Thyroid Hormone Receptor Gene Research Articles

The Developmental Toxicity and Endocrine-Disrupting Effects of Fenpropathrin on Gobiocypris rarus during the Early Life Stage.

In the present study, the developmental toxicity and endocrine-disrupting effects of fenpropathrin on Gobiocypris rarus during the early life stage were studied using a semi-static water exposure method. The results showed that the LOEC (lowest observed effect concentration) of fenpropathrin on the incubation of rare minnow embryos was above 2.5 μg·L-1. The LOEC and NOEC (no observed effect concentration) of fenpropathrin on the developmental malformations and death indicators were 2.0 and 1.5 μg·L-1, respectively. After exposure to 1.5 μg·L-1 of fenpropathrin for 31 days, the expressions of androgen receptor genes (AR) and sex hormone-synthesis-related genes (CYP17 and CYP19a) were significantly decreased and the expressions of thyroid hormone receptor genes (TRβ) and aryl hydrocarbon receptor genes (AhR1a and AhR2) were significantly increased in juvenile Gobiocypris rarus. The expression levels of the androgen receptor gene (AR), estrogen receptor gene (ER1), and the sex hormone-synthesis-related genes (HMGR, CYP17, and CYP19a) were significantly decreased, while the estrogen receptor gene (ER2a), thyroid hormone receptor gene (TRβ), and aromatic hydrocarbon receptor genes (AhR1a and AhR2) were upregulated in juvenile Gobiocypris rarus under exposure to 2.0 μg·L-1 of fenpropathrin. Relatively low concentrations of fenpropathrin can affect the expression of sex hormone receptor genes, genes related to sex hormone synthesis, thyroid hormone receptor genes, and aromatic hydrocarbon receptor genes, thus interfering with the reproductive system, thyroid system, and metabolic level in Gobiocypris rarus. Therefore, more attention should be paid to the endocrine-disrupting effect caused by the pyrethroid insecticides in the water environment. Furthermore, studies on the internal mechanism of the endocrine-disrupting effect of pyrethroid insecticides on fish is needed in the future.

From maternal glucocorticoid and thyroid hormones to epigenetic regulation of offspring gene expression: An experimental study in a wild bird species.

Offspring phenotype at birth is determined by its genotype and the prenatal environment including exposure to maternal hormones. Variation in both maternal glucocorticoids and thyroid hormones can affect offspring phenotype, but the underlying molecular mechanisms, especially those contributing to long-lasting effects, remain unclear. Epigenetic changes (such as DNA methylation) have been postulated as mediators of long-lasting effects of early-life environment. In this study, we determined the effects of elevated prenatal glucocorticoid and thyroid hormones on handling stress response (breath rate) as well as DNA methylation and gene expression of glucocorticoid receptor (GR) and thyroid hormone receptor (THR) in great tits (Parus major). Eggs were injected before incubation onset with corticosterone (the main avian glucocorticoid) and/or thyroid hormones (thyroxine and triiodothyronine) to simulate variation in maternal hormone deposition. Breath rate during handling and gene expression of GR and THR were evaluated 14 days after hatching. Methylation status of GR and THR genes was analyzed from the longitudinal blood cells sampled 7 and 14 days after hatching, as well as the following autumn. Elevated prenatal corticosterone level significantly increased the breath rate during handling, indicating an enhanced metabolic stress response. Prenatal corticosterone manipulation had CpG-site-specific effects on DNA methylation at the GR putative promoter region, while it did not significantly affect GR gene expression. GR expression was negatively associated with earlier hatching date and chick size. THR methylation or expression did not exhibit any significant relationship with the hormonal treatments or the examined covariates, suggesting that TH signaling may be more robust due to its crucial role in development. This study provides some support to the hypothesis suggesting that maternal corticosterone may influence offspring metabolic stress response via epigenetic alterations, yet their possible adaptive role in optimizing offspring phenotype to the prevailing conditions, context-dependency, and the underlying molecular interplay needs further research.

A Historical Reflection on Scientific Advances in Understanding Thyroid Hormone Action.

