Thyroid Hormone Regulation Research Articles

A unified mathematical model of thyroid hormone regulation and implication for personalized treatment of thyroid disorders

Current clinician practice for thyroid hormone regulation of patients is based upon guesswork and experience rather than quantified analysis, which exposes patients under longer risk and discomfort. To quantitatively analyze the thyroid regulation for patients of different thyroid states, we develop a two-dimensional mathematical model that can be applied to analyze the dynamic behaviors of thyroid hormones with or without drug intervention. The unified model can be employed to study the regulation of TSH (thyroid-stimulating hormone) and FT4 (free thyroxine) for euthyroid (normal thyroid) subjects, Hashimoto’s thyroiditis, and Graves’ disease patients, respectively. The results suggest that the level of TPOAb (thyroid peroxidase antibody) may be a factor determining whether the patient would progress from euthyroid state to subclinical or clinical hypothyroidism, and that increased TRAb (TSH receptor antibody) may lead Graves’ disease to deteriorate from the early stage to overt hyperthyroidism. Given the early blood-test data, we demonstrate the feasibility for healthcare professionals to apply our model in choosing an appropriate dosage regimen for patients to achieve the desired TSH and FT4 levels within a specified time frame. This proposed model has the potential to optimize personalized treatment and shorten the therapeutic time for patients suffering from Hashimoto’s thyroiditis and Graves’ disease.

Retraction.

Retraction: "Receptor for advanced glycation end products reveals a mechanism regulating thyroid hormone secretion through the SIRT1/Nrf2 pathway," by Xiao-Jun Chen, Xiao-Hua Gong, Jin-Ping Jie, Wei-Hui Yu, Xiong Chen, Xuan Du, Qi Zhou, and Wen-Jun Wu, J Cell Biochem. 2019; 4582-4598: The above article, published online on 15 October 2018 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/10.1002/jcb.27747) has been retracted by agreement between the authors, the journal's Editor in Chief, Prof. Dr. Christian Behl, and Wiley Periodicals LLC. The retraction has been agreed after the authors stated that the experimental data in the article could not be reproduced. Thus, the conclusions are considered to be invalid. The authors were not available for a final confirmation of the retraction.

Huge Obstructive Multinodular Goitre in a Pregnant Lady With Pre -Eclampsia: A Therapeutic Dilemma

In pregnancy there are changes in regulation of thyroid hormone that can affect hypothalamic pituitary thyroid axis. This goitrogenic stimulation can lead to enlargement of thyroid gland. We present a case of 37-year-old woman gravida 4, para 3 at 27-week gestation, who was referred for management of a huge multinodular goitre with impending upper airway obstruction. Severe pre-eclampsia made airway narrower due to oedema at pharyngeal and glottic region. In case of no life-threatening airway, surgery can be electively performed after delivery as to avoid preterm labour. However, if emergency lower segment caesarean section is needed, preferably it to be done under regional anaesthesia in severe preeclampsia cases. If this fails, general anaesthesia may be required with awake fiberoptic, jet ventilation and bronchoscopy standby in case of difficult intubation due to constricted airway. Our patient underwent emergency lower segment caesarean section under spinal anaesthesia at 31 weeks gestation due to severe pre-eclampsia. Right hemithyroidectomy was done three months postnatal. Obstructive symptoms resolved after operation.International Journal of Human and Health Sciences Vol. 05 No. 04 October’21 Page: 514-518

Effects of genetic selection on activity of corticotropic and thyrotropic axes in modern broiler chickens

