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Giri D, Mugesh G. Thyroid Hormone Deiodination-Mechanisms and Small Molecule Enzyme Mimics. Biomolecules 2025; 15:529. [PMID: 40305277 PMCID: PMC12025243 DOI: 10.3390/biom15040529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/01/2025] [Accepted: 04/03/2025] [Indexed: 05/02/2025] Open
Abstract
Thyroid hormones, biosynthesized in the follicular cells in the thyroid gland, play a crucial role in regulating various important biological processes. The thyroid hormone is synthesized as pro-hormone L-thyroxine (T4), while the active form is primarily produced through the phenolic ring deiodination of T4 by iodothyronine deiodinase enzymes (DIOs). Three distinct isoforms of the enzyme are known, which, despite having almost similar amino acid sequences in their active site, differ in their regioselectivity of deiodination towards T4 and its metabolites. However, the precise mechanism and the origin of the differences in the regioselectivity of deiodination by DIOs are still not fully understood. Over the years, several research groups have attempted to mimic this system with small molecules to gain some insight into the reactivity and mechanism. In this review, we will explore the recent developments on the biomimetic deiodination of T4 and its derivatives by using selenium-based enzyme mimetics. For example, naphthalene-based molecules, featuring a 1,8-dichalcogen atom, have been shown to perform tyrosyl ring deiodination of T4 and T3, producing rT3 and 3,3'-T2, respectively. The modification of the electron density around the phenolic ring through substitutions in the 4'-hydroxyl group can alter the regioselectivity of the deiodination by deiodinase mimics. Additionally, we will highlight the recent progress in the development of a dipeptide-based DIO1 mimic, as well as the deiodination of other halogenated thyronine derivatives by mimics.
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Affiliation(s)
| | - Govindasamy Mugesh
- Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India;
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2
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Soares De Oliveira L, Ritter MJ. Thyroid hormone and the Liver. Hepatol Commun 2025; 9:e0596. [PMID: 39699315 PMCID: PMC11661762 DOI: 10.1097/hc9.0000000000000596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 10/16/2024] [Indexed: 12/20/2024] Open
Abstract
It is known that thyroid hormone can regulate hepatic metabolic pathways including cholesterol, de novo lipogenesis, fatty acid oxidation, lipophagy, and carbohydrate metabolism. Thyroid hormone action is mediated by the thyroid hormone receptor (THR) isoforms and their coregulators, and THRβ is the main isoform expressed in the liver. Dysregulation of thyroid hormone levels, as seen in hypothyroidism, has been associated with dyslipidemia and metabolic dysfunction-associated fatty liver disease. Given the beneficial effects of thyroid hormone in liver metabolism and the advances illuminating the use of thyroid hormone analogs such as resmetirom as therapeutic agents in the treatment of metabolic dysfunction-associated fatty liver disease, this review aims to further explore the relationship between TH, the liver, and metabolic dysfunction-associated fatty liver disease. Herein, we summarize the current clinical therapies and highlight future areas of research.
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Soares De Oliveira L, Kaserman JE, Van Der Spek AH, Lee NJ, Undeutsch HJ, Werder RB, Wilson AA, Hollenberg AN. Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes. Mol Metab 2024; 90:102057. [PMID: 39481850 PMCID: PMC11615914 DOI: 10.1016/j.molmet.2024.102057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 10/08/2024] [Accepted: 10/24/2024] [Indexed: 11/03/2024] Open
Abstract
OBJECTIVE Thyroid hormone (TH) action is mediated by thyroid hormone receptor (THR) isoforms. While THRβ1 is likely the main isoform expressed in liver, its role in human hepatocytes is not fully understood. METHODS To elucidate the role of THRβ1 action in human hepatocytes we used CRISPR/Cas9 editing to knock out THRβ1 in induced pluripotent stem cells (iPSC). Following directed differentiation to the hepatic lineage, iPSC-derived hepatocytes were then interrogated to determine the role of THRβ1 in ligand-independent and -dependent functions. RESULTS We found that the loss of THRβ1 promoted alterations in proliferation rate and metabolic pathways regulated by T3, including gluconeogenesis, lipid oxidation, fatty acid synthesis, and fatty acid uptake. We observed that key genes involved in liver metabolism are regulated through both T3 ligand-dependent and -independent THRβ1 signaling mechanisms. Finally, we demonstrate that following THRβ1 knockout, several key metabolic genes remain T3 responsive suggesting they are THRα targets. CONCLUSIONS These results highlight that iPSC-derived hepatocytes are an effective platform to study mechanisms regulating TH signaling in human hepatocytes.
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Affiliation(s)
- Lorraine Soares De Oliveira
- Department of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA 02118, USA; Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Joseph E Kaserman
- Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA; Department of Medicine, Section of Pulmonary and Critical Care Medicine, Chobanian & Avedisian School of Medicine, Boston Medical Center, MA 02118, USA
| | - Anne H Van Der Spek
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam 1081 HV, Netherlands
| | - Nora J Lee
- Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Hendrik J Undeutsch
- Department of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA 02118, USA; Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Rhiannon B Werder
- Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Andrew A Wilson
- Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA; Department of Medicine, Section of Pulmonary and Critical Care Medicine, Chobanian & Avedisian School of Medicine, Boston Medical Center, MA 02118, USA.
| | - Anthony N Hollenberg
- Department of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA 02118, USA; Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA.
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Liu M, Hu C, Li J, Zhou B, Lam PKS, Chen L. Thyroid Endocrine Disruption and Mechanism of the Marine Antifouling Pollutant 4,5-Dichloro-2-n-octyl-4-isothiazolin-3-one. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; 58:19189-19198. [PMID: 39344067 DOI: 10.1021/acs.est.4c07614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
The antifoulant 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) is an emerging pollutant in the marine environment, which may disrupt the thyroid endocrine system. However, DCOIT toxicity in relation to thyroid endocrine disruption and the underlying mechanisms remains largely unclear. In this study, in vivo, in silico, in vitro, and ex vivo assays were performed to clarify DCOIT's thyroid toxicity. First, marine medaka (Oryzias melastigma) were exposed to environmentally realistic concentrations of DCOIT for an entire life cycle. The results demonstrated that DCOIT exposure potently stimulated the hypothalamic-pituitary-thyroid axis, characterized by hyperthyroidism symptom induction and prevalent key gene and protein upregulation in the brain. Moreover, the in silico and in vitro results evidenced that DCOIT could bind to thyroid hormone receptor β (TRβ) and interact synergistically with triiodothyronine, thus promoting GH3 cell proliferation. The CUT&Tag experiment found that DCOIT interfered with the affinity fingerprint of TRβ to target genes implicated in thyroid hormone signaling cascade regulation. Furthermore, ex vivo, Chem-seq revealed that DCOIT directly bound to the genomic sequences of thyrotropin-releasing hormone receptor b and thyroid-stimulating hormone receptor in marine medaka brain tissues. In conclusion, the current multifaceted evidence confirmed that DCOIT has a strong potency for thyroid endocrine system disruption and provided comprehensive insights into its toxicity mechanisms.
