Iodide Transport Research Articles

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The cover image is based on the Article Lithium iodide transport in double gyroid nanochannels formed by zwitterion‐containing solid polymer electrolytes by Karim Aissou et al., https://doi.org/10.1002/pol.20240206. image

Lithium iodide transport in double gyroid nanochannels formed by zwitterion‐containing solid polymer electrolytes

AbstractThe fabrication of nanostructured block copolymer (BCP) films endowed with lithium ion‐conducting gyroid (GYR) nanochannels is an appealing solution to build solid polymer electrolytes (SPEs) that combines high ionic conductivity (IC) with suitable mechanical properties. However, the formation of a well‐developed GYR structure remains challenging to achieve from the self‐assembly of polyelectrolyte BCP chains. To overcome this issue, large ion conducting gyroid grains were produced within freestanding polystyrene‐block‐poly(2‐vinylpyridine)‐block‐poly(ethylene oxide) (PS‐b‐P2VP‐b‐PEO) films by combining a solvent vapor annealing (SVA) treatment with an infiltration process. Here, the SVA treatment enabled the manufacture of SPEs entirely composed of a GYR structure while the infiltration process allowed for the incorporation of an appropriate Li salt (i.e., lithium iodoacetate, LiIAc) within the 3D‐interconected nanochannels via a Menshutkin reaction. By using this SVA‐Infiltration strategy, it has been demonstrated that the creation of ion conducting GYR nanochannels enhances the ion transportation capacity of pyridine‐containing SPEs since substantially lower ICs were measured from analog PS‐b‐P2VP‐b‐PEO/LiIAc films having a nominally disordered as‐cast state. Remarkably, zwitterionic pyridinium‐based moieties formed inside the interpenetrated nanochannels enable an efficient migration of Li+ and I3− species, leading to an IC as high as 10−4 S cm−1 at 70°C.

Sirenian genomes illuminate the evolution of fully aquatic species within the mammalian superorder afrotheria

Sirenians of the superorder Afrotheria were the first mammals to transition from land to water and are the only herbivorous marine mammals. Here, we generated a chromosome-level dugong (Dugong dugon) genome. A comparison of our assembly with other afrotherian genomes reveals possible molecular adaptations to aquatic life by sirenians, including a shift in daily activity patterns (circadian clock) and tolerance to a high-iodine plant diet mediated through changes in the iodide transporter NIS (SLC5A5) and its co-transporters. Functional in vitro assays confirm that sirenian amino acid substitutions alter the properties of the circadian clock protein PER2 and NIS. Sirenians show evidence of convergent regression of integumentary system (skin and its appendages) genes with cetaceans. Our analysis also uncovers gene losses that may be maladaptive in a modern environment, including a candidate gene (KCNK18) for sirenian cold stress syndrome likely lost during their evolutionary shift in daily activity patterns. Genomes from nine Australian locations and the functionally extinct Okinawan population confirm and date a genetic break ~10.7 thousand years ago on the Australian east coast and provide evidence of an associated ecotype, and highlight the need for whole-genome resequencing data from dugong populations worldwide for conservation and genetic management.

LncRNA MALAT1-miR-339-5p-NIS axis is involved in the increased level of thyroid stimulating hormone (TSH) induced by combined exposure of high iodine and hyperlipidemia

Hypothyroidism and subclinical hypothyroidism were both characterized by elevated levels of thyroid stimulating hormone (TSH). Previous studies had found that high iodine or hyperlipidemia alone was associated with increased TSH level. However, their combined effects on TSH have not been elucidated. In this study, combination of high iodine and hyperlipidemia was established through the combined exposure of high-water iodine and high fat diet in Wistar rats. The results showed that combined exposure of high iodine and high fat can induce higher TSH level. The mRNA and protein levels of sodium iodide transporters (NIS) and type 1 deiodinase (D1) in thyroid tissues, which were crucial genes in the synthesis of thyroid hormones, decreased remarkably in combined exposure group. Mechanistically, down-regulated long non-coding RNA (lncRNA) metastasis associated in lung denocarcinoma transcript 1 (MALAT1) may regulate the expression of NIS by increasing miR-339-5p, and regulating D1 by increasing miR-224-5p. Then, the above findings were explored in subjects exposed to high water iodine and hyperlipidemia. The results indicated that in population combined with high iodine and hyperlipidemia, TSH level increased to higher level and lncRNA MALAT1-miR-339-5p-NIS axis was obviously activated. Collectively, this study found that combined exposure of high iodine and hyperlipidemia induced a higher level of TSH, and lncRNA MALAT1-miR-339-5p-NIS axis may play important role.