Commercial selection for meat-type (broiler) chickens has produced economically valuable birds with fast growth rates, enhanced muscle mass, and highly efficient feed utilization. The physiological changes that account for this improvement and unintended consequences associated with them remain largely unexplored, despite their potential to guide further advancements in broiler production efficiency. To identify effects of genetic selection on hormonal signaling in the adrenocorticotropic and thyrotropic axes, gene expression in muscle and liver and post-hatch circulating hormone concentrations were measured in legacy [Athens Canadian Random Bred (ACRB)] and modern (Ross 308) male broilers between embryonic days (e) 10 and e18 and post-hatch days (d) 10 and d40. No interactive effects or main effects of line were observed for adrenocorticotropic gene expression during either developmental period, although age effects appeared for corticosteroid-binding globulin in liver during embryogenesis and post-hatch and glucocorticoid receptor in both tissues post-hatch. There was a main line effect for circulating corticosterone, with levels in ACRB greater than those in Ross. Several thyrotropic genes exhibited line-by-age interactions during embryonic or post-hatch development. In liver, embryonic expression of thyroid hormone receptor beta was greater in ACRB on e12, and deiodinase 3 (DIO3) levels were greater in Ross on e14 and e16. In juvenile liver, deiodinase 2 (DIO2) expression was greater in ACRB on d10 but greater in Ross on d20, while DIO3 was higher in ACRB on d30 and d40. Levels of thyroid hormone receptor alpha mRNA exhibited a main line effect, with levels greater in ACRB juvenile breast muscle. Several thyrotropic genes exhibited main age effects, including DIO2 and DIO3 in embryonic breast muscle, thyroid hormone receptor alpha and thyroid hormone receptor beta in post-hatch liver, and DIO2 in post-hatch breast muscle. Circulating triiodothyronine displayed a main line effect, with levels in Ross significantly reduced as compared to ACRB. These findings suggest that in modern broilers, a decrease in levels of hormones that control basal metabolism triiodothyronine and the stress response circulating corticosterone, as well as altered expression of genes regulating thyroid hormone activity, could contribute to lower heat production, reduced stress response, and altered nutrient partitioning, leading to more efficient feed utilization and faster, more productive growth.

Case Study on Under-Activethyroid and its Associated Ailments

The purpose behind this case study is to examine the function of thyroid gland, understand the regulation of thyroid hormones, to correlate the symptoms with respect to thyroid dysfunction and its associated consequencesfollowed by clinical interventionsand the pharmaceutical care plan. A female patient with an age of 48 years old is suffering from hypothyroidism and was followed up, information was collected and analyzed. Pedigree analysis revealed that there is an important component of genetics in causation of disease and is reflected to be due to consanguineous marriages in previous generations of the patient which must have added the risk over general population, another consideration is the occurrence affected relatives who are third degree relatedand can support in the genetic component of the disease.

Common drugs that cause abnormalities in the thyroid gland functions and their impact on levels of serum biomarkers

The abnormal thyroid function in the duration of drug treatment has attracted increasing attention, these drugs included traditional drugs, such as glucocorticoid, nonsteroidal anti-inflammatory drug, iodine agent, etc.; also included new types of drugs, such as immune checkpoint inhibitors. The possible reasons causing abnormality of thyroid biomarkers included drugs' toxicity on thyroid, drug-drug interaction affecting synthetic thyroid hormones therapy, and drug's interference on biomarkers' measurement. This article focused on the influence and mechanisms of common drugs on the regulation, synthesis, release, transport and metabolism of thyroid hormones. Here also briefly introduced the mechanism of drug-drugs interaction on the effect of synthetic thyroid hormone; the interference and mechanism of some drugs on the laboratory measurement was also included. The aim of this article was to strengthen clinician's understanding on drug-induced thyroid diseases and to be alert to drugs' interference on the in-vitro measurement of biomarkers.

Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression

ObjectiveNonalcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from hepatosteatosis to progressive nonalcoholic steatohepatitis that can lead to cirrhosis. Humans with low levels of prohormone thyroxine (T4) have a higher incidence of NAFLD, and thyroid hormone treatment is very promising in all patients with NAFLD. Deiodinase type 1 (Dio1) is a hepatic enzyme that converts T4 to the bioactive T3 and therefore regulates thyroid hormone availability within hepatocytes. We investigated the role of this intrahepatic regulation during the progression of NAFLD. MethodsWe investigated hepatic thyroid hormone metabolism in two NAFLD models: wild-type mice fed a Western diet with fructose and Leprdb mice fed a methionine- and choline-deficient diet. AAV8-mediated liver-specific Dio1 knockdown was employed to investigate the role of Dio1 during the progression of NAFLD. Intrahepatic thyroid hormone levels, deiodinase activity, and metabolic parameters were measured. ResultsDio1 expression and activity were increased in the early stages of NAFLD and were associated with an increased T3/T4 ratio. Prevention of this increase by AAV8-mediated liver-specific Dio1 knockdown increased hepatic triglycerides and cholesterol and decreased the pACC/ACC ratio and acylcarnitine levels, suggesting there was lower β-oxidation. Dio1 siRNA KD in hepatic cells treated with fatty acids showed increased lipid accumulation and decreased oxidative phosphorylation. ConclusionHepatic Dio1 gene expression was modulated by dietary conditions, was increased during hepatosteatosis and early NASH, and regulated hepatic triglyceride content. These early adaptations likely represent compensatory mechanisms that reduce hepatosteatosis and prevent NASH progression.

