Search

Background: The thyroid gland is susceptible to abnormal epithelial cell growth, often resulting in thyroid dysfunction. The serine–threonine protein kinase mechanistic target of rapamycin (mTOR) regulates cellular metabolism, proliferation, and growth through two different protein complexes, mTORC1 and mTORC2. The PI3K-Akt-mTORC1 pathway's overactivity is well associated with heightened aggressiveness in thyroid cancer, but recent studies indicate the involvement of mTORC2 as well. Methods: To elucidate mTORC1's role in thyrocytes, we developed a novel mouse model with mTORC1 gain of function in thyrocytes by deleting tuberous sclerosis complex 2 (TSC2), an intracellular inhibitor of mTORC1. Results: The resulting TPO-TSC2KO mice exhibited a 70–80% reduction in TSC2 levels, leading to a sixfold increase in mTORC1 activity. Thyroid glands of both male and female TPO-TSC2KO mice displayed rapid enlargement and continued growth throughout life, with larger follicles and increased colloid and epithelium areas. We observed elevated thyrocyte proliferation as indicated by Ki67 staining and elevated cyclin D3 expression in the TPO-TSC2KO mice. mTORC1 activation resulted in a progressive downregulation of key genes involved in thyroid hormone biosynthesis, including thyroglobulin (Tg), thyroid peroxidase (Tpo), and sodium–iodide symporter (Nis), while Tff1, Pax8, and Mct8 mRNA levels remained unaffected. NIS protein expression was also diminished in TPO-TSC2KO mice. Treatment with the mTORC1 inhibitor rapamycin prevented thyroid mass expansion and restored the gene expression alterations in TPO-TSC2KO mice. Although total thyroxine (T4), total triiodothyronine (T3), and TSH plasma levels were normal at 2 months of age, a slight decrease in T4 and an increase in TSH levels were observed at 6 and 12 months of age while T3 remained similar in TPO-TSC2KO compared with littermate control mice. Conclusions: Our thyrocyte-specific mouse model reveals that mTORC1 activation inhibits thyroid hormone (TH) biosynthesis, suppresses thyrocyte gene expression, and promotes growth and proliferation. [ABSTRACT FROM AUTHOR]

Iodine is an essential micronutrient for producing thyroid hormone (TH); however, iodide excess can lead to adverse thyroidal effects. Unfortunately, the lack of a proper in vitro model system hampered the studies of the effect of iodide excess on thyroid physiology and pathology. Here, we demonstrated that excessive iodide intake downregulated the genes related to TH synthesis in the thyroids of mice. Since sodium iodide has no effect on these genes in cultured cell lines, we developed a three-dimensional (3D) culture system to enable the murine thyrocytes to form organoids in vitro with thyroid follicle-like structures and function and found that the in vivo effect of iodide excess could be mimicked in these thyroid organoids. Our data indicate that iodide excess mainly activated the XBP1-mediated unfolded protein response in both murine thyroid and thyroid organoids, while activation of XBP1 was able to mimic the sodium iodide effect on genes for the synthesis of TH in murine thyroid organoids. Lastly, our results suggest that XBP1 might transcriptionally repress the genes involved in the synthesis of TH. Based on these findings, we propose that iodide excess inhibits the transcription of genes related to TH synthesis through a mechanism involving XBP1-mediated action. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this study is to use machine learning techniques, Bagged CART, to classify hypothyroidism, which typically results from insufficient thyroid hormone synthesis in the body or seldom affects target tissues, and to identify potential risk factors. Materials and Methods: In this study, the open source data set obtained from the UCI database was used. The 10-fold cross-validation technique was used in the creation of the Bagged CART model from the Decision Tree Ensembles class to classify hypothyroid, and the performance criteria of this model were accuracy, balanced accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1-Score, G-mean and Matthews Correlation Coefficient ( MCC) was given. Then, the significance of the variable was calculated through the model created and possible risk factors for hypothyroidism were determined. Results: The accuracy, balanced accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1-Score, G-mean and Matthews Correlation Coefficient (MCC) performance criteria for the model created for the classification of hypothyroidism were 99.9%, 99.2%, 98.3%, 100.0%, 100.0%, 99.9%, 99.2%, 99.9%, and 99.1%, respectively. According to the created XGBoost model, the three most important factors that could be associated with hypothyroidism were determined as TBG, TSH, T4U, TT4, age, FTI, Query hypothroid, on thyroxine, on antithyroid medication, thyroid surgery, sex, TBG measured, sick, T3 mesured, Query hyperthyroid, goitre. Conclusion: In conclusion, considering the results of the machine learning model created in this study, the hypothyroidism classification performance was quite high and the significance of the variables and possible risk factors for hypothyroidism were determined. In the light of the findings, it is predicted that these risk factors may be useful in the clinic. [ABSTRACT FROM AUTHOR]