Late-onset dyshormonogenic goitrous hypothyroidism due to a homozygous mutation of the SLC26A7 gene: a case report

BackgroundIn this study, we used targeted next-generation sequencing (NGS) to investigate the genetic basis of congenital hypothyroidism (CH) in a 19-year-old Tunisian man who presented with severe hypothyroidism and goiter.Case presentationThe propositus reported the appearance of goiter when he was 18. Importantly, he did not show signs of mental retardation, and his growth was proportionate. A partial organification defect was detected through the perchlorate-induced iodide discharge test. NGS identified a novel homozygous mutation in exon 18 of the SLC26A7 gene (P628Qfs*11), which encodes for a new iodide transporter. This variant is predicted to result in a truncated protein. Notably, the patient's euthyroid brother was heterozygous for the same mutation. No renal acid–base abnormalities were found and the administration of 1 mg of iodine failed to correct hypothyroidism.ConclusionsWe described the first case of goitrous CH due to a homozygous mutation of the SLC26A7 gene diagnosed during late adolescence.

Selective transmembrane transport of iodide based on electrochemically induced iodide-trap BiOI/MWCNTs/PVA composite membrane

An electrochemically induced bismuth iodine oxide/multiwalled carbon nanotubes/polyvinyl alcohol (BiOI/MWCNTs/PVA) composite membrane electrode with iodide ion trap (I−-trap) was fabricated by prerelease of I− under reduction potential. The I−-trap BiOI/MWCNTs/PVA composite membrane with unique lattice confinement structures was used for the selective extraction of I− in an electrochemically switched ion permselective (ESIP) process. In the ESIP system, the direct uptake and release of I− were realized by applying a cell voltage-pulse potential (CV-PP) coupling circuit on the membranes to switch the oxidation/reduction state. The I−-trap BiOI/MWCNTs/PVA composite membrane exhibited a maximum flux of 8.32 mg·m−2·min−1 and superior electrochemical stability. The separation factors of I−/Br−, I−/Cl−, I−/NO3−, and I−/SO42−in the mixed solutions were 2.67, 3.71, 3.82, and 6.70 respectively. Therefore, such a novel I−-trap BiOI/MWCNTs/PVA composite membrane could be used in the ESIP system for the selective extraction of I− ions from low concentration solutions.

Abstract PO3-26-07: Epigenetic approaches to deliver a targeted radiotherapy for triple negative breast cancer

