Deiodinase Expression Research Articles

Cardiac recovery from pressure overload is not altered by thyroid hormone status in old mice.

Thyroid hormones (THs) are known to have various effects on the cardiovascular system. However, the impact of TH levels on preexisting cardiac diseases is still unclear. Pressure overload due to arterial hypertension or aortic stenosis and aging are major risk factors for the development of structural and functional abnormalities and subsequent heart failure. Here, we assessed the sensitivity to altered TH levels in aged mice with maladaptive cardiac hypertrophy and cardiac dysfunction induced by transverse aortic constriction (TAC). Mice at the age of 12 months underwent TAC and received T4 or anti-thyroid medication in drinking water over the course of 4 weeks after induction of left ventricular pressure overload. T4 excess or deprivation in older mice had no or only very little impact on cardiac function (fractional shortening), cardiac remodeling (cardiac wall thickness, heart weight, cardiomyocyte size, apoptosis, and interstitial fibrosis), and mortality. This is surprising because T4 excess or deprivation had significantly changed the outcome after TAC in young 8-week-old mice. Comparing the gene expression of deiodinases (Dio) 2 and 3 and TH receptor alpha (TRα) 1 and the dominant-negative acting isoform TRα2 between young and aged mice revealed that aged mice exhibited a higher expression of TRα2 and Dio3, while expression of Dio2 was reduced compared with young mice. These changes in Dio2 and 3 expressions might lead to reduced TH availability in the hearts of 12-month-old mice accompanied by reduced TRα action due to higher TRα2. In summary, our study shows that low and high TH availability have little impact on cardiac function and remodeling in older mice with preexisting pressure-induced cardiac damage. This observation seems to be the result of an altered expression of deiodinases and TRα isoforms, thus suggesting that even though cardiovascular risk is increasing with age, the response to TH stress may be dampened in certain conditions.

Regulation of Thyroid Hormone Gatekeepers by Thyrotropin in Tanycytes.

Background: Tanycytes are specialized glial cells within the mediobasal hypothalamus that have multiple functions, including hormone sensing and regulation of hypophysiotropic hormone secretion. There are ongoing discussions about the role of tanycytes in regulating the supply of hypothalamic thyroid hormones (THs) through the expression of TH transporters (Slc16a2, Slco1c1) and deiodinases (Dio2, Dio3). In this study, we investigated the potential feedback effect of thyrotropin (TSH) on the transcription of these gatekeeper genes on tanycytes. Methods: We analyzed the changes in the expression of TH-gatekeeper genes, in TSH-stimulated primary tanycytes, using quantitative polymerase chain reaction (qPCR). We also used RNAScope® in brain slices to further reveal the local distribution of the transcripts. In addition, we blocked intracellular pathways and used small-interfering RNA (siRNA) to elucidate differences in the regulation of the gatekeeper genes. Results: TSH elevated messenger RNA (mRNA) levels of Slco1c1, Dio2, and Dio3 in tanycytes, while Slc16a2 was mostly unaffected. Blockade and knockdown of the TSH receptor (TSHR) and antagonization of cAMP response element-binding protein (CREB) clearly abolished the increased expression induced by TSH, indicating PKA-dependent regulation through the TSHR. The TSH-dependent expression of Dio3 and Slco1c1 was also regulated by protein kinase C (PKC), and in case of Dio3, also by extracellular signal-regulated kinase (ERK) activity. Importantly, these gene regulations were specifically found in different subpopulations of tanycytes. Conclusions: This study demonstrates that TSH induces transcriptional regulation of TH-gatekeeper genes in tanycytes through the Tshr/Gαq/PKC pathway, in parallel to the Tshr/Gαs/PKA/CREB pathway. These differential actions of TSH on tanycytic subpopulations appear to be important for coordinating the supply of TH to the hypothalamus and aid its functions.

Two synchronous paraneoplastic endocrine syndromes in a 53-year-old male with broadly metastatic widely invasive Hürthle cell carcinoma.