Background: Various thyroid functional test abnormalities are commonly observed in chronic kidney disease (CKD) due to alterations in thyroid hormone synthesis, metabolism, and regulation. Objectives: The study aims at investigating the prevalence of thyroid function disorders in patients with CKD and its association with the degree of renal failure. Methods: A cross-sectional study was performed on patients with CKD, at the Nephrology unit, Hawler Teaching Hospital, Erbil, Iraq from 1 July 2020 to 31 December 2020. Demographic features such as age, sex, and body mass index (BMI) were recorded; blood tests were done, including serum-free triiodothyronine (FT3), free thyroxin (FT4), thyrotropin (TSH), and creatinine. The CKD-EPI (epidemiological) equation was used to estimate glomerular filtration rate (eGFR).The participants were classified according to their thyroid function, age, BMI, and eGFR. The association of thyroid dysfunction with gender, age, BMI, and eGFR was studied. Results: A total of 104 patients with CKD enrolled in the current study: Half of them were on conservative treatment, and the other half were on a chronic hemodialysis (HD) program. Fifty four (51.9%) of them were male, mean age was 53.99 ± 14.59 years, mean BMI was 25.19 ± 3.14 kg/m2, and most of them (63.5%) were overweight. According to eGFR classification, most of the participants (70.2%) were at stage 5 CKD, 20.2% at stage 4, and 9.6% at stage 3. From the study population, it was observed that 34 out of 104 (32.7%) participants presented with thyroid function disorders. Among them, 22 (21.2%) patients presented with subclinical hypothyroidism, seven (6.7%) had overt hypothyroidism, three (2.9%) hyperthyroidism, and two (1.9%) subclinical hyperthyroidism. Hypothyroidism (clinical and subclinical) was positively associated with increasing age and advanced CKD. Conclusion: Thyroid function disorders are common among patients with CKD. Hypothyroidism, the most prevalent one, was positively associated with increasing age, low eGFR, and in patients on HD therapy. [ABSTRACT FROM AUTHOR]

Thyroglobulin is a homodimeric glycoprotein that is essential for the generation of thyroid hormones in vertebrates. Upon secretion into the lumen of follicles in the thyroid gland, tyrosine residues within the protein become iodinated to produce monoiodotyrosine (MIT) and diiodotyrosine (DIT). A subset of evolutionarily conserved pairs of DIT (and MIT) residues can then engage in oxidative coupling reactions that yield either thyroxine (T4; produced from coupling of a DIT 'acceptor' with a DIT 'donor') or triiodothyronine (T3; produced from coupling of a DIT acceptor with an MIT donor). Although multiple iodotyrosine residues have been identified as potential donors and acceptors, the specificity and structural context of the pairings (i.e. which donor is paired with which acceptor) have remained unclear. Here, single‐particle cryogenic electron microscopy (cryoEM) was used to generate a high‐resolution reconstruction of bovine thyroglobulin (2.3 Å resolution in the core region and 2.6 Å overall), allowing the structural characterization of two post‐reaction acceptor–donor pairs as well as tyrosine residues modified as MIT and DIT. A substantial spatial separation between donor Tyr149 and acceptor Tyr24 was observed, suggesting that for thyroxine synthesis significant peptide motion is required for coupling at the evolutionarily conserved thyroglobulin amino‐terminus. [ABSTRACT FROM AUTHOR]

Congenital hypothyroidism (CH) is the most common neonatal metabolic disorder. Although it has been understood to be a monogenic disease, some CH patients are reported to carry two or more variants at different genes. Here, ten permanent congenital hypothyroidism (PCH) patients were retrospectively reviewed, with elevated levels of serum thyroid-stimulating hormone and levothyroxine dependence during follow-up between 2015 and 2019. Each affected individual carried digenic variants, which were heterozygous at two of pathogenic genes. In total, five pathogenic genes, TSHR, TG, TPO, DUOX2 and DUOXA2, were simultaneously identified in subjects that were involved in the same metabolic pathway: thyroid hormone biosynthesis. There were digenic variants at TSHR and DUOX2 combined in three patients, DUOX2 and TG combined in two patients, DUOX2 and DUOXA2 combined in two patients, TG and DUOXA2 combined in two patients, and TG and TPO combined in one patient. Additionally, seven novel variants, TSHR c.679G>A, DUOX2 c.127A>T, c.608-619del, c.959T>C, TG c.2307G>A, and c.6759_6765del, and DUOXA2 c.93T>G, were identified in these PCH patients. Along with a literature review on digenic variants in patients with CH, our findings illustrated the complexity of genetic etiology in CH.

Congenital hypothyroidism (CH) is the most common neonatal metabolic disorder. Although it has been understood to be a monogenic disease, some CH patients are reported to carry two or more variants at different genes. Here, ten permanent congenital hypothyroidism (PCH) patients were retrospectively reviewed, with elevated levels of serum thyroid-stimulating hormone and levothyroxine dependence during follow-up between 2015 and 2019. Each affected individual carried digenic variants, which were heterozygous at two of pathogenic genes. In total, five pathogenic genes, TSHR, TG, TPO, DUOX2 and DUOXA2 , were simultaneously identified in subjects that were involved in the same metabolic pathway: thyroid hormone biosynthesis. There were digenic variants at TSHR and DUOX2 combined in three patients, DUOX2 and TG combined in two patients, DUOX2 and DUOXA2 combined in two patients, TG and DUOXA2 combined in two patients, and TG and TPO combined in one patient. Additionally, seven novel variants, TSHR c.679G>A, DUOX2 c.127A>T, c.608-619del, c.959T>C, TG c.2307G>A, and c.6759_6765del, and DUOXA2 c.93T>G, were identified in these PCH patients. Along with a literature review on digenic variants in patients with CH, our findings illustrated the complexity of genetic etiology in CH. [ABSTRACT FROM AUTHOR]