Abstract The sodium iodide symporter (NIS, encoded by SLC5A5) is the sole transporter of iodide, and successfully exploited in thyroid cancer to uptake radioiodide (RAI). NIS is essentially undetected in normal mammary epithelial cells but elevated during lactation, and has a heterogeneous expression profile in breast cancer (BRCA), as evidenced by TCGA cohort and also in a ~120 sample TMA we have profiled. Furthermore, pre-clinical studies support an epigenetic mechanisms that involves Retinoic Acid Receptor alpha (RARa) to regulate SLC5A5 expression. Therefore, we have applied an orthogonal approach to both elucidate and target mechanisms that control NIS expression and function to deliver a therapeutic strategy that targets this transporter as a novel radiotherapy in BRCA. To understand the epigenetic control of expression we segregated samples in the TCGA-BRCA cohort into lower and upper quartile SLC5A5 expression and identified ~600 significant differentially expressed of genes (DEG). Interestingly, restricting analyses to either triple negative (TN) or tumors from African American (AA) patients doubled the number of DEGs. These DEGs were significantly associated with several transcription factors including LHX3, a pituitary development transcription factor regulated by thyroid signaling. The most significantly altered ~70 DEGs significantly clustered tumors by genomic ancestry and ERBB2/HER2 IHC status. The DEGs also supported a footprint of RARa signaling include PRAME, a known RARa co-repressor associated with histone deacetylase, and reflects the finding that NIS expression is highly responsive to SAHA treatment. To investigate if PRAME expression suppresses RARa regulation of SLC5A5 we have established a panel of BRCA cell lines (AU565, SKB3 SUM52 and MDA-MB-231) stably transfected with either CRISPR-VP64 (activator) and CRISPR-KRAB (repressor) to modulate PRAME and measure the epigenomic impact, the expression of SLC5A5 and the ability to transport RAI. In parallel we have applied a drug screen approach that targets non-canonical approaches to govern NIS expression, for example by targeting valosin-containing protein (VCP) that induces NIS proteolysis. In the first instance we have developed a therapeutic strategy to target NIS by inhibiting VCP. Specifically, we are screening a range of VCP inhibitors in combination with the HDAC inhibitor SAHA or the transcriptional potentiator, disulfiram metabolite Cu(DDC)2 in BRCA cell lines by testing the ability to augment RAI uptake. Remarkably, in MDA MB 231 cells, Cu(DDC)2 combined with the VCP inhibitor CB5339, resulted in a significant additive increase in RAI uptake and a prominent decrease in cell proliferation and survival. These studies combined with future murine and PDX testing of CRISPR-edited tumors and drug exposures will develop a comprehensive analyses of the mechanisms that control SLC5A5 expression across breast cancer cell types, how this can be most effectively targeted to restore NIS expression, and exploited to promote RAI as a novel targeted BRCA radiotherapy. Citation Format: Katie Brookes, Martin Read, Sajad Wani, Sissy Jhiang, Daniel Stover, Mathew Ringel, Christopher McCabe, Moray Campbell. Epigenetic approaches to deliver a targeted radiotherapy for triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-26-07.

Solute Carrier Family 26 Member 4 (SLC26A4), A Potential Therapeutic Target for Asthma.

Asthma is a prevalent respiratory condition with multifaceted pathomechanisms, presenting challenges for therapeutic development. The SLC (Solute Carrier) gene family, encompassing diverse membrane transport proteins, plays pivotal roles in various human diseases by facilitating solute movement across biological membranes. These solutes include ions, sugars, amino acids, neurotransmitters, and drugs. Mutations in these ion channels have been associated with numerous disorders, underscoring the significance of SLC gene families in physiological processes. Among these, the SLC26A4 gene encodes pendrin, an anion exchange protein involved in transmembrane transport of chloride, iodide, and bicarbonate. Mutations in SLC26A4 are associated with Pendred syndrome. Elevated SLC26A4 expression has been linked to airway inflammation, hyperreactivity, and mucus production in asthma. Here, we review novel insights from SLC gene family members into the mechanisms of substrate transport and disease associations, with specific emphasis on SLC26A4. We explore triggers inducing SLC26A4 expression and its contributions to the pathogenesis of pulmonary diseases, particularly asthma. We summarize the inhibitors of SLC26A4 that have shown promise in the treatment of different phenotypes of diseases. While SLC26A4 inhibitors present potential treatments for asthma, further research is imperative to delineate their precise role in asthma pathogenesis and develop efficacious therapeutic strategies targeting this protein.

Differentiating Benign from Malignant Thyroid Tumors by Kinase Activity Profiling and Dabrafenib BRAF V600E Targeting.