Unlike medullary thyroid carcinomas, follicular cell-derived thyroid malignancies have rarely been associated with paraneoplastic endocrine syndromes. An ultrarare case of a middle-aged man with heavily treated broadly metastatic radioactive iodine-refractory widely invasive Hürthle cell carcinoma (HCC) of the thyroid with two synchronous paraneoplastic endocrine syndromes, T3 thyrotoxicosis and hypercalcemia of malignancy, is discussed here. The levothyroxine-induced T3 thyrotoxicosis was a gradual process that became more noticeable as the tumor burden, refractory to different modalities of therapy, expanded. The 1,25-dihydroxyvitamin-D-mediated hypercalcemia, on the other hand, developed in a manner of weeks, as it usually happens. It is important to emphasize that in patients with metastatic Hürthle cell and follicular carcinomas of the thyroid, on TSH suppressive therapy, the unexplained and progressive decline in FT4 and rise in FT3 levels, resulting in an elevated FT4/FT3 ratio, could be an indication of augmented type 1 (D1) and/or type 2 (D2) deiodinase expression in tumoral tissue, causing an increased conversion from the prohormone T4 into the active metabolite T3 via outer ring deiodination. Albeit extremely rare, some patients with thyroid cancer can present with more than one concomitant paraneoplastic syndrome. Although medullary thyroid carcinoma is the thyroid malignancy that is usually associated with paraneoplastic endocrine syndromes, follicular cell-derived thyroid cancers have been rarely described as being the culprit. In patients with metastatic Hürthle cell and follicular thyroid carcinomas, the unexplained and progressive decline in FT4 and rise in FT3 levels could be an indication of augmented type 1 (D1) and/or type 2 (D2) deiodinase expression in tumoral tissue, causing an increased conversion from T4 into T3 leading to T3 thyrotoxicosis.

FRI492 Malaria In Pregnancy And Lipopolyssacharide Lead To Sex-specific Changes In The Expression Of Genes Involved In The Placental Metabolism Of Thyroid Hormones

Abstract Disclosure: K.N. Fontes: None. V.S. Monteiro: None. C.B. Andrade: None. A.C. Valim: None. V.M. Nascimento: None. D.E. Teixeira: None. A.A. Pinheiro: None. E. Bloise: None. T.M. Ortiga-Carvalho: None. Infection during gestation promotes marked changes in placental physiology, leading to intrauterine growth restriction (IUGR), preterm labor (PTL) and neurodevelopmental disorders. Infection in pregnant women or mice may impact thyroid hormones’ (TH) metabolism and the importance of TH for the development of the placenta and conceptus is widely described in the literature. Our main aim was to evaluate changes in the expression of specific genes involved in placental TH metabolism triggered by malaria in pregnancy (MiP) or bacterial lipopolyssacharide (LPS), in the male and female placenta. Female C57BL/6 mice (8-10 weeks of age) were mated. In the MiP model, dams were infected ip with Plasmodium Berghei ANKA-infected erythrocytes (PBA; 5x105 infected-erythrocytes, n=10) or injected with PBS (contro; n=10) at gestational day (GD)13.5 and sacrificed at GD18.5. In the LPS model, dams were injected ip with LPS (150 µg/kg, n=10) or PBS (control; n=10) at GD17.5 and sacrificed at GD18.5. Maternal blood was collected to evaluate PBA parasitemia. Placental disks were collected from dams delivering at term (GD18.5), and qPCR was performed to evaluate the mRNA expression of genes involved in placental TH metabolism. MiP was confirmed by analysis of parasitemia (15.9%), and resulted in increased maternal spleen weight (P<0.05). As expected, MiP induced PTL (at GD17.5) in 23.1% of dams. Fetal weight and fetal/placental weight ratio were reduced in MiP (at term), compared to control (P<0.05). In the LPS model, 33.3% of dams went into PTL (at GD17.5) and fetal weight was reduced in LPS group (at term), compared to control (P<0.05). In both models, mRNA of the Cxcl1 chemokine (P<0.05) was increased in the male and female placenta at term (P<0.05). Male MiP placentas exhibited a reduction in Slc7a8 (P<0.05) and Dio2 (P<0.05) mRNA expression, whereas female MiP placentas exhibited a reduction in Slc7a8 (P<0.05) and an increase in Slco1c1 and Dio1 (P<0.05) at term. LPS increased Dio1 (P<0.05) mRNA in the male term placenta, and increased Ccl2 (P<0.05) mRNA in the term female placenta. In the present study, MiP was associated with sex-specific changes in the placental expression of TH transporters and deiodinases, while LPS injection promoted a limited effect on placental TH metabolism, but increased the expression of placental inflammatory markers at term. We speculate that these changes may result in reduced TH transport from mother to fetus, leading to IUGR among surviving fetuses, especially in pregnancies threatened by MiP. Presentation: Friday, June 16, 2023