Context: Compounds to treat hypothyroidism in the absence of cardiac side effects are urgently required. In this regard, γ-aminobutyric acid (GABA) has gained interest due to its anti-anxiolytic, antihypertensive and antioxidant properties, and reported benefits to the thyroid system. Objective: We investigated the ability of GABA to ameliorate fluoride-induced thyroid injury in mice, and investigated the mechanism(s) associated with GABA-induced protection. Materials and methods: Adult male Kumning mice (N = 90) were exposed to NaF (50 mg/kg) for 30 days as a model of hypothyroidism. To evaluate the effects of GABA administration, fluoride-exposed mice received either thyroid tablets, or low (25 mg/kg), medium (50 mg/kg) or high (75 mg/kg) concentrations of pure GABA orally for 14 days groups (N = 10 each). The effects of low (50 mg/kg); medium (75 mg/kg) and high (100 mg/kg) concentrations of laboratory-separated GABA were assessed for comparison. Effects on thyroid hormone production, oxidative stress, thyroid function-associated genes, and side-effects during therapy were measured. Results: GABA supplementation in fluoride-exposed mice significantly increased the expression of thyroid TG, TPO, and NIS (P

The dwarf musk deer, or Chinese forest musk deer (Moschus berezovskii) is an endangered artiodactyl species native to a narrow region in southern and central China as well as northernmost Vietnam. This species is well known for the habit of male musk deer to secrete musk from the musk gland. Unmated male forest musk deer secrete a greater amount of musk than mated males, which probably allows them to attract a greater number of females. However, transcriptome data for this species are deficient, and the potential transcriptional pathways of musk production remain unknown. In this study, we used RNA-sequencing (RNA-Seq) to perform an in-depth survey of transcriptome data from musk gland and to compare the transcriptome differences between mated- and unmated sexually mature Chinese forest musk deer. There were 13,009 and 12,995 genes were expressed in unmated and mated musk glands tissue. In addition to analyzing these genes, we analyzed the differentially expressed genes in musk gland tissue between mated and unmated Chinese forest musk deer males. One hundred and thirty seven genes were found differentially expressed. We found that some genes in “PPAR signaling pathway”, “PI3K-Akt signaling pathway” and “Thyroid hormone synthesis” pathways may be associated with musk production and the secretion of the musk deer. The annotated genes and differentially expressed genes in this study can be applied in conservation or utilization study of musk deer in the future.

Copyright of Turkish Journal of Obstetrics & Gynecology is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The dwarf musk deer, or Chinese forest musk deer (Moschus berezovskii) is an endangered artiodactyl species native to a narrow region in southern and central China as well as northernmost Vietnam. This species is well known for the habit of male musk deer to secrete musk from the musk gland. Unmated male forest musk deer secrete a greater amount of musk than mated males, which probably allows them to attract a greater number of females. However, transcriptome data for this species are deficient, and the potential transcriptional pathways of musk production remain unknown. In this study, we used RNA-sequencing (RNA-Seq) to perform an in-depth survey of transcriptome data from musk gland and to compare the transcriptome differences between mated- and unmated sexually mature Chinese forest musk deer. There were 13,009 and 12,995 genes were expressed in unmated and mated musk glands tissue. In addition to analyzing these genes, we analyzed the differentially expressed genes in musk gland tissue between mated and unmated Chinese forest musk deer males. One hundred and thirty seven genes were found differentially expressed. We found that some genes in "PPAR signaling pathway", "PI3K-Akt signaling pathway" and "Thyroid hormone synthesis" pathways may be associated with musk production and the secretion of the musk deer. The annotated genes and differentially expressed genes in this study can be applied in conservation or utilization study of musk deer in the future. [ABSTRACT FROM AUTHOR]

Context: Compounds to treat hypothyroidism in the absence of cardiac side effects are urgently required. In this regard, γ-aminobutyric acid (GABA) has gained interest due to its anti-anxiolytic, antihypertensive and antioxidant properties, and reported benefits to the thyroid system. Objective: We investigated the ability of GABA to ameliorate fluoride-induced thyroid injury in mice, and investigated the mechanism(s) associated with GABA-induced protection. Materials and methods: Adult male Kumning mice (N = 90) were exposed to NaF (50 mg/kg) for 30 days as a model of hypothyroidism. To evaluate the effects of GABA administration, fluoride-exposed mice received either thyroid tablets, or low (25 mg/kg), medium (50 mg/kg) or high (75 mg/kg) concentrations of pure GABA orally for 14 days groups (N = 10 each). The effects of low (50 mg/kg); medium (75 mg/kg) and high (100 mg/kg) concentrations of laboratory-separated GABA were assessed for comparison. Effects on thyroid hormone production, oxidative stress, thyroid function-associated genes, and side-effects during therapy were measured. Results: GABA supplementation in fluoride-exposed mice significantly increased the expression of thyroid TG, TPO, and NIS (P < 0.05), significantly improved the thyroid redox state (P < 0.05), modulated the expression of thyroid function-associated genes, conferred liver metabolic protection, and prevented changes to myocardial morphology, thus reducing side effects. Both pure and laboratory-separated GABA displayed comparative protective effects. Discussion and conclusion: Our findings support the assertion that GABA exerts therapeutic potential in hypothyroidism. The design and use of human GABA trials to improve therapeutic outcomes in hypothyroidism are now warranted. [ABSTRACT FROM AUTHOR]