Background: Thyroid hormone (TH) has actions in every tissue of the body and is essential for normal development, as well as having important actions in the adult. The earliest markers of TH action that were identified and monitored clinically, even before TH could be measured in serum, included oxygen consumption, basal metabolic rate, serum cholesterol, and deep tendon reflex time. Cellular, rodent, amphibian, zebrafish, and human models have been used to study TH action. Summary: Early studies of the mechanism of TH action focused on saturable-specific triiodothyronine (T3) nuclear binding and direct actions of T3 that altered protein expression. Additional effects of TH were recognized on mitochondria, stimulation of ion transport, especially the sodium potassium ATPase, augmentation of adrenergic signaling, role as a neurotransmitter, and direct plasma membrane effects. The cloning of the thyroid hormone receptor (THR) genes in 1986 and report of the THR crystal structure in 1995 produced rapid progress in understanding the mechanism of TH nuclear action, as well as the development of modified THR ligands. These findings revealed nuances of TH signaling, including the role of nuclear receptor coactivators and corepressors, repression of positively stimulated genes by the unliganded receptor, THR isoform-specific actions of TRα (THRA) and TRβ (THRB), and THR binding DNA as a heterodimer with retinoid-x-receptor (RXR) for genes positively regulated by TH. The identification of genetic disorders of TH transport and signaling, especially Resistance to Thyroid Hormone (RTH) and monocarboxylate transporter 8 (Mct8) defects, has been highly informative with respect to the mechanism of TH action. Conclusions: The impact of THR isoform, post-translational modifications, receptor cofactors, DNA response element, and selective TH tissue uptake, on TH action, have clinical implications for diagnosing and treating thyroid disease. Additionally, these findings have led to the development of novel TH and TH analogue therapies for metabolic, neurological, and cardiovascular diseases.

Noncoding Mutations in a Thyroid Hormone Receptor Gene That Impair Cone Photoreceptor Function.

The function of a hormone receptor requires mechanisms to control precisely where, when, and at what level the receptor gene is expressed. An intriguing case concerns the selective induction of thyroid hormone receptor β2 (TRβ2), encoded by Thrb, in the pituitary and also in cone photoreceptors, in which it critically regulates expression of the opsin photopigments that mediate color vision. Here, we investigate the physiological significance of a candidate enhancer for induction of TRβ2 by mutagenesis of a conserved intron region in its natural context in the endogenous Thrb gene in mice. Mutation of e-box sites for bHLH (basic-helix-loop-helix) transcription factors preferentially impairs TRβ2 expression in cones whereas mutation of nearby sequences preferentially impairs expression in pituitary. A deletion encompassing all sites impairs expression in both tissues, indicating bifunctional activity. In cones, the e-box mutations disrupt chromatin acetylation, blunt the developmental induction of TRβ2, and ultimately impair cone opsin expression and sensitivity to longer wavelengths of light. These results demonstrate the necessity of studying an enhancer in its natural chromosomal context for defining biological relevance and reveal surprisingly critical nuances of level and timing of enhancer function. Our findings illustrate the influence of noncoding sequences over thyroid hormone functions.

Effect of experimentally induced prepubertal hyperthyroidism on postubertal reproductive activity in male rats

This study was carried out to investigate the effect of induced prepubertal hyperthyroidism on the reproductive functions of male rats at the pubertal stage. Hyperthyroidism was induced by supplementing thyroxin in drinking water (0.002% w/v) and drenching of 200 μg/kg body weight. Sixty immature males (aged 50 days) were allocated to control and hyperthyroid (PH) groups, administered with distilled water and thyroxin, respectively. Each group was subdivided into three subgroups, sacrificed after 15 days (C15 and PH15), after administration for 15 days and left without treatment for 15 days (C15+ and PH15+), or after 30 days (C30 and PH30). After each period, body weight and relative weight of genital organs were recorded. Serum concentrations of thyroid stimulating hormone (TSH), thyroxin (TT4), triiodothyronine (TT3), follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone was assessed. The expression levels of testicular inha and thyroid hormone receptor (THR) genes were analyzed. Histopathological examination of testis was studied. Compared with control, PH group male rats showed decreased body weight gain and genital organ weights at all experimental periods, increased levels of serum TT4, TT3, and LH, decreased levels of TSH, FSH, and testosterone, and lower expression levels of testicular inha and THR genes. Testicular sections of PH group male rats, showed reduced germinal epithelium, vacuolation, and decreased the number of spermatocytes and Sertoli cells compared with control. In conclusion, the disturbed fluctuations of sex steroid hormones due to prepubertal hyperthyroidism might cause retardation of the testes’ development.