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Affiliation(s)
- Mengyuan Liu
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chenyan Hu
- School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430072, China
| | - Jiali Li
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Bingsheng Zhou
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Paul K S Lam
- Office of the President, Hong Kong Metropolitan University, 30 Good Shepherd Street, Hong Kong SAR, China
| | - Lianguo Chen
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
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Graceffo E, Opitz R, Megges M, Krude H, Schuelke M. RNA Sequencing Reveals a Strong Predominance of THRA Splicing Isoform 2 in the Developing and Adult Human Brain. Int J Mol Sci 2024; 25:9883. [PMID: 39337374 PMCID: PMC11432079 DOI: 10.3390/ijms25189883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/05/2024] [Accepted: 09/08/2024] [Indexed: 09/30/2024] Open
Abstract
Thyroid hormone receptor alpha (THRα) is a nuclear hormone receptor that binds triiodothyronine (T3) and acts as an important transcription factor in development, metabolism, and reproduction. In mammals, THRα has two major splicing isoforms, THRα1 and THRα2. The better-characterized isoform, THRα1, is a transcriptional stimulator of genes involved in cell metabolism and growth. The less-well-characterized isoform, THRα2, lacks the ligand-binding domain (LBD) and is thought to act as an inhibitor of THRα1 activity. The ratio of THRα1 to THRα2 splicing isoforms is therefore critical for transcriptional regulation in different tissues and during development. However, the expression patterns of both isoforms have not been studied in healthy human tissues or in the developing brain. Given the lack of commercially available isoform-specific antibodies, we addressed this question by analyzing four bulk RNA-sequencing datasets and two scRNA-sequencing datasets to determine the RNA expression levels of human THRA1 and THRA2 transcripts in healthy adult tissues and in the developing brain. We demonstrate how 10X Chromium scRNA-seq datasets can be used to perform splicing-sensitive analyses of isoforms that differ at the 3'-end. In all datasets, we found a strong predominance of THRA2 transcripts at all examined stages of human brain development and in the central nervous system of healthy human adults.
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Affiliation(s)
- Eugenio Graceffo
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Department of Neuropediatrics, 13353 Berlin, Germany;
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Einstein Center for Neurosciences Berlin, 10117 Berlin, Germany
| | - Robert Opitz
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Institute of Experimental Pediatric Endocrinology, 13353 Berlin, Germany; (R.O.); (H.K.)
| | - Matthias Megges
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Department of Pediatric Endocrinology, 13353 Berlin, Germany;
| | - Heiko Krude
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Institute of Experimental Pediatric Endocrinology, 13353 Berlin, Germany; (R.O.); (H.K.)
| | - Markus Schuelke
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Department of Neuropediatrics, 13353 Berlin, Germany;
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Einstein Center for Neurosciences Berlin, 10117 Berlin, Germany
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Neurocure Clinical Research Center, 10117 Berlin, Germany
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6
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Carrera ARM, Eleazar EG, Caparanga AR, Tayo LL. Theoretical Studies on the Quantitative Structure-Toxicity Relationship of Polychlorinated Biphenyl Congeners Reveal High Affinity Binding to Multiple Human Nuclear Receptors. TOXICS 2024; 12:49. [PMID: 38251005 PMCID: PMC10821279 DOI: 10.3390/toxics12010049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/31/2023] [Accepted: 01/02/2024] [Indexed: 01/23/2024]
Abstract
Polychlorinated biphenyls (PCBs) are organic chemicals consisting of a biphenyl structure substituted with one to ten chlorine atoms, with 209 congeners depending on the number and position of the chlorine atoms. PCBs are widely known to be endocrine-disrupting chemicals (EDCs) and have been found to be involved in several diseases/disorders. This study takes various molecular descriptors of these PCBs (e.g., molecular weight) and toxicity endpoints as molecular activities, investigating the possibility of correlations via the quantitative structure-toxicity relationship (QSTR). This study then focuses on molecular docking and dynamics to investigate the docking behavior of the strongest-binding PCBs to nuclear receptors and compares these to the docking behavior of their natural ligands. Nuclear receptors are a family of transcription factors activated by steroid hormones, and they have been investigated to consider the impact of PCBs on humans in this context. It has been observed that the docking affinity of PCBs is comparable to that of the natural ligands, but they are inferior in terms of stability and interacting forces, as shown by the RMSD and total energy values. However, it is noted that most nuclear receptors respond to PCBs similarly to how they respond to their natural ligands-as shown in the RMSF plots-the most similar of which are seen in the ER, THR-β, and RAR-α. However, this study is performed purely in silico and will need experimental verification for validation.
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Affiliation(s)
- Andrei Raphael M. Carrera
- School of Graduate Studies, Mapúa University, Manila 1002, Philippines; (A.R.M.C.); (E.G.E.)
- School of Chemical, Biological, and Materials Engineering and Sciences, Mapúa University, Manila 1002, Philippines;
| | - Elisa G. Eleazar
- School of Graduate Studies, Mapúa University, Manila 1002, Philippines; (A.R.M.C.); (E.G.E.)
- School of Chemical, Biological, and Materials Engineering and Sciences, Mapúa University, Manila 1002, Philippines;
| | - Alvin R. Caparanga
- School of Chemical, Biological, and Materials Engineering and Sciences, Mapúa University, Manila 1002, Philippines;
| | - Lemmuel L. Tayo
- School of Chemical, Biological, and Materials Engineering and Sciences, Mapúa University, Manila 1002, Philippines;
- Department of Biology, School of Medicine and Health Sciences, Mapúa University, Makati 1200, Philippines
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7
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de Souza JS. Thyroid hormone biosynthesis and its role in brain development and maintenance. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 142:329-365. [PMID: 39059990 DOI: 10.1016/bs.apcsb.2023.12.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Thyroid hormones are critical modulators in the physiological processes necessary to virtually all tissues, with exceptionally fundamental roles in brain development and maintenance. These hormones regulate essential neurodevelopment events, including neuronal migration, synaptogenesis, and myelination. Additionally, thyroid hormones are crucial for maintaining brain homeostasis and cognitive function in adulthood. This chapter aims to offer a comprehensive understanding of thyroid hormone biosynthesis and its intricate role in brain physiology. Here, we described the mechanisms underlying the biosynthesis of thyroid hormones, their influence on various aspects of brain development and ongoing maintenance, and the proteins in the brain that are responsive to these hormones. This chapter was geared towards broadening our understanding of thyroid hormone action in the brain, shedding light on potential therapeutic targets for neurodevelopmental and neurodegenerative disorders.
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Affiliation(s)
- Janaina Sena de Souza
- Department of Pediatrics and Cellular & Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA, United States.
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8
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Wilpert NM, Tonduti D, Vaia Y, Krude H, Sarret C, Schuelke M. Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review. Neuropsychiatr Dis Treat 2023; 19:2195-2216. [PMID: 37881807 PMCID: PMC10595182 DOI: 10.2147/ndt.s379703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/07/2023] [Indexed: 10/27/2023] Open
Abstract
Introduction The SCL16A2 gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients' perspective and identify clinical endpoints that are clinically relevant to their daily life. Methods We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials. Results We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5-9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints. Discussion We recommend that future trials should define a relevant improvement in "development" and/or other patient-relevant outcomes compared to natural history as treatment goals.