Paternal developmental thyrotoxicosis disrupts neonatal leptin leading to increased adiposity and altered physiology of the melanocortin system.

The genetic code does not fully explain individual variability and inheritance of susceptibility to endocrine conditions, suggesting the contribution of epigenetic factors acting across generations. We used a mouse model of developmental thyrotoxicosis (Dio3-/- mouse) to analyze endocrine outcomes in the adult offspring of Dio3-/- males using standard methods for body composition, and baseline and fasting hormonal and gene expression determinations in serum and tissues of relevance to the control of energy balance. Compared to controls, adult females with an exposed father (EF females) exhibited higher body weight and fat mass, but not lean mass, a phenotype that was much milder in EF males. After fasting, both EF females and males exhibited a more pronounced decrease in body weight than controls. EF females also showed markedly elevated serum leptin, increased white adipose tissue mRNA expression of leptin and mesoderm-specific transcript but decreased expression of type 2 deiodinase. EF females exhibited decreased serum ghrelin, which showed more pronounced post-fasting changes in EF females than in control females. EF female hypothalami also revealed significant decreases in the expression of pro-opiomelanocortin, agouti-related peptide, neuropeptide Y and melanocortin receptor 4. These markers also showed larger changes in response to fasting in EF females than in control females. Adult EF females showed no abnormalities in serum thyroid hormones, but pituitary expression of thyrotropin-releasing hormone receptor 1 and thyroid gland expression of thyroid-stimulating hormone receptor, thyroid peroxidase and iodotyrosine deiodinase were increased at baseline and showed differential regulation after fasting, with no increase in Trhr1 expression and more pronounced reductions in Tshr, Tpo and Iyd. In EF males, these abnormalities were generally milder. In addition, postnatal day 14 (P14) serum leptin was markedly reduced in EF pups. A paternal excess of thyroid hormone during development modifies the endocrine programming and energy balance in the offspring in a sexually dimorphic manner, with baseline and dynamic range alterations in the leptin-melanocortin system and thyroid gland, and consequences for adiposity phenotypes. We conclude that thyroid hormone overexposure may have important implications for the non-genetic, inherited etiology of endocrine and metabolic pathologies.

Altered thyroid feedback loop in Klinefelter syndrome: a cohort study from infancy through the transition into adulthood.

Thyroid dysfunction has been claimed contributing to the spectrum of Klinefelter syndrome (KS); however, studies are scarce. In a retrospective longitudinal study, we aimed at describing the hypothalamus-pituitary-thyroid (HPT) axis and thyroid ultrasonographic (US) appearance in patients with KS throughout the life span. 254 patients with KS (25.9±16.1 years) were classified according to their pubertal and gonadal status and compared with different groups of non-KS age-matched subjects with normal thyroid function, treated and untreated hypogonadism, or chronic lymphocytic thyroiditis. We assessed serum thyroid hormone levels, anti-thyroid antibodies, US thyroid parameters, in vitro pituitary type 2 deiodinase (D2) expression and activity. Thyroid autoimmunity was more prevalent among subjects with KS at all ages, although the Ab negative vs. positive cohorts were not different. Signs of thyroid dysfunction (reduced volume, lower echogenicity, and increased inhomogeneity) were more prominent in KS than in euthyroid controls. Free thyroid hormones were lower in pre-pubertal, pubertal, and adult subjects with KS, while TSH values were only lower in adults. Peripheral sensitivity to thyroid hormones was unaltered in KS, suggesting a dysfunctional HPT axis. Testosterone (T) was the only factor associated with thyroid function and appearance. In vitro testing demonstrated an inhibitory effect of T on pituitary D2 expression and activity, supporting enhanced central sensing of circulating thyroid hormones in hypogonadism. From infancy through adulthood, KS is characterized by increased morpho-functional abnormalities of the thyroid gland, combined with a central feedback dysregulation sustained by the effect of hypogonadism on D2 deiodinase.

