados pela expressão direcionada de mutações BRAF, indicam, à semelhança dos rearranjos RET/PTC, que ele induz ou facilita a instabilidade genômica, a alta invasividade e, por fim, uma profunda desdiferenciação tumoral com supressão mais significativa da apoptose. Uma análise da expressão gênica diferencial do CPT associado com mutações BRAF versus o CPT caracterizado por outras alterações gênicas mostra uma redução importante da expressão dos genes relacionados com a maquinaria do metabolismo do iodo intratiroideano, aumento da regulação do mRNA do Glut-1, silenciamento gênico induzido por metilação dos genes supressores tumorais e aumento da regulação das proteínas pró-angiogênicas, como a VEGF. A correlação da mutação BRAF com os achados clínico-patológicos do CPT mostra resultados controversos, com vários estudos indicando associação com parâmetros clínico-patológicos desfavoráveis e outros não confirmando esses achados. Esta revisão sumariza os estudos a favor ou não do papel da mutação BRAF como um marcador prognóstico no CPT. Indicaremos, também, quais informações são ainda necessárias para a introdução rotineira deste indicador na prática clínica.