Beyond classic concepts in thyroid homeostasis: Immune system and microbiota

It has long been known that thyroid hormones have implications for multiple physiological processes and can lead to serious illness when there is an imbalance in its metabolism. The connections between thyroid hormone metabolism and the immune system have been extensively described, as they can participate in inflammation, autoimmunity, or cancer progression. In addition, changes in the normal intestinal microbiota involve the activation of the immune system while triggering different pathophysiological disorders. Recent studies have linked the microbiota and certain bacterial fragments or metabolites to the regulation of thyroid hormones and the general response in the endocrine system. Even if the biology and function of the thyroid gland has attracted more attention due to its pathophysiological importance, there are essential mechanisms and issues related to it that are related to the interplay between the intestinal microbiota and the immune system and must be further investigated. Here we summarize additional information to uncover these relationships, the knowledge of which would help establish new personalized medical strategies.

Cryo-EM: A new dawn in thyroid biology

The thyroid gland accumulates the rare dietary element iodine and incorporates it into iodinated thyroid hormones, utilising several tightly regulated reactions and molecular mechanisms. Thyroid hormones are essential in vertebrates and play a central role in many biological processes, such as development, thermogenesis and growth. The control of these functions is exerted through the binding of hormones to nuclear thyroid hormone receptors that rule the transcription of numerous metabolic genes. Over the last 50 years, thyroid biology has been studied extensively at the cellular and organismal levels, revealing its multiple clinical implications, yet, a complete molecular understanding is still lacking. This includes the atomic structures of crucial pathway components that would be needed to elucidate molecular mechanisms. Here we review the currently known protein structures involved in thyroid hormone synthesis, regulation, transport, and actions. We also highlight targets for future investigations that will significantly benefit from recent advances in macromolecular structure determination by electron cryo-microscopy (cryo-EM). As an example, we demonstrate how cryo-EM was crucial to obtain the structure of the large thyroid hormone precursor protein, thyroglobulin. We discuss modern cryo-EM compared to other structure determination methods and how an integrated structural and cell biological approach will help filling the molecular knowledge gap in our understanding of thyroid hormone metabolism. Together with clinical, cellular and high-throughput 'omics' studies, atomic structures of thyroid components will provide an important framework to map disease mutations and to interpret and predict thyroid phenotypes.

Cells to Systems Screening for Thyroid Hormone Disrupting Chemicals in the Brain

Precisely timed and regulated thyroid hormone (TH) levels are essential for vertebrate development and metabolism. To detect environmental chemicals that disrupt TH action, we developed an integrated luciferase reporter cell line in rat pituitary GH3 cells that is TH responsive through activation of endogenous thyroid hormone receptors (TRs). High throughput screening as part of the Tox21 program identified several non-TH related positive hits as RXR agonists, a supposed “silent” heterodimer partner for TRs. These data showed RXR agonists can affect TR signaling at least in pituitary cells. We extended these results to our sensitive and specific in vivo model for TH action, Xenopus laevis metamorphosis. We previously demonstrated that RXR agonists like organotins and the pharmaceutical bexarotene, strongly potentiate (and RXR antagonists inhibit) TH induced metamorphic programs, at the morphological, cellular (e.g. apoptosis or proliferation), transgenic reporter gene levels, and transcriptomic responses in tadpole tails. We have now extended this analysis to include RNA-Seq experiments over distinct time points in the tadpole brain, a common target of TH in humans and frogs, revealing specific gene sets particularly affected by TH and RXR ligands working in concert. Very few genes were affected by RXR ligands alone. The remarkable overlap between the environmental toxicant tributyltin and the synthetic and specific RXR ligand bexarotene regulated transcriptomes provides strong evidence that they have a common molecular target in multiple tissues. We have also created germline mutations in all RXR family members in Xenopus tropicalis (alpha, beta and gamma), and both copies of the duplicated TR beta gene in Xenopus laevis via genome editing approaches. This will allow us to further investigate TR-RXR heterodimer function across tissues and developmental timeframes, and in response to known and suspected TR and RXR ligands. Our studies revealed an unanticipated degree of TR and RXR ligand interactions in vitro and in vivo, highlighting a surprising role of RXRs as avenues for TH endocrine disruption, including the brain.