Differentiated non-medullary thyroid cancer (NMTC) can be effectively treated by surgery followed by radioactive iodide therapy. However, a small subset of patients shows recurrence due to a loss of iodide transport, a phenotype frequently associated with BRAF V600E mutations. In theory, this should enable the use of existing targeted therapies specifically designed for BRAF V600E mutations. However, in practice, generic or specific drugs aimed at molecular targets identified by next generation sequencing (NGS) are not always beneficial. Detailed kinase profiling may provide additional information to help improve therapy success rates. In this study, we therefore investigated whether serine/threonine kinase (STK) activity profiling can accurately classify benign thyroid lesions and NMTC. We also determined whether dabrafenib (BRAF V600E-specific inhibitor), as well as sorafenib and regorafenib (RAF inhibitors), can differentiate BRAF V600E from non-BRAF V600E thyroid tumors. Using 21 benign and 34 malignant frozen thyroid tumor samples, we analyzed serine/threonine kinase activity using PamChip®peptide microarrays. An STK kinase activity classifier successfully differentiated malignant (26/34; 76%) from benign tumors (16/21; 76%). Of the kinases analyzed, PKC (theta) and PKD1 in particular, showed differential activity in benign and malignant tumors, while oncocytic neoplasia or Graves' disease contributed to erroneous classifications. Ex vivo BRAF V600E-specific dabrafenib kinase inhibition identified 6/92 analyzed peptides, capable of differentiating BRAF V600E-mutant from non-BRAF V600E papillary thyroid cancers (PTCs), an effect not seen with the generic inhibitors sorafenib and regorafenib. In conclusion, STK activity profiling differentiates benign from malignant thyroid tumors and generates unbiased hypotheses regarding differentially active kinases. This approach can serve as a model to select novel kinase inhibitors based on tissue analysis of recurrent thyroid and other cancers.

Obesity and Impact On Thyroid Hormone and Subclinical Hypothyroidism

Background: Obesity is a metabolic disorder due to physical inactivity associated with increased consumption of calories. The excess calorie is stored as fat in adipose tissue, the fat loaded adipose tissue stimulates inflammatory pathway. The secreted inflammatory cytokines influence the sodium iodide transporter on the surface of thyroid gland. It causes decreased Thyroid hormone (TH) secretion & elevated Thyroid Stimulation Hormone (TSH). the energy metabolism of the body is regulated by TH, decreased TH secretion in obesity disturbs energy metabolism. Material & Methods: The study population are the patients attending OPD of medicine a tertiary hospital in Bhopal, Madhya Pradesh (Central India). Total 25 patients are selected for the study based on their anthropometric measurements (Weight, Height, BMI) confirmed them as obese. Of them 16 are males and 9 are females aged >35 years and are compared with equal number of age matched control population. Results: The values obtained after investigation of various parameters of study as well as control is analysed using SPSS software. The obtained mean, SD values of these parameters are as follows. Conclusion: The obesity due to excessive calorie intake with low physical activity deposits more fat into adipose tissue. The fat loaded adipocytes not only increases blood lipids but also aggravates inflammatory pathways. The secreted inflammatory cytokines (IL-1, 12,18, TNF- α , IFN influences thyroid function by a change in lodide transport across the thyroid gland.

Bilateral Shifts in Deuterium Supply Similarly Change Physiology of the Pituitary-Thyroid Axis, but Differentially Influence Na+/I- Symporter Production.

Deuterium, a stable isotope of hydrogen, is abundant in organisms. It is known to produce various biological effects. However, its impact in thyroid hormone synthesis and secretion is poorly studied. The aim of this investigation was to evaluate the dynamics of thyroid hormones and pituitary thyroid-stimulating hormone secretion during bilateral shifts in deuterium supply and assess a possible role of the Na+/I- symporter (NIS), the main iodide transporter, in altered thyroid function. The experiment was performed on adult male Wistar rats, which consumed deuterium-depleted ([D] = 10 ppm) and deuterium-enriched ([D] = 500,000 ppm) water for 21 days. The assessment of total thyroxine and triiodothyronine and their free fractions, as well as thyroid-stimulating hormone in blood serum, revealed the rapid response of the thyroid gland to shifts in the deuterium/protium balance. The present investigation shows that the bilateral changes in the deuterium body content similarly modulate thyroid hormone production and functional activity of the pituitary gland, but the responses of the thyroid and pituitary glands differ. The response of the thyroid cells was to increase the synthesis of the hormones and the pituitary thyrotropes, in order to reduce the production of the thyroid-stimulating hormone. The evaluation of NIS serum levels found a gradual increase in the rats that consumed deuterium-enriched water and no differences in the group exposed to deuterium depletion. NIS levels in both groups did not correlate with thyroid hormones and pituitary thyroid-stimulating hormone production. The data obtained show that thyroid gland has a higher sensitivity to shifts in the deuterium body content than the hypothalamic-pituitary complex, which responded later but similarly in the case of deuteration or deuterium depletion. It indicates a different sensitivity of the endocrine glands to alterations in deuterium content. It suggests that thyroid hormone production rate may depend on deuterium blood/tissue and cytosol/organelle gradients, which possibly disturb the secretory process independently of the NIS.