Acute nitrite exposure interferes with intestinal thyroid hormone homeostasis in grass carp (Ctenopharyngodon idellus)

Nitrite in the aquatic environment potentially disturbs thyroid hormone (TH) homeostasis in peripheral tissues, but little is known about TH metabolism in the intestine. This study investigated the serum concentrations of THs and thyroid-stimulating hormone (TSH) as well as the activity of intestinal iodothyronine deiodinases (IDs) of grass carp (Ctenopharyngodon idellus) exposed to various concentrations of nitrite (0, 8, 25, or 50 mg/L) for 96 h. Acute nitrite exposure significantly altered the triiodothyronine (T3) levels and the morphology of thyroid follicles at 96 h. Thyroxine (T4), free T4 levels and intestinal IDs activities showed an increase trend under nitrite stress. After 96 h exposure, nitrite down-regulated the expressions levels of intestinal Akt1 protein, sugar transporter genes, and thyroid hormone receptor (TR) signaling pathway genes except for tr ɑ1 and tr ɑ2. Moreover, the expressions levels of pparγ, cpt1α, cd36, fabp2 and fatp4 were down-regulated, whereas fabp6 and lpl were up-regulated in the 50 mg/L exposure group at 96 h. The results indicate that acute nitrite exposure has the potential to disturb the homeostasis of intestinal TH metabolism, which in turn alters TRs genes transcription, down-regulates sugar transporter activities, and promotes the energy expenditure in gut of grass carp.

Larval metamorphosis is inhibited by methimazole and propylthiouracil that reveals possible hormonal action in the mussel Mytilus coruscus

Larval metamorphosis in bivalves is a key event for the larva-to-juvenile transformation. Previously we have identified a thyroid hormone receptor (TR) gene that is crucial for larvae to acquire “competence” for the metamorphic transition in the mussel Mytilus courscus (Mc). The mechanisms of thyroid signaling in bivalves are still largely unknown. In the present study, we molecularly characterized the full-length of two iodothyronine deiodinase genes (McDx and McDy). Phylogenetic analysis revealed that deiodinases of molluscs (McDy, CgDx and CgDy) and vertebrates (D2 and D3) shared a node representing an immediate common ancestor, which resembled vertebrates D1 and might suggest that McDy acquired specialized function from vertebrates D1. Anti-thyroid compounds, methimazole (MMI) and propylthiouracil (PTU), were used to investigate their effects on larval metamorphosis and juvenile development in M. coruscus. Both MMI and PTU significantly reduced larval metamorphosis in response to the metamorphosis inducer epinephrine. MMI led to shell growth retardation in a concentration-dependent manner in juveniles of M. coruscus after 4 weeks of exposure, whereas PTU had no effect on juvenile growth. It is hypothesized that exposure to MMI and PTU reduced the ability of pediveliger larvae for the metamorphic transition to respond to the inducer. The effect of MMI and PTU on larval metamorphosis and development is most likely through a hormonal signal in the mussel M. coruscus, with the implications for exploring the origins and evolution of metamorphosis.