Thyroid stimulating hormone (TSH) consists of an α-subunit and a unique β-subunit. The first in-frame TSHβ splice variant produced by the cells of immune system was identified in 2009. The TSHβ splice variant and native TSHβ exhibit different expression profiles, and research has been conducted to elucidate the role of the TSHβ splice variant in different diseases. However, understanding of the fundamental physiological characteristics of the TSHβ splice variant is currently limited. To verify whether the TSHβ splice variant has the potential to induce thyroid follicular cells to synthesize thyroid hormone, in vivo and in vitro stimulation experiments were conducted in the present study. A total of 60 C57BL/6 mice were divided into control-, 5 and 10 µg TSHβ splice variant-treated groups at random. Mice were sacrificed at 0.5, 1 and 4 h after intraperitoneal injection, and serum levels of tri-iodothyronine (T3) and thyroxine (T4) were determined using a radioimmunoassay. Thyroid follicular cells were isolated from the thyroids of mice, and stimulated with 2 µg/ml TSHβ splice variant. Supernatants were collected, and the levels of T3 and T4 were detected. The protein expression levels of the sodium-iodide symporter, thyroperoxidase and thyroglobulin in thyroid follicular cells were quantified using western blot analysis. To verify whether the TSHβ splice variant expression was regulated by the hypothalamus-pituitary-thyroid (HPT) axis, similar to native TSHβ, a total of 60 C57BL/6 mice were equally divided into control, 2 mg/kg T3 intraperitoneal injection and 0.05 mg/kg thyroid-releasing hormone intraperitoneal injection groups at random. Mice were sacrificed at 1 and 4 h after injection. Alterations in the expression of the TSHβ splice variant in the pituitary, thyroid, peripheral blood leukocytes and spleen tissues were detected using western blot analysis. The present study demonstrated that the TSHβ splice variant is not regulated by the HPT axis and may affect thyroid hormone synthesis. Modifications in the expression of the TSHβ splice variant may occur in a uniquely regulated manner to provide peripheral immunological compartments with a source of activated cells, particularly under immune stress. [ABSTRACT FROM AUTHOR]

Iodine is an important trace element involved in thyroid hormone biosynthesis, while diet-induced obesity is reported to disturb the trace element metabolic balance. Herein, we studied the host-specific responses involved in modulating thyroid function and gut microbiota in obese mice after the iodine treatment and analyzed the possible causes for these responses. Obesity in the mice was induced by a high-fat diet, and the obese and normal mice were treated with the same iodine dosage (18 μg/kg/day) continuously for 8 weeks. Iodine treatment in the obese mice showed a weight-reducing effect, increased the thyroid hormone concentrations, altered the transcriptions of genes involved in thyroid hormone biosynthesis, and modulated the gut microbiota with an increased abundance of pathogenic bacteria and decreased the proportion of beneficial bacteria. However, completely different or even opposite response profiles were observed in the normal hosts. Our work indicated that obesity may exacerbate the risk of thyroid disease with a relatively safe dose of iodine, and individual differences should be considered with trace element supplementation. [ABSTRACT FROM AUTHOR]

Endocrine disruptors have gained widespread attention owing to their severe adverse health impacts. These produce enormous burden of disease and are associated with high economic cost especially in developed countries. Environmental pollutants causing endocrine disruption include pesticides, industrial wastes, packaging materials, food constituents, plastics, and cosmetic products. Likewise, pharmaceutical drugs have the endocrine disrupting potential through a wide array of mechanisms. Antipsychotic, antiepileptic, antihypertensive, antiviral, antidiabetic, and anticancer drugs are among the foremost non-hormonal endocrine disruptors. Several drugs affect thyroid hormone synthesis via interaction with iodine uptake to the release of T3 and T4 by thyrocytes. Prolonged use of some drugs increase susceptibility to diabetes mellitus either by direct destruction of β cells or enhanced insulin resistance. Other drugs may cause serious developmental defects in male or female reproductive system. Appropriate understanding of the mechanisms of endocrine disruption associated with non-hormonal drugs will guide future drug development and help us prevent and cure endocrine-related toxicity of pharmaceuticals. Therefore, this review focuses on endocrine disruption by pharmaceutical drugs as their side effect. [ABSTRACT FROM AUTHOR]

We investigated the genetic cause of thyroid dyshormonogenesis in a girl with congenital hypothyroidism. Genetic analysis showed that she was homozygous for a hitherto not described mutation (c.1432_1433delGT, p.V478KfsX11) in the solute carrier family 26 member 7 (SLC26A7) gene. SLC26A7 is proposed to be an anion transporter in the thyroid gland. The mutation leads to a frameshift and a premature stop codon. The predicted protein is truncated and very likely to be nonfunctional if it was expressed at all. In addition, in silico studies predict the mutation to be pathogenic. [ABSTRACT FROM AUTHOR]