Sodium/Iodide Symporter Analysis for Prognostication and Management in Thyroglobulin-elevated Negative Iodine Scintigraphy Syndrome: Current Advances and Future Prospects

ABSTRACT Well-differentiated thyroid cancers are typically managed with surgery followed by radioiodine ablation. These cancers often retain the ability to concentrate intracellular iodine. However, cancer cell dedifferentiation frequently confers radioiodine resistance, termed thyroglobulin-elevated negative iodine scintigraphy (TENIS) syndrome. Elucidation of the sodium/iodide symporter (NIS) mechanism that mediates active iodide transport has enabled advances in the pathophysiologic understanding and clinical management of TENIS syndrome. This review summarizes molecular cloning of the NIS gene and implications for thyroid biology. It highlights studies of NIS gene regulation across tissues and utilization of NIS as a reporter gene to restore radioiodine uptake in advanced thyroid cancers. Quantitative NIS expression analyses and correlations with radioiodine uptake are also discussed. Overall, this review underscores the vital role of NIS-mediated iodide transport in thyroid pathophysiology and modern radioiodine therapeutic paradigms for advanced thyroid cancers, including TENIS syndrome. Further research into mechanisms underlying differential NIS expression and therapeutic modulation of NIS activity is warranted.

Overlimiting current by iodide electrode oxidation in aqueous media: an electrogenerated iodine interphase with positively charged channels stimulating in situ electrokinetic iodide transport

Overlimiting current by I− electrode oxidation on a Pt ultramicroelectrode in an aqueous solution was investigated, which was attributed to the formation of a positively charged porous iodine interphase in situ stimulating electrokinetic I− transport.

Modulation of transmembrane anion transport of porphyrin boxes by dynamic window size engineering

The development of synthetic transmembrane anion transport systems is of considerable interest, not only for mimicking the functions of natural transmembrane proteins but also for practical applications. We have recently reported a porous organic cage, porphyrin box (PB(8)) having multiple windows surrounded by octyl chains as an iodide selective anion channel. Herein, we report the modulation of transmembrane transport of halides ([Formula: see text], [Formula: see text], and [Formula: see text] by dynamic window size engineering of the cage with different alkyl chain lengths (hexyl PB(6), octyl PB(8) and decyl PB(10)). ‘Apparent’ transport rates were measured by the HPTS fluorescence assay, which shows a gradual decrease in the transport rate upon increasing the length of alkyl chains of PB. We calculate the transport rate per PB in order to make a fair comparison as the ‘apparent’ transport rate is proportional to the number of PBs embedded in the lipid membrane. The transport rate per PB reveals that increasing the length of the alkyl chains of PBs results in a substantial fall in the iodide transport rate while only marginally decreasing the transport rates of bromide and chloride, thereby decreasing the selectivity of iodide transport.

Structural insights into the mechanism of the sodium/iodide symporter.