Effect of the Fetal THRB Genotype on the Placenta.

Pregnant women with mutations in the thyroid hormone receptor beta (THRB) gene expose their fetuses to high TH levels shown to be detrimental to a normal fetus (NlFe) but not to an affected (AfFe) fetus. However, no information is available about differences in placental TH regulators. To investigate whether there are differences in placentas associated with a NlFe compared to an AfFe, we had the unique opportunity to study placentas from two pregnancies of the same woman with THRB mutation G307D. One placenta supported a NlFe while the other an AfFe. Sections of placentas were collected and frozen at -80°C after term delivery of NlFe and AfFe. Two placentas from healthy women of similar gestational age were also obtained. The fetal origin of the placental tissues was established by gDNA quantitation of genes on the X and Y chromosomes and THRB gene. Expression and enzymatic activity of deiodinases 2 and 3 were measured. The following genes expression was also quantitated: MCT10, MCT8, LAT1, LAT2, THRB, THRA. The placenta carrying the AfFe exhibited a significant reduction of deiodinase 2 and 3 activities as well as the expression of the thyroid hormone transporters MCT10, LAT1 and LAT2 and the THRA. Here, we present the first study of the effect of fetal THRB genotype on the placenta. Though limited by virtue of the rarity of THRB mutations and sample availability, we show that the fetal THRB genotype influences the levels of thyroid hormone regulators in the placenta.

Uncovering Actions of Type 3 Deiodinase in the Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD).

To evaluate the role of D3 in the progression of MAFLD in an animal model. Male/adult Sprague Dawley rats (n = 20) were allocated to a control group (2.93 kcal/g) and high-fat diet group (4.3 kcal/g). Euthanasia took place on the 28th week. D3 activity and expression, Uncoupling Protein 2 (UCP2) and type 1 deiodinase (D1) expression, oxidative stress status, mitochondrial, Krebs cycle and endoplasmic reticulum homeostasis in liver tissue were measured. We observed an increase in D3 activity/expression (p < 0.001) related to increased thiobarbituric acid reactive substances (TBARS) and carbonyls and diminished reduced glutathione (GSH) in the MAFLD group (p < 0.05). There was a D3-dependent decrease in UCP2 expression (p = 0.01), mitochondrial capacity, respiratory activity with increased endoplasmic reticulum stress in the MAFLD group (p < 0.001). Surprisingly, in an environment with lower T3 levels due to high D3 activity, we observed an augmented alpha-ketoglutarate dehydrogenase (KGDH) and glutamate dehydrogenase (GDH) enzymes activity (p < 0.05). Induced D3, triggered by changes in the REDOX state, decreases T3 availability and hepatic mitochondrial capacity. The Krebs cycle enzymes were altered as well as endoplasmic reticulum stress. Taken together, these results shed new light on the role of D3 metabolism in MAFLD.

Temporal expression of thyroid hormone regulating genes (tsh-b, tsh-r, dio2 and dio3) and their correlation with annual reproductive cycle of the Indian freshwater catfish, Heteropneustes fossilis (Bloch).

Photoperiod and temperature are well-established environmental cues for gonadal growth in seasonally reproducing organisms. The photoperiod is known to regulate seasonal reproduction via induction of thyroid hormone regulating genes in the saccus vasculosus (SV) of fishes. However, SV is absent in many seasonally breeding fishes, including Heteropneustes fossilis. H. fossilis is a long-day breeding catfish in which gonadal recrudescence begins six months earlier than spawning. The present study attempted to analyse the expression of thyroid hormone-regulating genes (tsh-b, tsh-r, dio2 and dio3) in the brain, liver and ovary. In the brain, upregulated expression of thyrotropin-beta subunit (tsh-b), deiodinase2 (dio2) and deiodinase3 (dio3) genes is concomitant with the increasing photoperiod and temperature in nature, which may appear to regulate seasonal reproduction. Both deiodinases, dio2 and dio3, were also upregulated in the liver and ovarian tissue during the gonadal growth phase. The upregulation of deiodinases may enhance the metabolism and activity of tissues, thereby facilitating their respective roles. The expression of these genes was also assessed in the brain, liver, ovary, kidney, skin, spleen and gill tissues during the spawning period. The ubiquitous expression of deiodinases may point to enhanced activity in their organ-specific role. The present study speculates that expression of tsh-b, tsh-r, dio2 and dio3 genes during the reproductive phase of H. fossilis might be involved in the regulation of seasonal reproduction.