Generation of Adult Stem Cell Derived Organoid Cultures From Thyroid Follicular Cells

Abstract The thyroid is essential for maintaining systemic homeostasis by regulating thyroid hormone concentrations in the bloodstream. Due to the limited number of representative model systems, there is limited understanding of fundamental thyroid biology as well as thyroid carcinogenesis. To fill the caveats in the understanding of thyroid cell biology, we aimed to develop an adult stem cell-derived three-dimensional (3D) organoid culture system using murine and human thyroid follicular cells (TFCs). We have succeeded to grow such an organoid culture system that harbours the complete machinery of hormone production visualised by the presence of colloid in the lumen and essential transporters and enzymes in a polarised cell layer. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1/TTF1. Moreover, the thyroid hormone precursor thyroglobulin is expressed in both cultures to similar levels as in tissue. Extensive characterisation furthermore identifies known and new biological insights in TFC subclassification, subcellular organisation and hormone production using state-of-the art techniques like single cell RNA sequencing, transmission electron microscopy and genome editing. These 3D in vitro cultures allow for a variety of thyroid-related studies including the progression of wild type cells towards cancer. Additionally, due to the success of generating patient-specific tumour organoids of primary differentiated thyroid carcinoma and metastasis, insights in drug resistance and metastases can be identified. In short, this newly developed organoid culture of murine and human wild type TFCs as well as tumour tissue opens up an extensive area of research that will help understand the drivers for growth and development of thyroid (cancer) cells and enable studies upon drug responsiveness.

Analysis of Hypothalamic TRH Neurons in Regulating Thyroid Hormone Levels

Thyroid hormone (TH) is a major regulator of development and metabolism. An important mechanism controlling TH production is the negative feedback at the hypothalamic and pituitary level and it has been suggested that thyroid hormone receptor β (TRβ) is the main mediator of TH actions in the hypothalamic paraventricular nucleus (PVN). Nevertheless, the direct actions of TH and TRβ in the negative regulation of TRH have yet to be demonstrated in vivo. Here we used two approaches to investigate the TRH neuron. First, we used a chemogenetic tool to directly investigate the role of TRH neurons on the regulation of thyroid hormone levels. Mice expressing Cre-recombinase in TRH neurons received bilateral injections of the activating designer receptors exclusively activated by designer drugs (DREADD) directly into the PVN. Activation of TRH neurons produced a rapid and sustained increase in circulating TSH levels in both males and females. TSH levels increased approximately 10-fold from baseline within 15 minutes of injection of CNO, returning to baseline within 2.5 hours. TH levels were increased approximately 2-fold in males and females. Therefore, using a chemogenetic approach, we were able to directly evaluated the role of PVN TRH neurons on the control of thyroid activity, for the first time. Next, we generated mice deficient in TRβ specifically in neurons expressing melanocortin 4 receptor (MC4R), which overlaps with TRH expression in the PVN. Knockout mice (KO) developed normally and showed no change in TH and TSH levels. TRH mRNA levels in the PVN of KO mice were similar to control mice. To investigate if the deletion of TRβ in the PVN changes the sensitivity of the HPT axis to T3, mice were rendered hypothyroid and given increasing doses of T3 for 2 weeks. Results show no difference in TRH mRNA or serum TSH between controls and KO. Surprisingly, despite the presence of detectable genomic recombination on the TRβ gene in the PVN, there was no difference in TRβ mRNA expression between control and KO mice, suggesting that either MC4R-positive neurons do not express TRβ or they represent a very small population of TRβ-positive cells in the PVN. Present data show that TRH neuron activation rapidly stimulates TSH release and increases TH levels, demonstrating a major role of these neurons in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. Nevertheless, deletion of TRβ from MC4R neurons had no major effect on either TRH or TH levels in in mice. Additionally, TRβ in MC4R-positive TRH neurons in the PVN is not necessary for TH-induced suppression of TRH mRNA. Although further studies are necessary, these data suggest that there are distinct populations of hypophysiotropic TRH neurons in the PVN, some of which are not regulated by thyroid hormone and TRβ.