Transcriptomics technologies have been used for risk assessment of chemicals, mainly to predict the modes of action (MOAs) of chemicals or identify biomarkers. Transcriptomics data may also be helpful to understand MOAs of chemicals at the molecular level in more detail. As an example of the known MOAs, there are two MOAs of thyroid toxicity: inhibition of thyroid hormone synthesis ("direct" effect) and hypermetabolism of thyroid hormone by enzyme induction in liver ("indirect" effect). In the present study, global profiles of gene expression were analyzed in rats treated with chemicals acting directly on the thyroid (thyroid peroxidase inhibitors such as propylthiouracil and methimazole) and chemicals acting indirectly on the thyroid (hepatic enzyme inducers such as phenobarbital and pregnenolone‐16α‐carbonitrile) using microarrays. Using a subtraction method between these two types of chemicals, we identified characteristic gene expression changes on the thyroid hormone synthesis pathway by direct‐acting chemicals. Based on the functions of these genes, alterations of their expression seem to indicate the results of thyroid peroxidase inhibition, and might be helpful in more accurate evaluation of MOAs for thyroid toxicity. Transcriptomics may be helpful to understand MOAs of chemicals at the molecular level. In this study, we analyzed global profiles of gene expression in rats treated with chemicals acting directly/indirectly on the thyroid (thyroid peroxidase inhibitors/hepatic enzyme inducers). Characteristic gene expression changes were identified on thyroid hormone synthesis pathway by direct‐acting chemicals. Alterations of their expression seem to indicate the results of thyroid peroxidase inhibition, and be helpful to accurate evaluation of MOAs for thyroid toxicity. [ABSTRACT FROM AUTHOR]

Background A single dose of potassium iodide (KI) is recommended to reduce the risk of thyroid cancer during nuclear accidents. However in case of prolonged radioiodine exposure, more than one dose of KI may be necessary. This work aims to evaluate the potential toxic effect of repeated administration of KI. Methods Adult Wistar rats received an optimal dose of KI 1 mg/kg over a period of 1, 4 or 8 days. Results hormonal status (TSH, FT4) of treated rats was unaffected. Contrariwise, a sequential Wolff-Chaikoff effect was observed, resulting in a prompt decrease of NIS and MCT8 mRNA expression (−58% and −26% respectively), followed by a delayed decrease of TPO mRNA expression (−33%) in conjunction with a stimulation of PDS mRNA expression (+62%). Conclusion we show for the first time that repeated administration of KI at 1 mg/kg/24h doesn't cause modification of thyroid hormones level, but leads to a reversible modification of the expression of genes involved in the synthesis and secretion of thyroid hormones. [ABSTRACT FROM AUTHOR]

Krüppel-like zinc finger proteins form one of the largest families of transcription factors. They function as key regulators of embryonic development and a wide range of other physiological processes, and are implicated in a variety of pathologies. GLI-similar 1-3 (GLIS1-3) constitute a subfamily of Krüppel-like zinc finger proteins that act either as activators or repressors of gene transcription. GLIS3 plays a critical role in the regulation of multiple biological processes and is a key regulator of pancreatic β cell generation and maturation, insulin gene expression, thyroid hormone biosynthesis, spermatogenesis, and the maintenance of normal kidney functions. Loss of GLIS3 function in humans and mice leads to the development of several pathologies, including neonatal diabetes and congenital hypothyroidism, polycystic kidney disease, and infertility. Single nucleotide polymorphisms in GLIS3 genes have been associated with increased risk of several diseases, including type 1 and type 2 diabetes, glaucoma, and neurological disorders. GLIS2 plays a critical role in the kidney and GLIS2 dysfunction leads to nephronophthisis, an end-stage, cystic renal disease. In addition, GLIS1-3 have regulatory functions in several stem/progenitor cell populations. GLIS1 and GLIS3 greatly enhance reprogramming efficiency of somatic cells into induced embryonic stem cells, while GLIS2 inhibits reprogramming. Recent studies have obtained substantial mechanistic insights into several physiological processes regulated by GLIS2 and GLIS3, while a little is still known about the physiological functions of GLIS1. The localization of some GLIS proteins to the primary cilium suggests that their activity may be regulated by a downstream primary cilium-associated signaling pathway. Insights into the upstream GLIS signaling pathway may provide opportunities for the development of new therapeutic strategies for diabetes, hypothyroidism, and other diseases. [ABSTRACT FROM AUTHOR]

Objective. Thyroid dyshormonogenesis (DH) is a genetically heterogeneous inherited disorder caused by thyroid hormone synthesis abnormalities. This study aims at comprehensively characterizing the mutation spectrum in Chinese patients with DH. Subjects and Methods. We utilized next-generation sequencing to screen for mutations in seven DH-associated genes (TPO, DUOX2, TG, DUOXA2, SLC26A4, SLC5A5, and IYD) in 21 Chinese Han patients with DH from Xinjiang Province. Results. Twenty-eight rare nonpolymorphic variants were found in 19 patients (90.5%), including 19, 5, 3, and 1 variants in DUOX2, TG, DUOXA2, and SLC26A4, respectively. Thirteen (62%) patients carried monogenic mutations, and six (28.5%) carried oligogenic mutations. Fifteen (71%) patients carried 2 or more DUOX2 (14) or DUOXA2 (1) variants. The genetic basis of DH in nine (43%) patients harboring biallelic or triallelic pathogenic variants was resolved. Seventeen patients (81%) carried DUOX2 mutations, most commonly p.R1110Q or p.K530X. No correlations were found between DUOX2 mutation types or numbers and clinical phenotypes. Conclusions. DUOX2 mutations were the most predominant genetic alterations of DH in the study cohort. Oligogenicity may explain the genetic basis of disease in many DH patients. Functional studies and further clinical studies with larger DH patient cohorts are needed to validate the roles of the mutations identified in this study. [ABSTRACT FROM AUTHOR]