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Affiliation(s)
- Nina-Maria Wilpert
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Pediatric Neurology, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health (BIH), Center for Chronically Sick Children, Berlin, Germany
| | - Davide Tonduti
- Unit of Pediatric Neurology, C.O.A.L.A. (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children’s Hospital, Università Degli Studi Di Milano, Milan, Italy
| | - Ylenia Vaia
- Unit of Pediatric Neurology, C.O.A.L.A. (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children’s Hospital, Università Degli Studi Di Milano, Milan, Italy
| | - Heiko Krude
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Experimental Pediatric Endocrinology, Berlin, Germany
| | - Catherine Sarret
- Centre de Compétence des Leucodystrophies et Leucoencéphalopathies de Cause Rare, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France
| | - Markus Schuelke
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Pediatric Neurology, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health (BIH), Center for Chronically Sick Children, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), NeuroCure Clinical Research Center, Berlin, Germany
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9
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An T, Lu L, Li G. Daily exposure to low concentrations Tetrabromobisphenol A interferes with the thyroid hormone pathway in HepG2 cells. FUNDAMENTAL RESEARCH 2023; 3:384-391. [PMID: 38933766 PMCID: PMC11197689 DOI: 10.1016/j.fmre.2022.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 03/04/2022] [Accepted: 03/10/2022] [Indexed: 01/31/2023] Open
Abstract
Tetrabromobisphenol A (TBBPA) is a flame retardant that adversely affects the environment and human health. The present study exposed HepG2 cells to low concentrations of TBBPA daily to investigate the changes in gene regulation, mainly related to pathways associated with the endocrine system. The quantitative polymerase chain reaction (qPCR) confirmed that prolonged exposure gradually activated the thyroid hormone and parathyroid hormone signaling pathways. The expression levels of genes related to the thyroid hormone signaling pathway were upregulated (1.15-8.54 times) after five generations of exposure to 1 and 81 nM TBBPA. Furthermore, co-exposure to 81 nM TBBPA and 0.5 nM thyroid hormone receptor antagonist for five generations significantly reduced the expression of thyroid hormone and parathyroid hormone receptors. Meanwhile, 81 nM TBBPA inhibited the activation of the Ras pathway and downregulated Ras gene expression level (3.7 times), indicating the association between the toxic effect and thyroid hormone receptors. Additionally, our experiments revealed that the thyroid hormone pathway regulated the induction of the Ras signaling pathway by TBBPA. The study thus proves that daily exposure to TBBPA interferes with the thyroid hormone signaling pathway and subsequently the endocrine system.
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Affiliation(s)
- Taicheng An
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou 510006, China
- Guangzhou Key Laboratory of Environmental Catalysis and Pollution Control, Key Laboratory of City Cluster Environmental Safety and Green Development of the Ministry of Education, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Lirong Lu
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou 510006, China
| | - Guiying Li
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou 510006, China
- Guangzhou Key Laboratory of Environmental Catalysis and Pollution Control, Key Laboratory of City Cluster Environmental Safety and Green Development of the Ministry of Education, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
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10
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Morthorst JE, Holbech H, De Crozé N, Matthiessen P, LeBlanc GA. Thyroid-like hormone signaling in invertebrates and its potential role in initial screening of thyroid hormone system disrupting chemicals. INTEGRATED ENVIRONMENTAL ASSESSMENT AND MANAGEMENT 2023; 19:63-82. [PMID: 35581168 PMCID: PMC10083991 DOI: 10.1002/ieam.4632] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/30/2022] [Accepted: 05/12/2022] [Indexed: 05/07/2023]
Abstract
This review examines the presence and evolution of thyroid-like systems in selected aquatic invertebrates to determine the potential use of these organisms in screens for vertebrate thyroid hormone axis disrupting chemicals (THADCs). Such a screen might support the phasing out of some vertebrate testing. Although arthropods including crustaceans do not contain a functional thyroid signaling system, elements of such a system exist in the aquatic phyla mollusks, echinoderms, tunicates, and cephalochordates. These phyla can synthesize thyroid hormone, which has been demonstrated in some groups to induce the nuclear thyroid hormone receptor (THR). Thyroid hormone may act in these phyla through interaction with a membrane integrin receptor. Thyroid hormone regulates inter alia metamorphosis but, unlike in vertebrates, this does not occur via receptor activation by the ligands triiodothyronine (T3) and thyroxine (T4). Instead, the unliganded nuclear receptor itself controls metamorphosis in mollusks, echinoderms, and tunicates, whereas the T3 derivative tri-iodothyroacetic acid (TRIAC) acts as a THR ligand in cephalochordates. In view of this, it may be possible to develop an invertebrate-based screen that is sensitive to vertebrate THADCs that interfere with thyroid hormone synthesis or metabolism along with interaction with membrane receptors. The review makes some recommendations for the need to develop an appropriate test method. Integr Environ Assess Manag 2023;19:63-82. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).
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Affiliation(s)
| | - Henrik Holbech
- Department of BiologyUniversity of Southern DenmarkOdense MDenmark
| | - Noémie De Crozé
- Laboratoire Recherche Environnementale, L'ORÉAL Recherche & InnovationAulnay‐sous‐BoisFrance
| | | | - Gerald A. LeBlanc
- Department of Biological SciencesNorth Carolina State UniversityRaleighNorth CarolinaUSA
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11
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Chen ZF, Lin ZC, Lu SQ, Chen XF, Liao XL, Qi Z, Cai Z. Azole-Induced Color Vision Deficiency Associated with Thyroid Hormone Signaling: An Integrated In Vivo, In Vitro, and In Silico Study. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2022; 56:13264-13273. [PMID: 36082512 DOI: 10.1021/acs.est.2c05328] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Azoles that are used in pesticides, pharmaceuticals, and personal care products can have toxic effects on fish. However, there is no information regarding azole-induced visual disorder associated with thyroid disruption. We evaluated changes in retinal morphology, optokinetic response, transcript abundance of the genes involved in color perception and hypothalamic-pituitary-thyroid (HPT) axis, and thyroid hormone (TH) levels in zebrafish larvae exposed to common azoles, such as climbazole (CBZ, 0.1 and 10 μg/L) and triadimefon (TDF, 50 and 500 μg/L), at environmentally relevant and predicted worst-case environmental concentrations. Subsequently, the effect of azoles on TH-dependent GH3 cell proliferation and thyroid receptor (TR)-regulated transcriptional activity, as well as the in silico binding affinity between azoles and TR isoforms, was investigated. Azole exposure decreased cell densities of the ganglion cell layer, inner nuclear layer, and photoreceptor layer. Zebrafish larvae exposed to environmentally relevant concentrations of CBZ and TDF showed a decrease in optokinetic response to green-white and red-white stripes but not blue-white stripes, consistent with disturbance in the corresponding opsin gene expression. Azole exposure also reduced triiodothyronine levels and concomitantly increased HPT-related gene expression. Molecular docking analysis combined with in vitro TR-mediated transactivation and dual-luciferase reporter assays demonstrated that CBZ and TDF exhibited TR antagonism. These results are comparable to those obtained from a known TR antagonist, namely, TR antagonist 1, as a positive control. Therefore, damage to specific color perception by azoles appears to result from lowered TH signaling, indicating the potential threat of environmental TH disruptors to the visual function of fish.
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Affiliation(s)
- Zhi-Feng Chen
- Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Zhi-Cheng Lin
- Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Si-Qi Lu
- Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Xiao-Fan Chen
- Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Xiao-Liang Liao
- Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Zenghua Qi
- Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Zongwei Cai
- Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong 999077, China
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12
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Liao XH, Avalos P, Shelest O, Ofan R, Shilo M, Bresee C, Likhite S, Vit JP, Heuer H, Kaspar B, Meyer K, Dumitrescu AM, Refetoff S, Svendsen CN, Vatine GD. AAV9-MCT8 Delivery at Juvenile Stage Ameliorates Neurological and Behavioral Deficits in a Mouse Model of MCT8-Deficiency. Thyroid 2022; 32:849-859. [PMID: 35350867 PMCID: PMC9469747 DOI: 10.1089/thy.2022.0034] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Background: Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor disability disorder that also manifests characteristic abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in monocarboxylate transporter 8 (MCT8), a specific TH plasma membrane transporter widely expressed in the central nervous system (CNS). MCT8 mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. Earlier work has shown that intravenous (IV), but not intracerebroventricular adeno-associated virus serotype 9 (AAV9) -based gene therapy given to newborn Mct8 knockout (Mct8-/y) male mice increased triiodothyronine (T3) brain content and partially rescued TH-dependent gene expression, suggesting a promising approach to treat this neurological disorder. Methods: The potential of IV delivery of AAV9 carrying human MCT8 was tested in the well-established Mct8-/y/Organic anion-transporting polypeptide 1c1 (Oatp1c1)-/ - double knockout (dKO) mouse model of AHDS, which, unlike Mct8-/y mice, displays both neurological and TH phenotype. Further, as the condition is usually diagnosed during childhood, treatment was given intravenously to P30 mice and psychomotor tests were carried out blindly at P120-P140 after which tissues were collected and analyzed. Results: Systemic IV delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive functions at P120-P140, which was accompanied by a near normalization of T3 content and an increased response of positively regulated TH-dependent gene expression in different brain regions examined (thalamus, hippocampus, and parietal cortex). The effects on serum TH concentrations and peripheral tissues were less pronounced, showing only improvement in the serum T3/reverse T3 (rT3) ratio and in liver deiodinase 1 expression. Conclusion: IV administration of AAV9, carrying the human MCT8, to juvenile dKO mice manifesting AHDS has long-term beneficial effects, predominantly on the CNS. This preclinical study indicates that this gene therapy has the potential to ameliorate the devastating neurological symptoms in patients with AHDS.