Deiodinases in thyroid tumorigenesis.

The three deiodinase selenoenzymes are key regulators of intracellular thyroid hormone (TH) levels. The two TH-activating deiodinases (type 1 deiodinase and type 2 deiodinase (D2)) are normally expressed in follicular thyroid cells and contribute to overall TH production. During thyroid tumorigenesis, the deiodinase expression profile changes to customize intracellular TH levels to different requirements of cancer cells. Differentiated thyroid cancers overexpress the TH-inactivating type 3 deiodinase (D3), likely to reduce the TH signaling within the tumor. Strikingly, recent evidence suggests that during the late stage of thyroid tumorigenesis, D2 expression raises and this, together with a reduction in D3 expression levels, increases TH intracellular signaling in dedifferentiated thyroid cancers. These findings call into question the different functions of TH in the various stages of thyroid cancers.

Vandetanib downregulates type 2 deiodinase in fibro/adipogenic progenitors.

Treatment with tyrosine kinase inhibitors (TKIs) has been associated with alterations in circulating thyroid hormone levels, possibly related to perturbations in peripheral thyroid hormone metabolism. In this study, we evaluated the effect of the multi-kinase inhibitor vandetanib on the expression of the three deiodinase selenoenzymes, responsible for the thyroid hormone activation (type 1 and type 2 deiodinases) or for its inactivation (type 3 deiodinase). Here, we show that the multi-kinase inhibitor vandetanib determines a strong cell-specific downregulation of type 2 deiodinase (D2) expression and a significant reduction in D2 enzymatic activity. This occurs in the diffused population of fibro/adipogenic progenitors, which reside in different tissues - including the muscles - and normally express D2. Given the widespread diffusion of mesenchymal cells within the body, our results may explain at least partially the alterations in thyroid hormone levels that occur in vandetanib-treated patients. Our findings represent a step forward into the understanding of the mechanisms by which TKIs induce hypothyroidism and identify a resident cell population in which such an effect takes place.

Factors of local conversion of iodothyronines correlate with indicators of hormonal, biochemical, and hematological profiles in patients with spinal canal and dural sac stenosis of the lumbar spine

In order to find out the mechanisms of pathogenesis of degenerative-dystrophic diseases of the spine, it is of particular interest to search for body parameters which are directly or indirectly interrelated with the key factors of peripheral conversion of nidus iodothyronines and constitute a system of network interactions, affecting metabolic indicators at the local and systemic level.The aim. To search for correlations of local key factors of peripheral conversion of Ligamentum flavum iodothyronines with indicators of biochemical, hematological and hormonal blood profiles of patients with stenosing processes of the spinal canal and dural sac in the lumbar spine.Materials and methods. 33 patients (15 males, 18 females) with stenosing processes of the spinal canal and dural sac in the lumbar spine were examined (mean age – 45.73 ± 1.95 years). The expression of deiodinase genes and other candidate genes was determined in Ligamentum flavum biopsies collected during surgical treatment. Biochemical, hematological and hormonal parameters were determined in peripheral blood. The resulting data array was processed in order to find correlations between the parameters of systemic and local metabolism.Results. The relationships of deiodinases with the expression of GDF5, MMP1, MMP3 and TIMP1 in Ligamentum flavum (p &lt; 0.05) were found. Of the hormonal profile of the blood serum, the most significant indicators were thyreotropin, free triiodothyronine and thyroperoxidase antibodies. In the biochemical profile, levels of direct bilirubin, total cholesterol, HDL and LDL cholesterol and triglycerides changed along with the expression of deiodinases. Correlative relationships with the expression of deiodinases were found for the following hematological analytes of whole peripheral blood: hemoglobin, mean corpuscular hemoglobin concentration, numbers of granulocytes, lymphocytes, eosinophils, monocytes, band neutrophils, red cell distribution width and platelet crit. The data obtained indicate the involvement of peripheral conversion factors in the pathogenetic process and provide information to form a new view on the pathogenesis of degenerative-dystrophic processes in the Ligamentum flavum of patients with stenosing processes of the spinal canal and the dural sac in the lumbar spine.