Perfluorododecanoic acid (PFDoA), a kind of perfluorinated carboxylic acid (PFCA) with 12 carbon atoms, has an extensive industrial utilization and is widespread in both wildlife and the water environment, and was reported to have the potential to cause a disruption in the thyroid hormone system homeostasis. In this study, zebrafish embryos/larvae were exposed to different concentrations of PFDoA (0, 0.24, 1.2, 6 mg/L) for 96 h post-fertilization (hpf). PFDoA exposure caused obvious growth restriction connected with the reduced thyroid hormones (THs) contents in zebrafish larvae, strengthening the interference effect on the growth of fish larvae. The transcriptional level of genes within the hypothalamic-pituitary-thyroid (HPT) axis was analyzed. The gene expression levels of thyrotropin-releasing hormone ( trh ) and corticotrophin-releasing hormone ( crh ) were upregulated upon exposure to 6 mg/L of PFDoA, and iodothyronine deiodinases ( dio2 ) was upregulated in the 1.2 mg/L PFDoA group. The transcription of thyroglobulin ( tg ) and thyroid receptor ( trβ ) were significantly downregulated upon exposure to 1.2 mg/L and 6 mg/L of PFDoA. PFDoA could also decrease the levels of sodium/iodide symporter ( nis ) and transthyretin ( ttr ) gene expression in a concentration-dependent manner after exposure. A significant decrease in thyroid-stimulating hormoneβ ( tshβ ), uridinediphosphate-glucuronosyltransferase ( ugt1ab ) and thyroid receptor ( trα ) gene expression were observed at 6 mg/L PFDoA exposure. Upregulation and downregulation of iodothyronine deiodinases ( dio1 ) gene expression were observed upon the treatment of 1.2 mg/L and 6 mg/L PFDoA, respectively. All the data demonstrated that gene expression in the HPT axis altered after different PFDoA treatment and the potential mechanisms of the disruption of thyroid status could occur at several steps in the process of synthesis, regulation, and action of thyroid hormones. [ABSTRACT FROM AUTHOR]

Background: The association between dilated cardiomyopathy (DCM) and low thyroid hormone (TH) levels has been previously described. In these patients abnormal thyroid function is significantly related to impaired left ventricular (LV) function and increased risk of death. Although TH was originally thought to be produced exclusively by the thyroid gland, we recently reported TH biosynthesis in the human ischemic heart. Objectives: Based on these findings, we evaluated whether the genes required for TH production are also altered in patients with DCM. Methods: Twenty-three LV tissue samples were obtained from patients with DCM (n = 13) undergoing heart transplantation and control donors (n = 10), and used for RNA sequencing analysis. The number of LV DCM samples was increased to 23 to determine total T4 and T3 tissue levels by ELISA. Results: We found that all components of TH biosynthesis are expressed in human dilated heart tissue. Expression of genes encoding thyroperoxidase (–2.57-fold, P < 0.05) and dual oxidase 2 (2.64-fold, P < 0.01), the main enzymatic system of TH production, was significantly altered in patients with DCM and significantly associated with LV remodeling parameters. Thyroxine (T4) cardiac tissue levels were significantly increased (P < 0.01), whilst triiodothyronine (T3) levels were significantly diminished (P < 0.05) in the patients. Conclusions: Expression of TH biosynthesis machinery in the heart and total tissue levels of T4 and T3, are altered in patients with DCM. Given the relevance of TH in cardiac pathology, our results provide a basis for new gene-based therapeutic strategies for treating DCM. [ABSTRACT FROM AUTHOR]

Thyroid hormones (THs) are evolutionarily old hormones, having effects on metabolism in bacteria, invertebrates and vertebrates. THs bind specific distributor proteins (THDPs) to ensure their efficient distribution through the blood and cerebrospinal fluid in vertebrates. Albumin is a THDP in the blood of all studied species of vertebrates, so may be the original vertebrate THDP. However, albumin has weak affinity for THs. Transthyretin (TTR) has been identified in the blood across different lineages in adults vs juveniles. TTR has intermediate affinity for THs. Thyroxine-binding globulin has only been identified in mammals and has high affinity for THs. Of these THDPs, TTR is the only one known to be synthesised in the brain and is involved in moving THs from the blood into the cerebrospinal fluid. We analysed the rates of evolution of these three THDPs: TTR has been most highly conserved and albumin has had the highest rate of divergence. [ABSTRACT FROM AUTHOR]

Much research has focused on vertebrate thyroid hormone (TH) synthesis and their function in development and metabolism. While important differences in TH synthesis and signaling exist, comparative studies between vertebrates fail to explain the evolutionary origins of this important regulatory axis. For that, one needs to make sense out of the diverse TH effects which have been described in invertebrate phyla but for which a mechanistic understanding is largely missing. Almost every major group of non-vertebrate animals possesses the capability to synthesize and metabolize thyroid hormones and there is evidence for a nuclear thyroid hormone receptor mediated mechanism in the bilateria, especially in molluscs, echinoderms, cephalochordates and ascidians. Still, genomic pathways cannot fully explain many observed effects of thyroid hormones in groups such as cnidarians, molluscs, and echinoderms and it is therefore possible that TH may signal via other mechanisms, such as non-genomic signaling systems via membrane bound or cytoplasmic receptors. Here we provide a brief review of TH actions in selected invertebrate species and discuss the hypothesis that non-genomic TH action may have played a critical role in TH signaling throughout animal evolution. [ABSTRACT FROM AUTHOR]