Thyroid Hormone Resistance Syndrome Presenting as Exercise Induced Asthma

Background: Pathogenic variants in the thyroid hormone receptor (THRB) gene are associated with thyroid hormone resistance. Over 85% of the genetic mutations are in the beta TR gene. The disorder is characterized mainly by elevated thyroid hormone levels, unsuppressed levels of TSH, and goiter. Clinical case: An 11-year-old male initially seen at the PCP office for tachycardia and chest discomfort, especially during school exercise. He reported shortness of breath. His symptoms will resolve at rest. He was diagnosed initially with asthma and was put on Singular, Pulmicort, and albuterol as needed. His symptoms did not improve with this treatment, and he reported symptoms worsened with albuterol. He had a normal Echocardiogram and chest X-ray. A mild goiter was noted on his physical exam. Thyroid ultrasound showed an enlarged thyroid gland. An ovoid echogenic focus in the inferior thyroid lobe measuring 4 X 7 X 8mm was identified. The nodule was wider than tall, with a solid appearance with no internal color flow. Evaluation in our clinic showed normal TSH at 1.624mcIU/mL (0.35-5.5). FT4 was high at 1.54ng/dL (0.82-1.40), and FT3 elevated at 6.3pg/mL (3.3-4.8). Thyroid antibodies and thyroid-stimulating immunoglobulin (TSI) were normal. A 24 hour I-123 thyroid uptake was approximately 55% (10-30%) with no focal increased or decreased uptake. Given his elevated thyroid hormone levels with unsuppressed TSH in the context of goiter and tachycardia, genetic testing for the Thyroid receptor gene was done. He was found to be heterozygous for a pathogenic variant in THRB, c.1286G>A (p.Arg429Gln). This genotype is consistent with a diagnosis of autosomal dominant Thyroid hormone resistance. The patient was started on Atenolol, given his elevated heart rate, and he reported improvement in his symptoms during exercise. Conclusion: Thyroid hormone resistance was first described as a clinical entity in 1967. The phenotype can vary among individuals. It is characterized by a reduced responsiveness of target tissue to thyroid hormone and binding affinity. The disease can present with goiter, behavioral issues, abnormal growth, and tachycardia. Affected individuals may have attention deficit-hyperactivity disorders (ADHD) and language difficulties. Thyroid hormone resistance can be misdiagnosed, as in our patient. He was diagnosed with asthma and was put on unnecessary medications that worsened his symptoms. Thyroid hormone resistance can also be misdiagnosed with Graves’ disease, given the elevated thyroid hormone. It is essential to highlight the importance of genetic testing in these cases, as an accurate diagnosis will prevent unnecessary treatments with potentially serious side effects.

Transcriptome Profiling of Long Non-coding RNAs During the Atlantic Salmon Smoltification Process.

For salmon aquaculture, one of the most critical phase is the parr-smolt transformation. Studies around this process have mainly focused on physiological changes and the Na+/K+-ATPase activity during the osmoregulatory activity. However, understanding how the salmon genome regulates the parr-smolt transformation, specifically the molecular mechanisms involved, remains uncovered. This study aimed to explore the transcriptional modulation of long non-coding RNAs (lncRNAs), as key molecular regulators, during the freshwater (FW) to seawater (SW) transfer in Atlantic salmon. Transcriptome sequencing was performed from gill samples of Atlantic salmon adapted from FW to SW through gradual salinity changes from 0 to 30 PSU. The results showed that most transcripts differently modulated were downregulated in all salinity conditions. Relevant biological processes were associated with growth, collagen formation, immune response, metabolism, and heme transport. Notably, 2864 putative lncRNAs were identified in Atlantic salmon gills differently expressed during fish smoltification. The highest number of lncRNAs differently modulated was observed at 30 PSU. Correlation expression analysis suggests putative regulatory roles of lncRNAs with smoltification-related genes. Herein, co-localization of Na+/K+-ATPase, growth hormone receptor, and thyroid hormone receptor genes with lncRNAs differentially expressed suggest putative regulatory mechanisms in the Atlantic salmon genome. The lncRNAs can be used as novel biomarkers for the fish smoltification process. Here, the lncRNA_145326 and lncRNA_18762 are putatively related to the parr-smolt transfer in Atlantic salmon. This study is the first description of lncRNAs with putative regulatory roles in Atlantic salmon during the SW adaptation.