Thyroid hormone regulators in human cerebral cortex development.

Brain development is critically dependent on the timely supply of thyroid hormones. The thyroid hormone transporters are central to the action of thyroid hormones in the brain, facilitating their passage through the blood-brain barrier. Mutations of the monocarboxylate transporter 8 (MCT8) cause the Allan-Herndon-Dudley syndrome, with altered thyroid hormone concentrations in the blood and profound neurological impairment and intellectual deficit. Mouse disease models have revealed interplay between transport, deiodination, and availability of T3 to receptors in specific cells. However, the mouse models are not satisfactory, given the fundamental differences between the mouse and human brains. The goal of the present work is to review human neocortex development in the context of thyroid pathophysiology. Recent developments in single-cell transcriptomic approaches aimed at the human brain make it possible to profile the expression of thyroid hormone regulators in single-cell RNA-Seq datasets of the developing human neocortex. The data provide novel insights into the specific cellular expression of thyroid hormone transporters, deiodinases, and receptors.

RELEVANCE OF DEIODINASE ENZYMES IN HEART TRANSPLANT – PRELIMINARY STUDY

<h3>Objective</h3> The hypothalamic-pituitary-thyroid (HPT) axis plays a critical role in the regulation of metabolism throughout the neuroendocrine system. The low triiodothyronine (T3) syndrome appears in several critical conditions that require intensive care, such as heart transplant (HTx) which is the gold standard therapeutic intervention for patients with end-stage chronic heart failure. Low T3 syndrome is hallmarked by reduced serum thyroid hormone (TH) levels; missing or reduced response of the HPT axis; and tissue-specific changes of the expression of deiodinase enzymes, catalyzing TH hormone metabolism. Current research aimed to study the interaction between cardiac deiodinase expression and adverse outcomes after HTx. <h3>Design and Method</h3> This prospective, single center study was approved by the IRB (65/2017). Patients who underwent heart transplant at the Heart and Vascular Centre of Semmelweis University between 2012 and 2020 were enrolled in current research. Demographic and perioperative laboratory parameters, thyroid disorders and adverse outcomes were recorded in our database. Expression of the TH activating Deiodinase 2 (DIO2) and TH inactivating Deiodinase 3 (DIO3) enzymes was measured with TaqMan qPCR in cardiac tissue samples and were normalized to hypoxanthine phosphoribosyl transferase (HPRT). cDNA content of samples was measured by Qubit, and 30 ng of cDNA was used in each qPCR reaction. Descriptive statistics, Spearman's correlation and Mann-Whitney U test were applied for the statistical analysis. <h3>Results</h3> The final analysis was performed on 294 patients, of whom 77 were female (26.2%) and 217 were male (73.8%). The median age of donors was 54 years (IQR 25-75: 45-59), while the median follow-up was 1223 days (IQR 25-75: 399-1990). Prior to surgery, 53 patients (18.0%) had subclinical serum TH levels, of whom 37 (12.6%) were on TH replacement. Patients required postoperative mechanical circulation support (n: 50; 17.0%), underwent rejection (n: 47; 16.0%), and reoperation (n: 34; 11.6%) had significantly lower DIO2 and DIO3 expression (respectively p: 0.016; 0.001; 0.044). However, cardiac DIO2 expression was significantly higher in patients with postoperative acute kidney injury (n: 75; 25.5%) (p: 0.033). <h3>Conclusions</h3> Our results emphasize the importance of cardiac TH metabolism during the perioperative period of heart transplant as DIO2 and DIO3 enzymes expressions may predict the occurrence of some complications after heart transplant. Unidirectional changes of the TH activating and inactivating deiodinases during the perioperative period of heart transplant do not suggest a coordinated cellular effort to shift TH signaling in the cardiac tissue except in patients with postoperative acute kidney injury.for observation.