Thyroid hormones (TH) are crucial for growth and development and play an important role in energy homeostasis. Although serum TH levels are relatively constant in the physiological state, TH bioavailability at the tissue and cellular level is dependent on local TH metabolism. Circulating TH produced by the thyroid can be metabolized by a number of different pathways resulting in 1) activation of TH 2) deactivation of TH or 3) excretion of TH and subsequent metabolites. These pathways play an essential role in determining local TH levels and action. The major classical pathways of TH metabolism are deiodination, sulfation, glucuronidation, and ether-link cleavage. This review provides an overview of these pathways, their relative contributions to TH levels in the serum and in various organs and the changes in these pathways elicited by fasting and illness. [ABSTRACT FROM AUTHOR]

Thyroid hormones (THs) play key roles in modulating the overall metabolism of the body, protein synthesis, fat metabolism, neuronal and bone growth, and cardiovascular as well as renal functions. In this review, we discuss on the thyroid hormone synthesis and activation, thyroid hormone receptors (TRs) and mechanism of action, applications of thyroid hormone analogues, particularly the compounds that are selective ligands for TRβ receptors, or enzyme inhibitors for the treatment of thyroidal disorders with a specific focus on thyroid peroxidase and iodothyronine deiodinases. We also discuss on the development of small-molecule deiodinase mimetics and their mechanism of deiodination, as these compounds have the potential to regulate the thyroid hormone levels. [ABSTRACT FROM AUTHOR]

Thyroid hormones (TH) 3,5,3′,5’- tetraiodothyronine or thyroxine (T4) and 3,5,3’- triiodothyronine (T3) contain iodine atoms as part of their structure, and their synthesis occur in the unique structures called thyroid follicles. Iodide reaches thyroid cells through the bloodstream that supplies the basolateral plasma membrane of thyrocytes, where it is avidly taken up through the sodium/iodide symporter (NIS). Thyrocytes are also specialized in the secretion of the high molecular weight protein thyroglobulin (TG) in the follicular lumen. The iodination of the tyrosyl residues of TG preceeds TH biosynthesis, which depends on the interaction of iodide, TG, hydrogen peroxide (H 2 O 2 ) and thyroid peroxidase (TPO) at the apical plasma membrane of thyrocytes. Thyroid hormone biosynthesis is under the tonic control of thyrotropin (TSH), while the iodide recycling ability is very important for normal thyroid function. We discuss herein the biochemical aspects of TH biosynthesis and release, highlighting the novel molecules involved in the process. [ABSTRACT FROM AUTHOR]

Since domestication, the genome landscape of cattle has been changing due to natural and artificial selection forces resulting in several general and specialized cattle breeds of the world. Identifying genomic regions affected due to these forces in livestock gives an insight into the history of selection for economically important traits and genetic adaptation to specific environments of the populations under consideration. This study explores the genes/genomic regions under selection in relation to the phenotypes of Holstein, Hanwoo, and N'Dama cattle breeds using Tajima's D, XP-CLR, and XP-EHH population statistical methods. The whole genomes of 10 Holstein (South Korea), 11 Hanwoo (South Korea), and 10 N'Dama (West Africa-Guinea) cattle breeds re-sequenced to ~11x coverage and retained 37 million SNPs were used for the study. Selection signature analysis revealed 441, 512, and 461 genes under selection from Holstein, Hanwoo, and N'Dama cattle breeds, respectively. Among all these, seven genes including ARFGAP3, SNORA70, and other RNA genes were common between the breeds. From each of the gene lists, significant functional annotation cluster terms including milk protein and thyroid hormone signaling pathway (Holstein), histone acetyltransferase activity (Hanwoo), and renin secretion (N'Dama) were enriched. Genes that are related to the phenotypes of the respective breeds were also identified. Moreover, significant breed-specific missense variants were identified in CSN3, PAPPA2 (Holstein), C1orf116 (Hanwoo), and COMMD1 (N'Dama) genes. The genes identified from this study provide an insight into the biological mechanisms and pathways that are important in cattle breeds selected for different traits of economic significance. [ABSTRACT FROM AUTHOR]

Deficiency in Krüppel-like zinc finger transcription factor GLI-similar 3 (GLIS3) in humans is associated with the development of congenital hypothyroidism. However, the functions of GLIS3 in the thyroid gland and the mechanism by which GLIS3 dysfunction causes hypothyroidism are unknown. In the current study, we demonstrate that GLIS3 acts downstream of thyroid-stimulating hormone (TSH) and TSH receptor (TSHR) and is indispensable for TSH/TSHR-mediated proliferation of thyroid follicular cells and biosynthesis of thyroid hormone. Using ChIP-Seq and promoter analysis, we demonstrate that GLIS3 is critical for the transcriptional activation of several genes required for thyroid hormone biosynthesis, including the iodide transporters Nis and Pds, both of which showed enhanced GLIS3 binding at their promoters. The repression of cell proliferation of GLIS3-deficient thyroid follicular cells was due to the inhibition of TSH-mediated activation of the mTOR complex 1/ribosomal protein S6 (mTORC1/RPS6) pathway as well as the reduced expression of several cell division-related genes regulated directly by GLIS3. Consequently, GLIS3 deficiency in a murine model prevented the development of goiter as well as the induction of inflammatory and fibrotic genes during chronic elevation of circulating TSH. Our study identifies GLIS3 as a key regulator of TSH/TSHR-mediated thyroid hormone biosynthesis and proliferation of thyroid follicular cells and uncovers a mechanism by which GLIS3 deficiency causes neonatal hypothyroidism and prevents goiter development. [ABSTRACT FROM AUTHOR]