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Affiliation(s)
- Xiao-Hui Liao
- Department of Medicine, The University of Chicago, Chicago, Illinois, USA
| | - Pablo Avalos
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Oksana Shelest
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Raz Ofan
- Department of Biotechnology Engineering, Faculty of Engineering Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
- The Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Michael Shilo
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Catherine Bresee
- Biostatistics Core, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Shibi Likhite
- The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
| | - Jean-Philippe Vit
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Heike Heuer
- Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany
| | - Brian Kaspar
- The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
| | - Kathrin Meyer
- The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
| | | | - Samuel Refetoff
- Department of Medicine, The University of Chicago, Chicago, Illinois, USA
- Department of Pediatrics, The University of Chicago, Chicago, Illinois, USA
- Committee on Genetics, The University of Chicago, Chicago, Illinois, USA
- Address correspondence to: Samuel Refetoff, MD, Department of Medicine, The University of Chicago, MC3090, 5841 South Maryland Avenue, Chicago, IL 60637, USA
| | - Clive N. Svendsen
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Address correspondence to: Clive N. Svendsen, PhD, The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Gad D. Vatine
- The Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer Sheva, Israel
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, Israel
- Address correspondence to: Gad D. Vatine, PhD, Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
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13
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Chang Wu Z, Wang Y, Huang X, Wu S, Bao W. A genome-wide association study of important reproduction traits in large white pigs. Gene 2022; 838:146702. [PMID: 35772658 DOI: 10.1016/j.gene.2022.146702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 06/13/2022] [Accepted: 06/24/2022] [Indexed: 11/04/2022]
Abstract
Augmenting the reproductive efficiency of sows remains the predominant challenge in the swine industry. This work was aimed at scrutinizing vital genetic markers for reproductive traits in this animal. This entailed probing of the records of vital attributes of Large White pigs (n = 695) inclusive of the total number of born (TNB), number of born alive (NBA), number of weaned pigs (NWP), number of healthy births (NHS), total litter weight of piglets born alive (BALWT), weaning litter weight (WNWT), and corrected litter weight at 21 days (W21). A genome-wide association study (GWAS) for the four litter traits and three traits of litter weight in the Denmark Large White population then ensued. We discovered seven significantly related SNPs and eleven potential candidate genes (e.g., TUSC3, THRB for TNB; STT3B for NBA). The subsequent functional enrichment analysis of these genes showed that the significant gene were associated with steroid hormone receptor activity. Our findings indicated that the genes TUSC3, THRB and STT3B probably contribute to litter traits in this population. This work reveals genetic mechanisms of reproduction traits and also supports ensuing genetic improvement employing marker-assisted selection in Large White pigs.
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Affiliation(s)
- Zheng Chang Wu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China; College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, P. R. China.
| | - Yifu Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China.
| | - Xiaoguo Huang
- Jiangsu Engineering Research Centre for Molecular Breeding of Pig, Changzhou 215000, Jiangsu Province, China.
| | - Shenglong Wu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China.
| | - Wenbin Bao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China.
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14
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Hönes GS, Härting N, Mittag J, Kaiser FJ. TRα2—An Untuned Second Fiddle or Fine-Tuning Thyroid Hormone Action? Int J Mol Sci 2022; 23:ijms23136998. [PMID: 35806002 PMCID: PMC9266318 DOI: 10.3390/ijms23136998] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 02/01/2023] Open
Abstract
Thyroid hormones (THs) control a wide range of physiological functions essential for metabolism, growth, and differentiation. On a molecular level, TH action is exerted by nuclear receptors (TRs), which function as ligand-dependent transcription factors. Among several TR isoforms, the function of TRα2 remains poorly understood as it is a splice variant of TRα with an altered C-terminus that is unable to bind T3. This review highlights the molecular characteristics of TRα2, proposed mechanisms that regulate alternative splicing and indications pointing towards an antagonistic function of this TR isoform in vitro and in vivo. Moreover, remaining knowledge gaps and major challenges that complicate TRα2 characterization, as well as future strategies to fully uncover its physiological relevance, are discussed.
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Affiliation(s)
- Georg Sebastian Hönes
- Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
- Correspondence:
| | - Nina Härting
- Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (N.H.); (F.J.K.)
| | - Jens Mittag
- Institute for Endocrinology and Diabetes-Molecular Endocrinology, Center of Brain Behavior and Metabolism CBBM, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany;
| | - Frank J. Kaiser
- Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (N.H.); (F.J.K.)
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15
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Zhao M, Xie H, Shan H, Zheng Z, Li G, Li M, Hong L. Development of Thyroid Hormones and Synthetic Thyromimetics in Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:1102. [PMID: 35163026 PMCID: PMC8835192 DOI: 10.3390/ijms23031102] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/12/2022] [Accepted: 01/18/2022] [Indexed: 02/05/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the fastest-growing liver disease in the world. Despite targeted agents which are needed to provide permanent benefits for patients with NAFLD, no drugs have been approved to treat NASH. Thyroid hormone is an important signaling molecule to maintain normal metabolism, and in vivo and vitro studies have shown that regulation of the 3,5,3'-triiodothyronine (T3)/ thyroid hormone receptor (TR) axis is beneficial not only for metabolic symptoms but also for the improvement of NAFLD and even for the repair of liver injury. However, the non-selective regulation of T3 to TR subtypes (TRα/TRβ) could cause unacceptable side effects represented by cardiotoxicity. To avoid deleterious effects, TRβ-selective thyromimetics were developed for NASH studies in recent decades. Herein, we will review the development of thyroid hormones and synthetic thyromimetics based on TR selectivity for NAFLD, and analyze the role of TR-targeted drugs for the treatment of NAFLD in the future.
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Affiliation(s)
- Man Zhao
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; (M.Z.); (H.X.); (H.S.); (Z.Z.)
| | - Huazhong Xie
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; (M.Z.); (H.X.); (H.S.); (Z.Z.)
| | - Hao Shan
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; (M.Z.); (H.X.); (H.S.); (Z.Z.)
| | - Zhihua Zheng
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; (M.Z.); (H.X.); (H.S.); (Z.Z.)
| | - Guofeng Li
- Health Science Centre, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen 518060, China;
| | - Min Li
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; (M.Z.); (H.X.); (H.S.); (Z.Z.)
| | - Liang Hong
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; (M.Z.); (H.X.); (H.S.); (Z.Z.)