Deiodinases control local cellular and systemic thyroid hormone availability.

Iodothyronine deiodinases (DIO) are a family of selenoproteins controlling systemic and local availability of the major thyroid hormone l-thyroxine (T4), a prohormone secreted by the thyroid gland. T4 is activated to the active 3,3'-5-triiodothyronine (T3) by two 5'-deiodinases, DIO1 and DIO2. DIO3, a 5-deiodinase selenoenzyme inactivates both the prohormone T4 and its active form T3. DIOs show species-specific different patterns of temporo-spatial expression, regulation and function and exhibit different mechanisms of reaction and inhibitor sensitivities. The main regulators of DIO expression and function are the thyroid hormone status, several growth factors, cytokines and altered pathophysiological conditions. Selenium (Se) status has a modest impact on DIO expression and translation. DIOs rank high in the priority of selenium supply to various selenoproteins; thus, their function is impaired only during severe selenium deficiency. DIO variants, polymorphisms, SNPs and rare mutations have been identified. Development of DIO isozyme selective drugs is ongoing. A first X-ray structure has been reported for DIO3. This review focusses on the biochemical characteristics and reaction mechanisms, the relationships between DIO selenoproteins and their importance for local and systemic provision of the active hormone T3. Nutritional, pharmacological, and environmental factors and inhibitors, such as endocrine disruptors, impact DIO functions.

Effects of the synthetic progestin levonorgestrel on some aspects of thyroid physiology in common carp (Cyprinus carpio)

The objective of the present study was to assess the effects of levonorgestrel (LNG), a synthetic progestin, on early development and the thyroid system of carp using morphological, histological, immunohistochemical, and gene expression analysis. Fish were exposed to LNG at three levels (3, 31, and 310 ng L−1) from eggs to the onset of juvenile stage (47 days). LNG had no significant effect on early development in common carp or on the occurrence of morphological anomalies. No pathological alterations of the thyroid follicles were found. Immunohistochemical examination of the thyroid follicles using antibodies against thyroxin did not show any differences in fish exposed to 310 ng L−1 LNG compared to the controls. mRNA expression of iodothyronine deiodinases (dio1, 2, 3) was differentially affected by LNG treatment during carp development. Most importantly, dio3 was markedly downregulated in fish exposed to all three LNG levels compared to the controls at the conclusion of the experiment (47 days post-fertilization). A decrease in dio1 or dio3 or an increase in dio2 transcription observed at different time points of the study may be a sign of hypothyroidism. mRNA expression of genes npr, esr1, and esr2b in the body and npr and esr2b in the head of fish exposed to 310 ng L−1 LNG was significantly upregulated compared to the solvent control group at the end of the test. Together, these results show that levonorgestrel caused parallel changes in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-gonad axes.

Hypothalamic remodeling of thyroid hormone signaling during hibernation in the arctic ground squirrel

Hibernation involves prolonged intervals of profound metabolic suppression periodically interrupted by brief arousals to euthermy, the function of which is unknown. Annual cycles in mammals are timed by a photoperiodically-regulated thyroid-hormone-dependent mechanism in hypothalamic tanycytes, driven by thyrotropin (TSH) in the pars tuberalis (PT), which regulates local TH-converting deiodinases and triggers remodeling of neuroendocrine pathways. We demonstrate that over the course of hibernation in continuous darkness, arctic ground squirrels (Urocitellus parryii) up-regulate the retrograde TSH/Deiodinase/TH pathway, remodel hypothalamic tanycytes, and activate the reproductive axis. Forcing the premature termination of hibernation by warming animals induced hypothalamic deiodinase expression and the accumulation of secretory granules in PT thyrotrophs and pituitary gonadotrophs, but did not further activate the reproductive axis. We suggest that periodic arousals may allow for the transient activation of hypothalamic thyroid hormone signaling, cellular remodeling, and re-programming of brain circuits in preparation for the short Arctic summer.