Background and objective: Adequate iodine status and normal thyroid hormone synthesis are important for optimal child development. In this study, we explored whether young children’s developmental status is associated with thyroid dysfunction in an area of chronic excessive iodine exposure. Methods: We included 298 children between 18 and 48 months of age residing in Algerian refugee camps. Early child development was measured using the Ages and Stages Questionnaires, third edition (ASQ-3), consisting of five domains: Communication, Gross Motor, Fine Motor, Problem Solving and Personal-Social. Due to poor discriminatory ability in the Gross Motor domain, the total ASQ-3 scores were calculated both including and excluding this domain. Urinary iodine concentration (UIC), thyroid hormones (TSH, FT3 and FT4), thyroid antibodies and serum thyroglobulin (Tg) were measured. Results: The median UIC was 451.6 μg/L, and approximately 72% of the children had a UIC above 300 μg/L. Furthermore, 14% had thyroid disturbances, of whom 10% had TSH outside the reference range. Children with thyroid disturbances and TSH outside the reference ranges had lower odds of being among the 66% highest total ASQ scores, with adjusted odds ratios (95% CI) of 0.46 (0.23, 0.93) and 0.42 (0.19, 0.94), respectively. Conclusion: We found an association between thyroid dysfunction and poorer developmental status among children with excessive iodine intake. The high iodine intake may have caused the thyroid dysfunction and hence the delayed developmental status; however, other influential factors cannot be excluded. Optimal child development is important for a sustainable future. With iodine excess being an increasing problem globally, this subject should be further explored. [ABSTRACT FROM AUTHOR]

Background Abnormal thyroid hormone (TH) metabolism is significantly associated with impaired left ventricular (LV) function and death. Although TH was traditionally thought to be produced exclusively by the thyroid gland, an increasing number of studies report TH production in other tissues. Based on these findings, we evaluated whether the genes required for TH biosynthesis are expressed in the human heart, and whether their expression is altered in patients with ischemic cardiomyopathy (ICM) and is related to epigenetic variations. Methods Twenty-three LV tissue samples were obtained from ICM patients (n = 13) undergoing heart transplantation and control donors (n = 10) for RNA sequencing analysis. We increased the LV samples to 27 for the ELISA determination of total T4 and T3 tissue levels. For epigenomic studies, 850 K Infinium MethylationEPIC BeadChip platform was performed. Results Using RNA-sequencing, we displayed the expression levels of all components required for TH biosynthesis in human heart tissue. We observed significantly altered expression of genes encoding thyroperoxidase (TPO; − 2.48-fold, P < 0.05) and dual oxidase 2 (2.83-fold, P < 0.05), the main enzymatic system of TH production, and significant relationships between their altered expression and LV remodeling parameters. In addition, epigenetic analysis revealed a differential methylation pattern in TPO , and triiodothyronine tissue levels were significantly decreased ( P < 0.01). Conclusions These results showed that the human heart expresses the TH biosynthesis machinery, being altered its main enzymatic system in patients with ICM. Given the relevance of TH in cardiac pathology, our results provide a foundation for new therapeutic approaches based on TPO for treating ICM. [ABSTRACT FROM AUTHOR]

Background: Excessive iodine intake may have adverse effects on the thyroid, particularly in children, but the safe upper iodine intake concentration in children is unclear. Objective: We assessed the adverse effects of high iodine intake from iodine-rich drinking water on thyroid size in children by examining associations between thyroid volume (Tvol), total goiter rate (TGR), and iodine intake. Design: In a multistage cross-sectional survey, we collected two 24-h urine samples on 2 nonconsecutive days and determined 24-h urinary iodine excretion, then calculated habitual daily iodine intake. Ultrasonographic Tvol was measured, and TGR was calculated based on international and Chinese reference ranges for Tvol in children. Results: This study included 2089 children from Shandong province, where the median (IQR) drinking water iodine concentration was 183 mg/L (69-406 mg/L). The median (IQR) 24-h urinary iodine concentrations for the 2 collections were 381 mg/L (203-649 mg/L) and 398 mg/L (202-687 mg/L), respectively. The median (IQR) habitual daily iodine intake of children was 298 mg/d (186-437 mg/d). Tvols were slightly higher in boys than in girls (P = 0.035). The overall TGR was 9.7% and did not differ by sex. The TGR was ~5% for children aged 7-10 and 11-14 y at iodine intakes of 200-249 and 250-299 mg/d, respectively. With the use of logistic regression and 2-step linear regression, a nonlinear association was observed between Tvol, TGR, and iodine intake, with a threshold intake of 150 mg/d. Conclusions: Tvol begins to increase in children when iodine intake is $ 150 mg/d, and the TGR exceeds 5% when daily iodine intake is $250 mg/d for children aged 7-10 y and $300 mg/d for children aged 11-14 y. Our findings suggest that 150-249 and 150-299 mg/d seem to be safe upper iodine intake ranges for children aged 7-10 and 11-14 y, respectively. [ABSTRACT FROM AUTHOR]