Ethionamide Alters Thyroid Receptor Gene Expression in Rats' Muscle

BACKGROUND: Ethionamide usage as one of the drug regimens still becomes a challenge due to high numbers of patients developing hypothyroid. Ethionamide had been associated with the inhibition of thyroid hormone (TH) synthesis and interestingly, ethionamide (C8H10N2S)-induced hypothyroidism is supported by its similar structure with thioamides, propythiouracil (C7H8N2S). However, hypothyroidism is not solely caused by its production, it could be caused by signaling alteration. Therefore, knowing that important TH action is determined via genomic pathway, alteration of this receptor could bring serious clinical problem. Unfortunately, there is limited study about the regulation of ethionamide and its connection on TH genomic signaling especially thyroid hormone receptor (TR) gene expression in soleus, gastrocnemius and cardiac muscle.METHODS: Thirty-eight rats were divided into control, ethionamide and propylthiouracyl groups. After 12-week treatment, rat were sacrificed, then gastrocnemius, soleus and cardiac muscles were dissected out, snap freezed using liquid nitrogen, and stored in -80oC until use. RNA was extracted and run for reverse transcription polymerase chain reaction (RT-PCR).RESULTS: In soleus muscle, ethionamide stimulated TR mRNA expressions and deiodinase compared to control group. In contrast, TRα1 gene expression was not affected by ethionamide administration. In gastrocnemius muscle, only TRβ1 gene and Dio2 gene expressions that were significantly increased compared to control group. In cardiac muscle, ethionamide significantly stimulated all the thyroid hormone receptor isoform and iodothyronine deiodinase gene expression compared to the control group.CONCLUSION: Long ethionamide treatment upregulates TR gene expressions and deiodinase in soleus and cardiac muscle, there is different expression pattern of soleus, gastrocnemius and cardiac muscle after ethionamide stimulation.KEYWORDS: ethionamide, hypothyroid, TRα1, TRα2, TRβ1, TRβ2

Analysis of Thyroid Hormone Receptor α-Knockout Tadpoles Reveals That the Activation of Cell Cycle Program Is Involved in Thyroid Hormone-Induced Larval Epithelial Cell Death and Adult Intestinal Stem Cell Development During Xenopus tropicalis Metamorphosis.

Background: There are two highly conserved thyroid hormone (triiodothyronine [T3]) receptor (TR) genes, TRα and TRβ, in all vertebrates, and the expression of TRα but not TRβ is activated earlier than T3 synthesis during development. In human, high levels of T3 are present during the several months around birth, and T3 deficiency during this period causes severe developmental abnormalities including skeletal and intestinal defects. It is, however, difficult to study this period in mammals as the embryos and neonates depend on maternal supply of nutrients for survival. However, Xenopus tropicalis undergoes a T3-dependent metamorphosis, which drastically changes essentially every organ in a tadpole. Of interest is intestinal remodeling, which involves near complete degeneration of the larval epithelium through apoptosis. Concurrently, adult intestinal stem cells are formed de novo and subsequently give rise to the self-renewing adult epithelial system, resembling intestinal maturation around birth in mammals. We have previously demonstrated that T3 signaling is essential for the formation of adult intestinal stem cells during metamorphosis. Methods: We studied the function of endogenous TRα in the tadpole intestine by using knockout animals and RNA-seq analysis. Results: We observed that removing endogenous TRα caused defects in intestinal remodeling, including drastically reduced larval epithelial cell death and adult intestinal stem cell proliferation. Using RNA-seq on intestinal RNA from premetamorphic wild-type and TRα-knockout tadpoles treated with or without T3 for one day, before any detectable T3-induced cell death and stem cell formation in the tadpole intestine, we identified more than 1500 genes, which were regulated by T3 treatment of the wild-type but not TRα-knockout tadpoles. Gene Ontology and biological pathway analyses revealed that surprisingly, these TRα-regulated genes were highly enriched with cell cycle-related genes, in addition to genes related to stem cells and apoptosis. Conclusions: Our findings suggest that TRα-mediated T3 activation of the cell cycle program is involved in larval epithelial cell death and adult epithelial stem cell development during intestinal remodeling.

Thyroid Hormone Resistant Syndrome

Thyroid hormone resistance (THR), also known as resistance to thyroid hormone (RTH), is an inherited condition characterized by reduced end-organ responsiveness to thyroid hormone, caused by mutations in the thyroid hormone receptor gene. Patients typically present with elevated thyroid hormone levels (T3 and T4) with normal, or slightly elevated thyroid-stimulating hormone (TSH) levels.1 In a majority of cases, the disease is caused by a mutation in the thyroid receptor beta (TR-beta) gene. Patients can present with signs and symptoms of hypothyroidism or hyperthyroidism or can be asymptomatic. We present a case of a 16-year-old male who was referred for endocrinologic evaluation after abnormal findings in the thyroid function panel.