The sodium/iodide symporter (NIS) is the essential plasma membrane protein that mediates active iodide (I-) transport into the thyroid gland, the first step in the biosynthesis of the thyroid hormones-the master regulators of intermediary metabolism. NIS couples the inward translocation of I- against its electrochemical gradient to the inward transport of Na+ down its electrochemical gradient1,2. For nearly 50 years before its molecular identification3, NIS was the molecule at the centre of the single most effective internal radiation cancer therapy: radioiodide (131I-) treatment for thyroid cancer2. Mutations in NIS cause congenital hypothyroidism, which must be treated immediately after birth to prevent stunted growth and cognitive deficiency2. Here we report three structures of rat NIS, determined by single-particle cryo-electron microscopy: one with no substrates bound; one with two Na+ and one I- bound; and one with one Na+ and the oxyanion perrhenate bound. Structural analyses, functional characterization and computational studies show the substrate-binding sites and keyresidues for transport activity. Our results yield insights into how NIS selects, couples and translocates anions-thereby establishing a framework for understanding NIS function-and how it transports different substrates with different stoichiometries and releases substrates from its substrate-binding cavity into the cytosol.

Adherens Junction Integrity Is a Critical Determinant of Sodium Iodide Symporter Residency at the Plasma Membrane of Thyroid Cells.

While most cases of differentiated thyroid carcinoma (DTC) are associated with a good prognosis, a significant number progress to advanced disease exhibiting aggressive clinical characteristics and often becoming refractory to radioactive iodine (RAI) treatment, the current gold-standard therapeutic option for metastatic disease. RAI-refractoriness is caused by defective functional expression of the sodium-iodide symporter (NIS), which is responsible for the active transport of iodide across the plasma membrane (PM) into thyroid follicles. NIS deficiency in these tumors often reflects a transcriptional impairment, but also its defective targeting and retention at the cells' PM. Using proteomics, we previously characterized an intracellular signaling pathway derived from SRC kinase that acts through the small GTPase RAC1 to recruit and bind the actin-anchoring adaptor EZRIN to NIS, regulating its retention at the PM of both non-transformed and cancer thyroid cells. Here, we describe how by reanalyzing the proteomics data, we identified cell-cell adhesion as the molecular event upstream the pathway involved in the anchoring and retention at the PM. We show that by interacting with NIS at the PM, adherens junction (AJ)-associated P120-catenin recruits and is phosphorylated by SRC, allowing it to recruit RAC1 to the complex. This enables SRC-phosphorylated VAV2 exchange factor to activate RAC1 GTPase, inducing NIS retention at the PM, thus increasing its abundance and function at the surface of thyroid cells. Our findings indicate that the loss of epithelial cell-cell adhesion may contribute to RAI refractoriness, indicating that in addition to stimulating NIS expression, successful resensitization therapies might require the employment of agents that improve cell-cell adhesion and NIS PM retention in refractory TC cells.

Histopathological Features of Pendred Syndrome Thyroids Align with Differences in the Expression of Thyroid-Specific Markers, Apical Iodide Transporters, and Ciliogenesis Process

Pendred syndrome (PDS) is an autosomal recessive disorder caused by mutations in the gene that encodes pendrin. Pendred thyroid tissue is supposedly altered by the absence of functional pendrin, but it is still unknown whether other iodide exchangers could compensate for the loss of the protein. Moreover, we have recently described that primary cilium, a conserved structure present at the apical surface of normal follicular cells, suffers different alterations in functional thyroid diseases. We aimed (1) to better understand the histopathological changes experienced by PDS thyroids, (2) to analyze the expression of different thyroid-specific genes and alternative iodide transporters and, finally, (3) to determine whether those changes may alter the morphological pattern of primary cilia in follicular cells. Thyroid samples from a series of four PDS patients were analyzed by immunohistochemistry, double immunofluorescence, and morphometry to evaluate changes in primary cilia frequency and length. We found thyroid follicular nodular disease in all PDS thyroids, frequently in association with follicular adenomas. There were only slight changes in the expression of thyroid-specific markers. Although no positivity for pendrin was found, cytoplasmic immunostaining for ANO-1, CLC-5, and CFTR was stronger in diffuse hyperplastic areas when compared to areas with highly cellular follicular nodules (HCFNs). HCFNs and follicular adenomas always showed diminished ciliary frequency and length. Our results suggest a direct relationship between the absence of functional pendrin and the loss of the normal thyroid architecture in PDS patients, which was also accompanied by differences in the expression of specific immunohistochemical markers and altered ciliogenesis. The present data may help the pathologist in screening for PDS.