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16
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Bundy JA, Yang JT, Morscher MA, Steiner RP, Adamczyk MJ, Weiner DS, Jacquet RD, Landis WJ. Induced hypothyroidism alters articular cartilage in skeletally immature miniature swine. Connect Tissue Res 2021; 62:643-657. [PMID: 33073630 DOI: 10.1080/03008207.2020.1839436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
PURPOSE/AIM Thyroid hormone has been implicated in the normal growth and development of articular cartilage; however, its effect on a disease state, such as hypothyroidism, is unknown. The purpose of this investigation was to compare normal articular cartilage from proximal femurs of immature miniature swine to proximal femurs from hypothyroid-induced immature miniature swine. MATERIALS AND METHODS Two 11-week-old male Sinclair miniature swine were made hypothyroid by administration of 6-propyl-2-thiouracil (PTU) in their drinking water; two control animals did not receive PTU. At 25 weeks of age, the animals were euthanized and their proximal femurs were fixed and decalcified. Samples were sectioned and analyzed by histology to define extracellular matrix (ECM) structure, immunohistochemistry (IHC) to identify types II and X collagen, and histomorphometry to assess articular cartilage mean total and localized height and cell density. Statistics included nested mixed-effects ANOVA with p ≤ 0.05 considered statistically significant. RESULTS Compared to controls, hypothyroid articular cartilage demonstrated statistically significant quantitative differences in mean tissue height, mean cell density and type II collagen localized zone height. Qualitative differences in ECM proteoglycans and overall collagen types were also found. Type X collagen was not detected in either hypothyroid or control articular cartilage specimens. CONCLUSIONS Significant changes in articular cartilage structure in hypothyroid compared to control immature miniature swine suggest that thyroid hormone is critical in the growth and development of articular cartilage. CLINICAL SIGNIFICANCE Understanding articular cartilage development in immature animal models may provide insight into healing or repair of degenerative human articular cartilage.
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Affiliation(s)
- Joshua A Bundy
- Department of Polymer Science, University of Akron, Akron, OH, USA.,Department of Biomedical Sciences, Marian University, Indianapolis, IN, USA
| | - Julianne T Yang
- Obstetrics and Gynecology, Stark Women's Center, Canton, OH, USA
| | | | | | - Mark J Adamczyk
- Department of Orthopedics, Akron Children's Hospital, Akron, OH, USA
| | - Dennis S Weiner
- Department of Orthopedics, Akron Children's Hospital, Akron, OH, USA
| | - Robin DiFeo Jacquet
- Department of Polymer Science, University of Akron, Akron, OH, USA.,Department of Orthopedics, Akron Children's Hospital, Akron, OH, USA
| | - William J Landis
- Department of Polymer Science, University of Akron, Akron, OH, USA
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17
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Abstract
The present review traces the road leading to discovery of L-thyroxine, thyroid hormone (3,5,3´-triiodo-L-thyronine, T3) and its cognate nuclear receptors. Thyroid hormone is a pleio-tropic regulator of growth, differentiation, and tissue homeostasis in higher organisms. The major site of the thyroid hormone action is predominantly a cell nucleus. T3 specific binding sites in the cell nuclei have opened a new era in the field of the thyroid hormone receptors (TRs) discovery. T3 actions are mediated by high affinity nuclear TRs, TRalpha and TRbeta, which function as T3-activated transcription factors playing an essential role as transcription-modulating proteins affecting the transcriptional responses in target genes. Discovery and characterization of nuclear retinoid X receptors (RXRs), which form with TRs a heterodimer RXR/TR, positioned RXRs at the epicenter of molecular endocrinology. Transcriptional control via nuclear RXR/TR heterodimer represents a direct action of thyroid hormone. T3 plays a crucial role in the development of brain, it exerts significant effects on the cardiovascular system, skeletal muscle contractile function, bone development and growth, both female and male reproductive systems, and skin. It plays an important role in maintaining the hepatic, kidney and intestine homeostasis and in pancreas, it stimulates the beta-cell proliferation and survival. The TRs cross-talk with other signaling pathways intensifies the T3 action at cellular level. The role of thyroid hormone in human cancers, acting via its cognate nuclear receptors, has not been fully elucidated yet. This review is aimed to describe the history of T3 receptors, starting from discovery of T3 binding sites in the cell nuclei to revelation of T3 receptors as T3-inducible transcription factors in relation to T3 action at cellular level. It also focuses on milestones of investigation, comprising RXR/TR dimerization, cross-talk between T3 receptors, and other regulatory pathways within the cell and mainly on genomic action of T3. This review also focuses on novel directions of investigation on relationships between T3 receptors and cancer. Based on the update of available literature and the author's experimental experience, it is devoted to clinicians and medical students.
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18
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Paisdzior S, Knierim E, Kleinau G, Biebermann H, Krude H, Straussberg R, Schuelke M. A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2. Int J Mol Sci 2021; 22:ijms22105338. [PMID: 34069457 PMCID: PMC8159125 DOI: 10.3390/ijms22105338] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/28/2021] [Accepted: 05/15/2021] [Indexed: 12/25/2022] Open
Abstract
The nuclear thyroid hormone receptors (THRs) are key mediators of thyroid hormone function on the cellular level via modulation of gene expression. Two different genes encode THRs (THRA and THRB), and are pleiotropically involved in development, metabolism, and growth. The THRA1 and THRA2 isoforms, which result from alternative splicing of THRA, differ in their C-terminal ligand-binding domain (LBD). Most published disease-associated THRA variants are located in the LBD of THRA1 and impede triiodothyronine (T3) binding. This keeps the nuclear receptor in an inactive state and inhibits target gene expression. Here, we investigated a new dominant THRA variant (chr17:g.38,241,010A > G, GRCh37.13 | c.518A > G, NM_199334 | p.(E173G), NP_955366), which is located between the DNA- and ligand-binding domains and affects both splicing isoforms. Patients presented partially with hypothyroid (intellectual disability, motor developmental delay, brain atrophy, and constipation) and partially with hyperthyroid symptoms (tachycardia and behavioral abnormalities) to varying degrees. Functional characterization of THRA1p.(E173G) by reporter gene assays revealed increased transcriptional activity in contrast to THRA1(WT), unexpectedly revealing the first gain-of-function mutation found in THRA1. The THRA2 isoform does not bind T3 and antagonizes THRA1 action. Introduction of p.(E173G) into THRA2 increased its inhibitory effect on THRA1, which helps to explain the hypothyroid symptoms seen in our patients. We used protein structure models to investigate possible underlying pathomechanisms of this variant with a gain-of-antagonistic function and suggest that the p.(E173G) variant may have an influence on the dimerization domain of the nuclear receptor.
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Affiliation(s)
- Sarah Paisdzior
- Institute of Experimental Pediatric Endocrinology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, D-13353 Berlin, Germany; (S.P.); (H.B.); (H.K.)
| | - Ellen Knierim
- NeuroCure Cluster of Excellence; Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, D-10117 Berlin, Germany;
- Department of Neuropediatrics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, D-13353 Berlin, Germany
| | - Gunnar Kleinau
- Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, D-10117 Berlin, Germany;
| | - Heike Biebermann
- Institute of Experimental Pediatric Endocrinology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, D-13353 Berlin, Germany; (S.P.); (H.B.); (H.K.)
| | - Heiko Krude
- Institute of Experimental Pediatric Endocrinology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, D-13353 Berlin, Germany; (S.P.); (H.B.); (H.K.)
| | - Rachel Straussberg
- Schneider Children’s Medical Center, Petach Tikva, Israel, Department of Child Neurology, Neurogenetic Service, affiliated to Sackler School of Medicine, Tel Aviv University, Ramat Aviv IL-69978, Israel
- Correspondence: (R.S.); (M.S.); Tel.: +972-3-9253870 (R.S.); +49-30-450566112 (M.S.); FAX: +972-3-9253871 (R.S.); +49-30-45066920 (M.S.)
| | - Markus Schuelke
- NeuroCure Cluster of Excellence; Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, D-10117 Berlin, Germany;
- Department of Neuropediatrics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, D-13353 Berlin, Germany
- Correspondence: (R.S.); (M.S.); Tel.: +972-3-9253870 (R.S.); +49-30-450566112 (M.S.); FAX: +972-3-9253871 (R.S.); +49-30-45066920 (M.S.)