Thyroid-Disrupting Activities of Groundwater from a Riverbank Filtration System in Wuchang City, China: Seasonal Distribution and Human Health Risk Assessment

The recombinant thyroid hormone receptor (TR) gene yeast assay was used to evaluate thyroid disruption caused by groundwater from the riverbank filtration (RBF) system in Wuchang City, China. To investigate seasonal fluctuations, groundwater was collected during three seasons. Although no TR agonistic activity was found, many water samples exhibited TR antagonistic activity. The bioassay-derived amiodarone hydrochloride (AH) equivalents ranged from 2.99 to 274.40 μg/L. Water samples collected from the riverbank filtration system during the dry season had higher TR antagonistic activity. All samples presented adverse 3,3′,5-triiodo-L-thyronine (T3) equivalent levels, ranging from −2.00 to −2.12 μg/kg. Following exposure to water samples with substantial TR antagonist activity, predicted hormonal changes in humans of different gender and age ranged from 0.65 to 1.48 μg/kg of T3, being 47% to 231% of normal. No obvious difference was found between genders or among age groups. Overall, the results revealed that the RBF system could remove the thyroid-disrupting chemicals in the river water to some extent. Considering the varying degrees of risk to human health, further treatment is needed to remove the potential thyroid-disrupting chemicals in pumping water after riverbank filtration to ensure drinking water safety.

Thyroid hormone receptor: A new player in epinephrine-induced larval metamorphosis of the hard-shelled mussel

Many marine invertebrate larvae undergo a dramatic morphological and physiological transition from a planktonic larva to a benthic juvenile. The mechanisms of this metamorphosis in bivalves are mainly unknown. The recent identification in bivalves of a thyroid hormone receptor (TR) gene raises the possibility that as occurs in vertebrate metamorphosis, TRs regulate this developmental process. An evolutionary study of TR receptors revealed they are ubiquitous in the molluscs. Knock-down of the TR gene in pediveliger larvae of the hard-shelled mussel, Mytilus coruscus (Mc), using electroporation of siRNA significantly (p < 0.01) reduced TR gene expression. TR gene knock-down decreased pediveliger larval metamorphosis by 54% and was associated with a significant (p < 0.01) reduction in viability compared to control larvae. The TR in the hard-shelled mussel appears to be an essential regulatory factor for the successful epinephrine-induced metamorphosis of the pediveliger larvae to post-larvae. It is hypothesised that the knock-down of TR by siRNA transfection affects the “competence” of pediveliger larvae for the metamorphic transition by reducing their ability to respond to the inducer. The involvement of TR in the epinephrine-induced metamorphosis of a mollusc, the hard-shelled mussel, suggests the role of TR in this process probably emerged early during evolution.

The enrichment and purification of hexabromocyclododecanes and its effects on thyroid in zebrafish

Hexabromocyclododecanes (HBCDs) are the third most highly produced brominated flame retardants (BFRs) all over the world. Based on the current research status of HBCDs, zebrafish were exposed to three dietary concentrations of HBCDs (0, 10, 100, 400 ng/g) for 56 days, and followed by clean food for 28 days. In order to investigate the enrichment and purification of HBCDs in zebrafish, HBCD enantiomers in zebrafish were determined using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). To investigate the effects of long-term exposure of HBCDs on thyroid dysfunction and oxidative stress in zebrafish, the concentrations of thyroid hormone (T3, T4, FT3 and FT4) and the activities of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH) were measured. RT-PCR was used to reveal the molecular mechanism of HBCDs' influence on thyroid hormone in zebrafish. The result of UPLC-MS/MS showed that there were three main reasons for the existence of α-HBCD as the major isomer in the organism. HBCDs had significant inhibitory effect on T3 and T4 in liver of adult zebrafish after 56 days’ exposure. Compared with the control group, the ratio of T3 and T4was significantly higher in the medium and high concentration group. The content of FT3 and FT4 in the liver tissue of zebrafish increased first and then decreased with the increase of exposure concentration. With the increase of exposure concentration, the content of MDA in zebrafish liver decreased firstly and then increased. The activity of SOD and CAT in zebrafish liver showed the opposite trend with MDA. And the concentration of GSH in liver decreased gradually, which showed a significant dose-effect relationship. HBCDs exposure has an inhibitory effect on thyroid hormone receptor gene (TRβ) and adrenocorticotropin-releasing hormone gene (Crh) in zebrafish.

Syndromes of Resistance to Thyroid Hormone Action.