Effect of perchlorate on ovarian morphology and histology, estrous cyclicity, steroidogenic enzyme activities and hormonal profiles in adult female rats

Perchlorate contamination is widespread for its industrial uses and natural occurrence. It is also used as an antithyroid drug. Perchlorate competitively inhibits iodide transport at the level of sodium-iodide symporter (NIS) in the thyroid gland, affecting thyroid hormone synthesis, resulting in alteration of thyroid gland structure and functions. Thyroid hormones are vital for proper functioning of the female reproductive system, since they modulate the metabolism and development of ovary and uterus. This study investigates the effect of perchlorate exposure for consecutive four weeks on the morphological and functional status of reproductive organs in adult female rats following parameters as the estrous cyclicity, histology of ovary and uterus, activities of steroidogenic enzymes, serum estradiol and estriol levels. Results revel irregular estrous cyclicity that ultimately ceased presenting a persistent estrous stage, hypertrophied ovary with corpora lutea of different sizes, large and inflated uterine lumen with proliferated endometrium comprising numerous secretory glands in the perchlorate exposed reproductive organs. The activities of steroidogenic enzymes (Δ⁵ 3β HSD and 17β HSD) were augmented that have heightened serum estriol level while the estradiol level was weakened. Therefore, an apparent hypertrophied and hyperfunctioning condition of ovary and uterus developed resembling pseudopregnancy on exposure of this iodide blocker

High concentration of estradiol has a negative correlation with free thyroxine during the second trimester of pregnancy.

ObjectiveTo explore the relationship between estradiol (E2) and thyroid function during the second trimester of pregnancy and the effect of E2 on sodium iodide transporter (NIS) expression in cultured thyroid cells.Materials and methodsWe analyzed relationships between E2 and thyroid function in 196 pregnant women during the second trimester. Multiple linear regression analysis was performed between E2 and thyroid function. The human thyroid Nthy-ori3-1 cells were cultured in different E2 concentrations, and the mRNA levels of NIS, estrogen receptor (ER)-α, and ER-β were measured by quantitative real-time PCR. Their protein levels were assessed by western blot.ResultsE2 was positively correlated with thyroid-stimulating hormone (TSH) and negatively correlated with free thyroxine (FT4) (P < 0.05). When we corrected for age, BMI, alanine aminotransferase, and serum creatinine, E2 was still negatively correlated with FT4 (P < 0.5) during the second trimester. In Nthy-ori3-1 cells treated with 10 nM E2, NIS and ER-β mRNA levels were significantly reduced, while ER-α mRNA level was not altered (P > 0.5). Moreover, 10 nM E2 significantly decreased protein levels of ER-β, phosphorylated versions of protein kinase A (p-PKA), phosphorylated versions of cAMP response element-binding protein (p-CREB), and NIS, while treatment with the ER-β inhibitor restored the expression of p-PKA, p-CREB, and NIS (P < 0.05).ConclusionHigh concentration of E2 has a negative correlation with FT4. High concentration of E2 can inhibit the NIS expression through the ER-β-mediated pathway, which may cause thyroid hormone fluctuations during pregnancy.

Genetic disorders of thyroid development, hormone biosynthesisand signalling.

Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate‐limiting for cellular entry of thyroid hormones (TH) (T4 and T3) into some tissues, with selenocysteine‐containing, deiodinase enzymes (DIO1 and DIO2) converting T4 to the biologically active hormone T3. TH regulate expression of target genes via hormone‐inducible nuclear receptors (TRα and TRβ) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired thyroid stimulating hormone receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of TH signalling encompass conditions due to defects in membrane TH transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to thyroid hormone due to pathogenic variants in either TRα or TRβ. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of TH transport, metabolism and action.