Thyroid hormone regulation of thermal acclimation in ectotherms: Physiological mechanisms and ecoevolutionary implications

The pathways that regulate adaptive thermal plasticity in ectothermic vertebrates have received little attention relative to those in birds and mammals. However, there is increasing evidence that thyroid hormone represents a critical regulator of thermal plasticity in both ectothermic and endothermic vertebrates. In this review, I summarize the evidence for thyroid hormone-mediated thermal compensation responses in ectothermic vertebrates, with specific focus on effects on the whole animal, skeletal muscle, and cardiac muscle. Interestingly, these effects can differ wildly between focal tissues and species. I move on to discuss what the role of thyroid hormone in ectotherm thermal plasticity can reveal about stressor interactions and central vs. peripheral levels of thyroid hormone regulation. Lastly, I focus on the conserved nature of thyroid hormone signaling in animal thermal responses, with specific reference to the ectotherm → endotherm spectrum. I use this framework to highlight research avenues that will further resolve the evolutionary trajectory of thyroid hormone actions across animals. I hope to emphasize what thyroid hormone-mediated cold acclimation in a 3 cm fish can contribute to ongoing debates surrounding the impacts of stressor interactions, the potential costs of plasticity, the evolution of endothermy, and the impacts of global change.

Prenatal Phthalates Exposure and Cord Thyroid Hormones: A Birth Cohort Study in Southern Taiwan.

Background: The regulation of thyroid hormones in the early stages of gestation plays a crucial role in the outcome of a pregnancy. Furthermore, thyroid hormones are fundamental for the fetal development of all organs, including endocrine hormone changes in uterus. Endocrine disrupting chemicals have been shown to have an effect on thyroid hormone homeostasis in newborns, which affects their later development. Few studies have proposed how phthalates could alter thyroid function through several mechanisms and the possible effects on thyroid hormone homeostasis of phthalates on pregnant women. However, the effects of cord blood phthalates and prenatal phthalate exposure on thyroid hormones in newborns remain unclear. Objectives: We aim to follow up on our previous established subjects and determine the correlation between phthalate exposure and thyroid hormones in pregnant women and newborns. Materials and methods: We recruited 61 pregnant women from the Obstetrics and Gynecology Department of a medical hospital in southern Taiwan and followed up. High performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) was used to analyze urine samples for five phthalate metabolites. Serum levels of thyroid hormones were analyzed using electrochemoluminescence immunoassay (ECLIA) method. We used Spearman and Pearson correlation coefficients to evaluate the correlation between each phthalate metabolites in serum and the thyroid hormone levels in fetus and parturient. Finally, multiple logistic regression was used to explore the relationship between hormones and their corresponding phthalate metabolites in cord blood. Results: High MBP in cord blood was correlated with negative cord serum TSH in newborns (r = −0.25, p < 0.06). By using multiple linear regression after adjusting for potential confounders (gestational and maternal age), cord serum MBP levels showed a negative association with cord serum TSH (β = 0.217, p < 0.05), cord serum T4 (β = 1.71, p < 0.05) and cord serum T4 × TSH (β = 42.8, p < 0.05), respectively. Conclusion: We found that levels of cord serum TSH and T4 in newborns was significantly negatively associated with cord serum MBP levels after adjusting for significant covariate. The fall in TSH in newborns may potentially be delaying their development.

Вплив транскраніальної магнітної стимуляції на концентрацію BDNF, кортизолу, тиреотропного гормону та тироксину в сироватці крові хворих на розсіяний склероз