Thyroid hormone (TH) action is crucial for the development of several tissues.A number of syndromes are associated with reduced responsiveness to thyroid hormones, expanding the original definition of thyroid hormone resistance, firstly described by Refetoff and collaborators in 1967, which is characterized by elevated circulating levels of T4 and T3 with measurable serum TSH concentrations, as a consequence of mutations of thyroid hormone receptor beta (TRβ), recently named as RTHβ. More recently, another form of insensitivity to TH has been identified due to mutations in the thyroid hormone receptor alpha (TRα), named RTHα. In this chapter we will focus the discussion on the phenotype of RTHβ and RTHα. These diseases share the same pathogenic mechanism caused by dominant negative mutations in TH receptor genes that reduce T3 binding or affect the recruitment of cofactors. As a consequence, thyroid hormone actions are impaired at the tissue level. The phenotypic manifestations of RTHβ and RTHα are to some extent correlated with the degree of disruption and the tissue distribution of the TRs being characterized by variable coexistence of hypothyroid or thyrotoxic manifestations in RTHβ or by a congenital hypothyroid features in RTHα despite normal TSH and borderline low free T4.

Thyroid Hormone Resistance in Identical Twin Sisters with Atrial Fibrillation: Case Report and Review of the Literature.

To report identical twin sisters harboring the A317T mutation in the thyroid hormone beta receptor gene (TR β) who developed atrial fibrillation and refractory congestive heart failure in the sixth decade of life. To critically assess whether the A317T mutation may be responsible for increased cardiotoxicity compared to other thyroid hormone beta receptor gene mutations. A 59-year-old woman referred for evaluation of abnormal thyroid function tests had been experiencing frequent spells of tachycardia associated with dyspnea, and dizziness necessitating multiple hospitalizations. Elevation in free thyroxine (T4), total triiodothyronine (T3) and inappropriately normal thyroid stimulating hormone (TSH) was consistent with a clinical diagnosis of thyroid hormone resistance. Magnetic resonance imaging of the brain was negative for a TSH-secreting pituitary adenoma. A blood sample was sent for thyroid hormone receptor gene mutational analysis, but it would require eight weeks to complete processing. A modified L-T3 suppression test was used to assess thyroid-pituitary axis feedback. After three weeks' of cytomel (L-T3) (25 micrograms daily) TSH decreased by 50%, and free T4 level decreased by 22% compared to baseline levels. Genetic testing revealed a heterozygous A317T mutation in the thyroid hormone beta receptor gene. Serial two-dimensional echocardiography demonstrated evolution to left atrial enlargement over a three-year period. Prior published literature suggests a less than 10% prevalence of atrial fibrillation in adults with thyroid hormone resistance harboring various TR-β gene mutations. Yet all five of five (100%) adults having the A317T mutation were reported to experience atrial fibrillation by age 50. A new kindred with resistance to thyroid hormone harboring the A317T disease-causative mutation is described in which identical twin sisters had a mid-life onset of atrial fibrillation and refractory congestive heart failure.

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Oral and dermal diflubenzuron exposure causes a hypothalamic–pituitary–thyroid (HPT) axis disturbance in the Mongolian racerunner (Eremias argus)

Diflubenzuron (DFB) is a potential endocrine-disrupting chemical. However, its thyroid endocrine effect on reptiles has not been reported. In this study, immature lizards (Eremias argus) were exposed to 20 mg kg−1 DFB once a week for 42 days through oral or dermal routes. Their body weight, plasma thyroid hormone levels, thyroid gland histology and the transcription of hypothalamic–pituitary–thyroid (HPT) axis-related genes in different tissues were assessed to explore the effects of DFB on the HPT axis of lizards. The body weight decreased significantly only after the dermal exposure to DFB. Triiodothyronine (T3) to thyroxine (T4) ratio in the male plasma also significantly increased after the dermal exposure. After oral exposure, the activity of thyroid gland was positively related to the thyroid hormone levels. Furthermore, the alterations in thyroid hormone levels affected the HPT axis-related gene expression, which was tissue dependent and sexually selected. The thyroid hormone receptor genes (trα and trβ) in the brain and thyroid were more sensitive to oral exposure. However, only the dermal treatment affected the trα, trβ and type 2 deiodinase (dio2) genes in the male liver. These results suggest that DFB exposure caused sex-specific changes in the thyroid function of lizards, and the dermal treatment may be an important route for the risk assessment of reptiles.