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19
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Lorenzi E, Lemaire BS, Versace E, Matsushima T, Vallortigara G. Resurgence of an Inborn Attraction for Animate Objects via Thyroid Hormone T 3. Front Behav Neurosci 2021; 15:675994. [PMID: 33953662 PMCID: PMC8092046 DOI: 10.3389/fnbeh.2021.675994] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 03/24/2021] [Indexed: 11/13/2022] Open
Abstract
For inexperienced brains, some stimuli are more attractive than others. Human neonates and newly hatched chicks preferentially orient towards face-like stimuli, biological motion, and objects changing speed. In chicks, this enhances exposure to social partners, and subsequent attachment trough filial imprinting. Early preferences are not steady. For instance, preference for stimuli changing speed fades away after 2 days in chicks. To understand the physiological mechanisms underlying these transient responses, we tested whether early preferences for objects changing speed can be promoted by thyroid hormone 3,5,3′-triiodothyronine (T3). This hormone determines the start of imprinting’s sensitive period. We found that the preference for objects changing speed can be re-established in female chicks treated with T3. Moreover, day-1 chicks treated with an inhibitor of endogenous T3 did not show any preference. These results suggest that the time windows of early predispositions and of sensitive period for imprinting are controlled by the same molecular mechanisms.
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Affiliation(s)
- Elena Lorenzi
- Center for Mind/Brain Sciences, University of Trento, Rovereto, Italy
| | | | - Elisabetta Versace
- Center for Mind/Brain Sciences, University of Trento, Rovereto, Italy.,Department of Biological and Experimental Psychology, School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom
| | - Toshiya Matsushima
- Department of Biology, Faculty of Science, Hokkaido University, Sapporo, Japan
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20
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Breton JM, Long KLP, Barraza MK, Perloff OS, Kaufer D. Hormonal Regulation of Oligodendrogenesis II: Implications for Myelin Repair. Biomolecules 2021; 11:290. [PMID: 33669242 PMCID: PMC7919830 DOI: 10.3390/biom11020290] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/10/2021] [Accepted: 02/13/2021] [Indexed: 02/07/2023] Open
Abstract
Alterations in myelin, the protective and insulating sheath surrounding axons, affect brain function, as is evident in demyelinating diseases where the loss of myelin leads to cognitive and motor dysfunction. Recent evidence suggests that changes in myelination, including both hyper- and hypo-myelination, may also play a role in numerous neurological and psychiatric diseases. Protecting myelin and promoting remyelination is thus crucial for a wide range of disorders. Oligodendrocytes (OLs) are the cells that generate myelin, and oligodendrogenesis, the creation of new OLs, continues throughout life and is necessary for myelin plasticity and remyelination. Understanding the regulation of oligodendrogenesis and myelin plasticity within disease contexts is, therefore, critical for the development of novel therapeutic targets. In our companion manuscript, we review literature demonstrating that multiple hormone classes are involved in the regulation of oligodendrogenesis under physiological conditions. The majority of hormones enhance oligodendrogenesis, increasing oligodendrocyte precursor cell differentiation and inducing maturation and myelin production in OLs. Thus, hormonal treatments present a promising route to promote remyelination. Here, we review the literature on hormonal regulation of oligodendrogenesis within the context of disorders. We focus on steroid hormones, including glucocorticoids and sex hormones, peptide hormones such as insulin-like growth factor 1, and thyroid hormones. For each hormone, we describe whether they aid in OL survival, differentiation, or remyelination, and we discuss their mechanisms of action, if known. Several of these hormones have yielded promising results in both animal models and in human conditions; however, a better understanding of hormonal effects, interactions, and their mechanisms will ultimately lead to more targeted therapeutics for myelin repair.
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Affiliation(s)
- Jocelyn M Breton
- Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
| | - Kimberly L P Long
- Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
| | - Matthew K Barraza
- Molecular and Cellular Biology, University of California Berkeley, Berkeley, CA 94720, USA
| | - Olga S Perloff
- Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA
| | - Daniela Kaufer
- Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
- Integrative Biology, University of California Berkeley, Berkeley, CA 94720, USA
- Canadian Institute for Advanced Research, Toronto, ON M5G1M1, Canada
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21
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Long KLP, Breton JM, Barraza MK, Perloff OS, Kaufer D. Hormonal Regulation of Oligodendrogenesis I: Effects across the Lifespan. Biomolecules 2021; 11:biom11020283. [PMID: 33672939 PMCID: PMC7918364 DOI: 10.3390/biom11020283] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/04/2021] [Accepted: 02/06/2021] [Indexed: 02/07/2023] Open
Abstract
The brain’s capacity to respond to changing environments via hormonal signaling is critical to fine-tuned function. An emerging body of literature highlights a role for myelin plasticity as a prominent type of experience-dependent plasticity in the adult brain. Myelin plasticity is driven by oligodendrocytes (OLs) and their precursor cells (OPCs). OPC differentiation regulates the trajectory of myelin production throughout development, and importantly, OPCs maintain the ability to proliferate and generate new OLs throughout adulthood. The process of oligodendrogenesis, the creation of new OLs, can be dramatically influenced during early development and in adulthood by internal and environmental conditions such as hormones. Here, we review the current literature describing hormonal regulation of oligodendrogenesis within physiological conditions, focusing on several classes of hormones: steroid, peptide, and thyroid hormones. We discuss hormonal regulation at each stage of oligodendrogenesis and describe mechanisms of action, where known. Overall, the majority of hormones enhance oligodendrogenesis, increasing OPC differentiation and inducing maturation and myelin production in OLs. The mechanisms underlying these processes vary for each hormone but may ultimately converge upon common signaling pathways, mediated by specific receptors expressed across the OL lineage. However, not all of the mechanisms have been fully elucidated, and here, we note the remaining gaps in the literature, including the complex interactions between hormonal systems and with the immune system. In the companion manuscript in this issue, we discuss the implications of hormonal regulation of oligodendrogenesis for neurological and psychiatric disorders characterized by white matter loss. Ultimately, a better understanding of the fundamental mechanisms of hormonal regulation of oligodendrogenesis across the entire lifespan, especially in vivo, will progress both basic and translational research.
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Affiliation(s)
- Kimberly L. P. Long
- Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA; (J.M.B.); (D.K.)
- Correspondence:
| | - Jocelyn M. Breton
- Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA; (J.M.B.); (D.K.)
| | - Matthew K. Barraza
- Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720, USA;
| | - Olga S. Perloff
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94143, USA;
| | - Daniela Kaufer
- Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA; (J.M.B.); (D.K.)
- Department of Integrative Biology, University of California, Berkeley, CA 94720, USA
- Canadian Institute for Advanced Research, Toronto, ON M5G 1M1, Canada
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Saeedi M, Yadegari M, Aghadoost S, Naderi M. Vocal tract discomfort and voice handicap index in patients undergoing thyroidectomy. LOGOP PHONIATR VOCO 2020; 47:49-55. [PMID: 33371756 DOI: 10.1080/14015439.2020.1864466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
PURPOSE This study aims to investigate the frequency and severity of vocal tract discomfort (VTD) symptoms and to determine the relationship between VTD and type of thyroidectomy, voice problem history, vocal abuse, and misuse behaviors, and the voice handicap index (VHI) in the thyroidectomy patients undergoing thyroidectomy, pre- and post-operatively pre- and post-thyroidectomy. MATERIALS The sample comprised 21 thyroidectomy patients undergoing thyroidectomy, including 10 patients with total thyroidectomy and 11 patients with partial thyroidectomy. The participants underwent videolaryngoscopy examination and completed the voice history questionnaire, the VTD scale, and the VHI, before and after the surgery. RESULTS Dryness was the most frequently occurring symptom, pre- and post-thyroidectomy. Participants with total thyroidectomy reported significantly higher frequency and severity of tickling than those in the preoperative status (p<.05). The frequency and severity of many VTD symptoms in the participants with voice problems and a vocal abuse and misuse history were higher than those without such a history at both assessment times (p<.05). There was significant correlation between the frequency and severity of VTD and VHI scores, pre-thyroidectomy pre-operatively (r = 0.488-0.575, p<.05). CONCLUSIONS An increment in the frequency and severity of tickling was reported by total thyroidectomy patients, post-thyroidectomy post-operatively. The type of thyroidectomy, voice problem history, and vocal abuse and misuse behaviors seem to influence the frequency and severity of VTD. Considering the correlation between VTD and VHI, the VTD scale provides important clinical information and can be used for evaluation and consultation purposes.