Thyroxine Metabolism in an Avian Model of Induced Thyrotoxicosis

Craniosynostosis (CS) is the premature fusion of cranial sutures which leads to abnormal cranial structure and causes abnormal neurocognition and behavior. Maternal thyroid disorders are associated with incidence of CS in infants. However, the mechanism of TH-induced CS is still obscure. Thyroxine (T4) metabolism is regulated by the expression of deiodinases. Type I and type II deiodinases (DIO1 and DIO2) remove iodine from T4 producing active triiodothyronine (T3). Deiodinase III (DIO3) inactivates both T4 and T3. Our lab is establishing a model to study the effects of thyrotoxicosis induced CS using fertilized chicken eggs. Eggs were injected into the air cell with either saline or 25 ng T4 on days E11 and E15 of embryonic development. Heart rates were measured daily from EKG recordings and on E19, tissue samples were collected for qRT-PCR analysis. The main objective was to validate the induced state of thyrotoxicosis by evaluating negative feedback mechanisms of thyroid hormone regulation following exposure by measuring expression of DIO1 and DIO3 in embryonic livers. Since livers are the main site of metabolism, we hypothesize that levels of DIO3 will increase following thyroxine exposure. Results demonstrated a significant upregulation of DIO3 2 days after exposure and a significant downregulation 4 days following exposure. No significant differences were observed in DIO1 on any of the days after exposure. These results, along with correlating heart rates, support our model by of induced thyrotoxicosis by demonstrating the metabolism of thyroxine in response to our treatment regimen.&#x0D; &#x0D; &#x0D; Acknowledgment of NASA West Virginia Space Grant Consortium (Grant #80NSSC20M0055) and the Genomics Core Facility and WV-INBRE (NIH grant P20GM103434).&#x0D;

Thyroid hormone tinkering elicits integrated phenotypic changes potentially explaining rapid adaptation of color vision in cichlid fish.

Vision is critical for most vertebrates, including fish. One challenge that aquatic habitats pose is the high variability in spectral properties depending on depth and the inherent optical properties of the water. By altering opsin gene expression and chromophore usage, cichlid fish modulate visual sensitivities to maximize sensory input from the available light in their respective habitat. Thyroid hormone (TH) has been proposed to play a role in governing adaptive diversification in visual sensitivity in Nicaraguan Midas cichlids, which evolved in less than 4000 generations. As suggested by indirect measurements of TH levels (i.e., expression of deiodinases), populations adapted to short wavelength light in clear lakes have lower TH levels than ones inhabiting turbid lakes enriched in long-wavelength light. We experimentally manipulated TH levels by exposing 2-week-old Midas cichlids to exogenous TH or a TH inhibitor and measured opsin gene expression and chromophore usage (via cyp27c1 expression). Although exogenous TH induces long-wavelength sensitivity by changing opsin gene expression and chromophore usage in a concerted manner, TH-inhibited fish exhibit a visual phenotype with sensitivities shifted to shorter wavelengths. Tinkering with TH levels in eyes results in concerted phenotypic changes that can provide a rapid mechanism of adaptation to novel light environments.

Developmental thyroid disruption permanently affects the neuroglial output in the murine subventricular zone.

SummaryNeural stem cells (NSCs) in the adult brain are a source of neural cells for brain injury repair. We investigated whether their capacity to generate new neurons and glia is determined by thyroid hormone (TH) during development because serum levels peak during postnatal reorganization of the main NSC niche, the subventricular zone (SVZ). Re-analysis of mouse transcriptome data revealed increased expression of TH transporters and deiodinases in postnatal SVZ NSCs, promoting local TH action, concomitant with a burst in neurogenesis. Inducing developmental hypothyroidism reduced NSC proliferation, disrupted expression of genes implicated in NSC determination and TH signaling, and altered the neuron/glia output in newborns. Three-month-old adult mice recovering from developmental hypothyroidism had fewer olfactory interneurons and underperformed on short-memory odor tests, dependent on SVZ neurogenesis. Our data provide readouts permitting comparison with adverse long-term events following thyroid disruptor exposure and ideas regarding the etiology of prevalent neurodegenerative diseases in industrialized countries.