CORRIGENDUM.

Molecular EcologyVolume 26, Issue 14 p. 3851-3851 CORRIGENDUMFree Access CORRIGENDUM This article corrects the following: Fine-grained adaptive divergence in an amphibian: genetic basis of phenotypic divergence and the role of nonrandom gene flow in restricting effective migration among wetlands Alex Richter-Boix, María Quintela, Marcin Kierczak, Marc Franch, Anssi Laurila, Volume 22Issue 5Molecular Ecology pages: 1322-1340 First Published online: January 7, 2013 First published: 04 July 2017 https://doi.org/10.1111/mec.14161AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat ALEX RICHTER - BOIX, MARIA QUINTELA, MARCIN KIERCZAK, MARC FRANCH, ANSSI LAURILA In the published paper (Richter-Boix et al. 2013), we incorrectly stated that we sequenced the protein-coding region of the thyroid hormone receptor gene (TRβ). The gene sequenced was in fact the gene C/EBP-1, a thyroid hormone receptor gene and transcription factor. As a consequence, instead of TRβ, it should read “the thyroid hormone receptor gene C/EBP-1” throughout the paper and supporting information of the article online. This error, however, does not strongly affect the main interpretation of our results. The C/EBP-1 gene, as the TRβ gene, is a thyroid hormone receptor with the dual function of repressing or activating thyroid-induced gene expression before or during tadpole metamorphosis. The C/EBP-1 gene, like TRβ, is a primary early TH-response gene during metamorphosis (Becker, Schneider, Davey, & Galton, 1995; Chen & Atkinson, 1997; Mochizuki, Goda, & Yamauchi, 2012; Murata & Yamauchi, 2005). It is not a general TH-receptor, but a specific one involved in the reprogramming of gene expression in the liver during amphibian metamorphosis (Chen & Atkinson, 1997; Chen, Hu, & Atkinson, 1994). The C/EBP-1 gene is a homologue to the mammalian C/EBP-α gene, which is known to play an essential role in cell cycle, hematopoiesis, differentiation and host immune response (Tsukada, Yoshida, Kominato, & Auron, 2011). Metamorphosis of a tadpole to a frog involves coordination between environmental cues, endocrine system and tissue-specific developmental programmes, like the one described in the tadpole liver tissue, which orchestrate changes in form and function required in the transition from aquatic to terrestrial lifestyle. We would like to thank Yvonne Meyer-Lucht for pointing this out. References Becker, K. B., Schneider, M. J., Davey, J. C., & Galton, V. A. (1995). The type III 5-deiodinase in Rana catesbeiana tadpoles is encoded by a thyroid hormone-responsive gene. Endocrinology, 136, 4424– 4431. Chen, Y., & Atkinson, B. G. (1997). Role for the Rana catesbeiana homologue of C/EBP α in the reprogramming of gene expression in the liver of metamorphosing tadpoles. Developmental Genetics, 20, 152– 162. Chen, Y., Hu, H., & Atkinson, B. G. (1994). Characterization and expression of C/EPB-like genes in the liver of Rana catesbeiana tadpoles during spontaneous and thyroid hormone-induced metamorphosis. Developmental Genetics, 15, 366– 377. Mochizuki, K., Goda, T., & Yamauchi, K. (2012). Gene expression profile in the liver of Rana catesbiana tadpoles exposed to low temperature in the presence of thyroid hormone. Biochemical and Biophysical Research Communications, 420, 845– 850. Murata, T., & Yamauchi, K. (2005). Low-temperature arrest of the triiodothyronine-dependent transcription in Rana catesbeiana red blood cells. Endocrinology, 146, 256– 264. Richter-Boix, A., Quintela, M., Kierczak, M., Franch, M., & Laurila, A. (2013). Fine-grained adaptive divergence in an amphibian: Genetic basis of phenotypic divergence and the role of nonrandom gene flow in restricting effective migration among wetlands. Molecular Ecology, 22, 1322– 1340. Tsukada, J., Yoshida, Y., Kominato, Y., & Auron, P. E. (2011). The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation. Cytokine, 54, 6– 19. Volume26, Issue14July 2017Pages 3851-3851 ReferencesRelatedInformation