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Affiliation(s)
- Masoumeh Saeedi
- New Hearing Technologies Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Meysam Yadegari
- New Hearing Technologies Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Samira Aghadoost
- Department of Speech Therapy, School of Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Naderi
- New Hearing Technologies Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Sanoh S, Hanada H, Kashiwagi K, Mori T, Goto-Inoue N, Suzuki KIT, Mori J, Nakamura N, Yamamoto T, Kitamura S, Kotake Y, Sugihara K, Ohta S, Kashiwagi A. Amiodarone bioconcentration and suppression of metamorphosis in Xenopus. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2020; 228:105623. [PMID: 32956954 DOI: 10.1016/j.aquatox.2020.105623] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 08/27/2020] [Accepted: 09/01/2020] [Indexed: 06/11/2023]
Abstract
Trace concentrations of a number of pharmaceutically active compounds have been detected in the aquatic environment in many countries, where they are thought to have the potential to exert adverse effects on non-target organisms. Amiodarone (AMD) is one such high-risk compound commonly used in general hospitals. AMD is known to alter normal thyroid hormone (TH) function, although little information is available regarding the specific mechanism by which this disruption occurs. Anuran tadpole metamorphosis is a TH-controlled developmental process and has proven to be useful as a screening tool for environmental pollutants suspected of disrupting TH functions. In the present study, our objective was to clarify the effects of AMD on Xenopus metamorphosis as well as to assess the bioconcentration of this pharmaceutical in the liver. We found that AMD suppressed spontaneous metamorphosis, including tail regression and hindlimb elongation in pro-metamorphic stage tadpoles, which is controlled by endogenous circulating TH, indicating that AMD is a TH antagonist. In transgenic X. laevis tadpoles carrying plasmid DNA containing TH-responsive element (TRE) and a 5'-upstream promoter region of the TH receptor (TR) βA1 gene linked to a green fluorescent protein (EGFP) gene, triiodothyronine (T3) exposure induced a strong EGFP expression in the hind limbs, whereas the addition of AMD to T3 suppressed EGFP expression, suggesting that this drug interferes with the binding of T3 to TR, leading to the inhibition of TR-mediated gene expression. We also found AMD to be highly bioconcentrated in the liver of pro-metamorphic X. tropicalis tadpoles, and we monitored hepatic accumulation of this drug using mass spectrometry imaging (MSI). Our findings suggest that AMD imposes potential risk to aquatic wildlife by disrupting TH homeostasis, with further possibility of accumulating in organisms higher up in the food chain.
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Affiliation(s)
- Seigo Sanoh
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.
| | - Hideki Hanada
- Amphibian Research Center, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
| | - Keiko Kashiwagi
- Amphibian Research Center, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
| | - Tsukasa Mori
- Department of Marine Science and Resources, Nihon University College of Bioresource Sciences, Kameino 1866, Fujisawa 252-0880, Japan.
| | - Naoko Goto-Inoue
- Department of Marine Science and Resources, Nihon University College of Bioresource Sciences, Kameino 1866, Fujisawa 252-0880, Japan.
| | - Ken-Ichi T Suzuki
- Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
| | - Junpei Mori
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.
| | - Naoki Nakamura
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.
| | - Takashi Yamamoto
- Program of Mathematical and Life Sciences, Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
| | - Shigeyuki Kitamura
- Nihon Pharmaceutical University, Komuro 10281, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan.
| | - Yaichiro Kotake
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.
| | - Kazumi Sugihara
- Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshinkai, Kure City, Hiroshima 737-0112, Japan.
| | - Shigeru Ohta
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan; Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 641-8509, Japan.
| | - Akihiko Kashiwagi
- Amphibian Research Center, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
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Ren XM, Yao L, Xue Q, Shi J, Zhang Q, Wang P, Fu J, Zhang A, Qu G, Jiang G. Binding and Activity of Tetrabromobisphenol A Mono-Ether Structural Analogs to Thyroid Hormone Transport Proteins and Receptors. ENVIRONMENTAL HEALTH PERSPECTIVES 2020; 128:107008. [PMID: 33095664 PMCID: PMC7584160 DOI: 10.1289/ehp6498] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
BACKGROUND Tetrabromobisphenol A (TBBPA) mono-ether structural analogs, identified as the by-products or transformation products of commercial TBBPA bis-ether derivatives, have been identified as emerging widespread pollutants. However, there is very little information regarding their toxicological effects. OBJECTIVE We aimed to explore the potential thyroid hormone (TH) system-disrupting effect of TBBPA mono-ether structural analogs. METHODS The binding potencies of chemicals toward human TH transport proteins [transthyretin (TTR) and thyroxine-binding globulin (TBG)] and receptors [TRα ligand-binding domain (LBD) and TRβ-LBD] were determined by fluorescence competitive binding assays. Molecular docking was used to simulate the binding modes of the chemicals with the proteins. The cellular TR-disrupting potencies of chemicals were assessed by a GH3 cell proliferation assay. The intracellular concentrations of the chemicals were measured by high-performance liquid chromatography and mass spectrometry. RESULTS TBBPA mono-ether structural analogs bound to TTR with half maximal inhibitory concentrations ranging from 0.1μM to 1.0μM but did not bind to TBG. They also bound to both subtypes of TR-LBDs with 20% maximal inhibitory concentrations ranging from 4.0μM to 50.0μM. The docking results showed that the analogs fit into the ligand-binding pockets of TTR and TR-LBDs with binding modes similar to that of TBBPA. These compounds likely induced GH3 cell proliferation via TR [with the lowest effective concentrations (LOECs) ranging from 0.3μM to 2.5μM] and further enhanced TH-induced GH3 cell proliferation (with LOECs ranging from 0.3μM to 1.2μM). Compared with TBBPA, TBBPA-mono(2,3-dibromopropyl ether) showed a 4.18-fold higher GH3 cell proliferation effect and 105-fold higher cell membrane transportation ability. CONCLUSION This study provided a possible mechanism underlying the difference in TTR or TR binding by novel TBBPA structural analogs. These compounds might exert TH system-disrupting effects by disrupting TH transport in circulation and TR activity in TH-responsive cells. https://doi.org/10.1289/EHP6498.