Design, contingent, and research methods. The study was conducted based on the Department of Autoimmune and Degenerative Diseases of the Nervous System, the Center for Multiple Sclerosis of the Institute of Neurology, Psychiatry, and Addiction of the National Academy of Medical Sciences of Ukraine. The results were obtained by examining 110 patients with multiple sclerosis (73 women and 37 men). The diagnosis was made according to the criteria of McDonald et al., 2017. All patients were divided into an intervention group who received a course of pTMS and a comparison group without the use of non-invasive neuromodulation. For noninvasive neuromodulation in the process of treatment and rehabilitation, rTMS was used. The course of treatment was performed on a MagVenture, MagPro X100, and an 8-shaped inductor (coil). Serum levels of cortisol, thyroid-stimulating hormone (TSH), total thyroxine (T4), and BDNF were determined. Results. The use of TMS did not significantly affect the serum cortisol content of patients with progressive types of MS but had a positive effect on GGAS in patients with remitting type. TMS increased the concentration of neurotrophin BDNF in the group of patients with RT MS, and less pronounced, but also significantly - in the group of VPT. TMS led to an increase in TSH levels in the group of patients with RT MS but did not affect the concentration of total thyroxine in the serum. The most sensitive to the effects of TMS is the remitting type of disease. Conclusion. Neurotrophins and hormones play an important role in the processes of remyelination and neuroplasticity. The use of selected parameters of rTMS has a positive effect on the hypothalamic-pituitary system of regulation of glucocorticoid and thyroid hormones, as well as on neurotrophic processes in the CNS in the development of multiple sclerosis. TMS opens new prospects for non-invasive neuromodulation in patients with MS.

Vitamin D deficiency is associated with thyroid diseases

Background The deficiency of vitamin D3 (VD) is a universal health issue, its role in different kind of diseases is being studied recently. However, its role in thyroid diseases is not well established yet. This study aims to determine the impact of VD in the pathogenesis of hypothyroidism and hyperthyroidism. Method. Three hundred Iraqi females with age ranged between 30 and 55 years participate in this research, 100 of them were hypothyroid patients, 100 females were hyperthyroid patients and the other 100 females were healthy volunteers served as controls. Thyroid hormones, VD, liver function parameters, and kidney function parameters were determined using different analysis techniques. Results. The levels of VD were significantly decreased in both hypothyroid and hyperthyroid patients (19.644 ± 10.524 for hypothyroid patients and 22.712 ± 11.249 for hyperthyroid patients vs. 30.880 ± 2.587 for controls, p <0.0001). Liver function parameters were within the normal ranges in all the patients. Creatinine and uric acid were within the normal ranges, while urea was significantly increased and out of the normal clinical range in both hypothyroid and hyperthyroid patients (39.560 ± 9.912 for hypothyroidism patients and 42.460 ±7.171 for hyperthyroid patients vs. 26.920 ± 5.033 for controls, p <0.0001). Conclusion. Vitamin D3 and kidney function tests must be included in the differential detection of thyroid diseases. Still, further investigations are needed to understand the underlying mechanism by which VD affects thyroid hormone regulation.

Using Single-Cell RNA-Seq Data to Trace Tissue Cells Responsive to Thyroid Hormones

Thyroid hormones mediate a remarkable range of functions in many tissues and organ systems through the thyroid hormone receptors—THRA and THRB. Tissues and organs are composed of heterogeneous cells of different cell types. These different cell types have varying receptor expression abilities, which lead to variable responses in thyroid hormone regulation. The tissue-specific Thra and Thrb gene expression patterns help us understand the action of thyroid hormones at the tissue level. However, the situation becomes complicated if we wish to focus on tissues more closely to trace the responsive cells, which is a vital step in the process of understanding the molecular mechanism of diseases related to thyroid hormone regulation. Single-cell RNA sequencing technology is a powerful tool used to profile gene expression programs in individual cells. The Tabula Muris Consortium generates a single-cell transcriptomic atlas across the life span of Mus musculus that includes data from 23 tissues and organs. It provides an unprecedented opportunity to understand thyroid hormone regulation at the cell type resolution. We demonstrated the approaches that allow application of the single-cell RNA-Seq data generated by the Tabula Muris Consortium to trace responsive cells in tissues. First, employing the single-cell RNA-Seq data, we calculated the ability of different cell types to express Thra and Thrb, which direct us to the cell types sensitive to thyroid hormone regulation in tissues and organs. Next, using a cell clustering algorithm, we explored the subtypes with low Thra or Thrb expression within the different cell types and identified the potentially responsive cell subtypes. Finally, in the liver tissue treated with thyroid hormones, using the single-cell RNA-Seq data, we successfully traced the responsive cell types. We acknowledge that the computational predictions reported here need to be further validated using wet-lab experiments. However, we believe our results provide powerful information and will be beneficial for wet lab researchers.

Second-Trimester Placental and Thyroid Hormones Are Associated With Cognitive Development From Ages 1 to 3 Years.

Adequate maternal thyroid hormone (TH) is necessary for fetal brain development. The role of placental human chorionic gonadotropin (hCG) in ensuring the production of TH is less well understood. The objective of the study was to evaluate 1) associations of placental hCG and its subunits, and maternal TH in the second trimester, and 2) the single and joint effects of TH and placental hormones on cognitive development and communication at ages 1 and 3 years. Fifty individuals (5%) were selected from the CANDLE (Conditions Affecting Neurocognitive Development and Early Learning) pregnancy cohort in Memphis, Tennessee, with recruitment from 2006 to 2011, to equally represent male and female fetuses. Participants were 68% Black and 32% White. Hormones measured were maternal thyroid (thyrotropin [TSH] and free thyroxine [FT4]) and placental hormones (hCG, its hyperglycosylated form [hCG-h], and free - [hCG] and -subunits [hCG]) in maternal serum (17-28 weeks). The primary outcome measurement was the Bayley Scales of Infant and Toddler Development. All forms of hCG were negatively associated with FT4 and not associated with TSH. hCG was associated with cognitive development at age 1 year and jointly interacted with TSH to predict cognitive development at age 3 years. This pilot study added insight into the thyrotropic actions of hCG in the second trimester, and into the significance of this mechanism for brain development. More research is warranted to elucidate differences between hCG, hCG, and hCG-h in relation to TH regulation and child brain function.

Genome-wide methylation analysis of pre-pregnancy women in hypothyroidism

Background Hypothyroidism is a systemic metabolic deficiency syndrome caused by a deficiency in thyroid hormone or a decrease in the action of thyroid hormones. It has a high incidence among women of child-bearing age, and pregnant women with hypothyroidism may have a higher risk of birth defects. Objective To explore the specific biological mechanism affecting the occurrence of hypothyroidism. Methods This study determined key molecules by comparing and analyzing the difference in methylation levels between pre-pregnancy women and normal controls using the Illumina Infinium MethylationEPIC BeadChip. Results 3493 Differential methylation positions (DMPs) related genes and 47 differentially methylated regions (DMRs) related genes were found between the Hypothyroidism group and the control group. Among them, miR-21 has been found to be closely related to thyroid hormone regulation. The results of enrichment analysis showed that the DMPs or DMRs-related genes are both significantly enriched in human T-cell leukemia virus 1 infection, osteoclast differentiation and sphingolipid signaling pathway, which were also closely related to the occurrence and development of hypothyroidism. In addition, the combined analysis of CNVs and DMRs showed that significant differences occurred near the regions of 16 M bp in chromosome 1 between the two groups, and the genes involved in these regions included NDUFS2, FCER1G and SHC1. Conclusion This work screened molecular markers and key signaling pathways that are involved in the development of hypothyroidism in pre-pregnancy women, which may provide new targets for the research and diagnosis of hypothyroidism in the future.

Absence of Both Thyroid Hormone Transporters MCT8 and OATP1C1 Impairs Neural Stem Cell Fate in the Adult Mouse Subventricular Zone.

SummaryAdult neural stem cell (NSC) generation in vertebrate brains requires thyroid hormones (THs). How THs enter the NSC population is unknown, although TH availability determines proliferation and neuronal versus glial progenitor determination in murine subventricular zone (SVZ) NSCs. Mice display neurological signs of the severely disabling human disease, Allan-Herndon-Dudley syndrome, if they lack both MCT8 and OATP1C1 transporters, or MCT8 and deiodinase type 2. We analyzed the distribution of MCT8 and OATP1C1 in adult mouse SVZ. Both are strongly expressed in NSCs and at a lower level in neuronal cell precursors but not in oligodendrocyte progenitors. Next, we analyzed Mct8/Oatp1c1 double-knockout mice, where brain uptake of THs is strongly reduced. NSC proliferation and determination to neuronal fates were severely affected, but not SVZ-oligodendroglial progenitor generation. This work highlights how tight control of TH availability determines NSC function and glial-neuron cell-fate choice in adult brains.