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Affiliation(s)
- Xiao-Min Ren
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences (UCAS), Beijing, China
| | - Linlin Yao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences (UCAS), Beijing, China
| | - Qiao Xue
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences (UCAS), Beijing, China
| | - Jianbo Shi
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences (UCAS), Beijing, China
- Institute of Environment and Health, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China
- Institute of Environment and Health, Jianghan University, Wuhan, China
| | - Qinghua Zhang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences (UCAS), Beijing, China
- Institute of Environment and Health, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China
- Institute of Environment and Health, Jianghan University, Wuhan, China
| | - Pu Wang
- Institute of Environment and Health, Jianghan University, Wuhan, China
| | - Jianjie Fu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences (UCAS), Beijing, China
- Institute of Environment and Health, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China
| | - Aiqian Zhang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences (UCAS), Beijing, China
- Institute of Environment and Health, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China
| | - Guangbo Qu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences (UCAS), Beijing, China
- Institute of Environment and Health, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China
- Institute of Environment and Health, Jianghan University, Wuhan, China
| | - Guibin Jiang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences (UCAS), Beijing, China
- Institute of Environment and Health, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China
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25
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Giannocco G, Kizys MML, Maciel RM, de Souza JS. Thyroid hormone, gene expression, and Central Nervous System: Where we are. Semin Cell Dev Biol 2020; 114:47-56. [PMID: 32980238 DOI: 10.1016/j.semcdb.2020.09.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 12/27/2022]
Abstract
Thyroid hormones (TH; T3 and T4) play a fundamental role in the fetal stage to the adult phase, controlling gene and protein expression in virtually all tissues. The endocrine and CNS systems have relevant interaction, and the TH are pivotal for the proper functioning of the CNS. A slight failure to regulate TH availability during pregnancy and/or childhood can lead to neurological disorders, for example, autism and cognitive impairment, or depression. In this review, we highlight how TH acts in controlling gene expression, its role in the CNS, and what substances widely found in the environment can cause in this tissue. We highlight the role of Endocrine Disruptors used on an everyday basis in the processing of mRNAs responsible for neurodevelopment. We conclude that TH, more precisely T3, acts mainly throughout its nuclear receptors, that the deficiency of this hormone, either due to the lack of its main substrate iodine, or by to incorrect organification of T4 and T3 in the gland, or by a mutation in transporters, receptors and deiodinases may cause mild (dysregulated mood in adulthood) to severe neurological impairment (Allan-Herndon-Dudley syndrome, presented as early as childhood); T3 is responsible for the expression of numerous CNS genes related to oxygen transport, growth factors, myelination, cell maturation. Substances present in the environment and widely used can interfere with the functioning of the thyroid gland, the action of TH, and the functioning of the CNS.
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Affiliation(s)
- Gisele Giannocco
- Departamento de Medicina, Laboratório de Endocrinologia e Medicina Translacional, Universidade Federal de São Paulo, UNIFESP/EPM, Rua Pedro de Toledo, 669 - 11 andar, São Paulo, SP 04039-032, Brazil; Departamento de Ciências Biológicas, Universidade Federal de São Paulo, UNIFESP, Diadema, SP 09920-000, Brazil
| | - Marina Malta Letro Kizys
- Departamento de Medicina, Laboratório de Endocrinologia e Medicina Translacional, Universidade Federal de São Paulo, UNIFESP/EPM, Rua Pedro de Toledo, 669 - 11 andar, São Paulo, SP 04039-032, Brazil
| | - Rui Monteiro Maciel
- Departamento de Medicina, Laboratório de Endocrinologia e Medicina Translacional, Universidade Federal de São Paulo, UNIFESP/EPM, Rua Pedro de Toledo, 669 - 11 andar, São Paulo, SP 04039-032, Brazil
| | - Janaina Sena de Souza
- Departamento de Medicina, Laboratório de Endocrinologia e Medicina Translacional, Universidade Federal de São Paulo, UNIFESP/EPM, Rua Pedro de Toledo, 669 - 11 andar, São Paulo, SP 04039-032, Brazil; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
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26
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Wilpert NM, Krueger M, Opitz R, Sebinger D, Paisdzior S, Mages B, Schulz A, Spranger J, Wirth EK, Stachelscheid H, Mergenthaler P, Vajkoczy P, Krude H, Kühnen P, Bechmann I, Biebermann H. Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression. Thyroid 2020; 30:1366-1383. [PMID: 32143555 DOI: 10.1089/thy.2019.0544] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background: Mutations of monocarboxylate transporter 8 (MCT8), a thyroid hormone (TH)-specific transmembrane transporter, cause a severe neurodevelopmental disorder, the Allan-Herndon-Dudley syndrome. In MCT8 deficiency, TH is not able to reach those areas of the brain where TH uptake depends on MCT8. Currently, therapeutic options for MCT8-deficient patients are missing, as TH treatment is not successful in improving neurological deficits. Available data on MCT8 protein and transcript levels indicate complex expression patterns in neural tissue depending on species, brain region, sex, and age. However, information on human MCT8 expression is still scattered and additional efforts are needed to map sites of MCT8 expression in neurovascular units and neural tissue. This is of importance because new therapeutic strategies for this disease are urgently needed. Methods: To identify regions and time windows of MCT8 expression, we used highly specific antibodies against MCT8 to perform immunofluorescence labeling of postnatal murine brains, adult human brain tissue, and human cerebral organoids. Results: Qualitative and quantitative analyses of murine brain samples revealed stable levels of MCT8 protein expression in endothelial cells of the blood-brain barrier (BBB), choroid plexus epithelial cells, and tanycytes during postnatal development. Conversely, the neuronal MCT8 protein expression that was robustly detectable in specific brain regions of young mice strongly declined with age. Similarly, MCT8 immunoreactivity in adult human brain tissue was largely confined to endothelial cells of the BBB. Recently, cerebral organoids emerged as promising models of human neural development and our first analyses of forebrain-like organoids revealed MCT8 expression in early neuronal progenitor cell populations. Conclusions: With respect to MCT8-deficient conditions, our analyses not only strongly support the contention that the BBB presents a lifelong barrier to TH uptake but also highlight the need to decipher the TH transport role of MCT8 in early neuronal cell populations in more detail. Improving the understanding of the spatiotemporal expression in latter barriers will be critical for therapeutic strategies addressing MCT8 deficiency in the future.
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Affiliation(s)
- Nina-Maria Wilpert
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Experimental Pediatric Endocrinology, Berlin, Germany
| | - Martin Krueger
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Robert Opitz
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Experimental Pediatric Endocrinology, Berlin, Germany
| | - David Sebinger
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Experimental Pediatric Endocrinology, Berlin, Germany
| | - Sarah Paisdzior
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Experimental Pediatric Endocrinology, Berlin, Germany
| | - Bianca Mages
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Angela Schulz
- Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, University of Leipzig, Leipzig, Germany
| | - Joachim Spranger
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology, Diabetes and Nutrition, Berlin, Germany
| | - Eva K Wirth
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology, Diabetes and Nutrition, Berlin, Germany
| | - Harald Stachelscheid
- Stem Cell Core Facility, Berlin Institute of Health, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany
| | - Philipp Mergenthaler
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Experimental Neurology, Department of Neurology, Center for Stroke Research Berlin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Peter Vajkoczy
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurosurgery, Berlin, Germany
| | - Heiko Krude
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Experimental Pediatric Endocrinology, Berlin, Germany
| | - Peter Kühnen
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Experimental Pediatric Endocrinology, Berlin, Germany
| | - Ingo Bechmann
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Heike Biebermann
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Experimental Pediatric Endocrinology, Berlin, Germany
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27
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Akinola LK, Uzairu A, Shallangwa GA, Abechi SE. Theoretical study on endocrine disrupting effects of polychlorinated dibenzo‐
p
‐dioxins using molecular docking simulation. J Appl Toxicol 2020; 41:233-246. [DOI: 10.1002/jat.4039] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 12/25/2022]
Affiliation(s)
- Lukman K. Akinola
- Department of Chemistry Ahmadu Bello University Zaria Nigeria
- Department of Chemistry Bauchi State University Gadau Nigeria
| | - Adamu Uzairu
- Department of Chemistry Ahmadu Bello University Zaria Nigeria
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28
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Deveau C, Jiao X, Suzuki SC, Krishnakumar A, Yoshimatsu T, Hejtmancik JF, Nelson RF. Thyroid hormone receptor beta mutations alter photoreceptor development and function in Danio rerio (zebrafish). PLoS Genet 2020; 16:e1008869. [PMID: 32569302 PMCID: PMC7332105 DOI: 10.1371/journal.pgen.1008869] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 07/02/2020] [Accepted: 05/18/2020] [Indexed: 01/16/2023] Open
Abstract
We investigate mutations in trβ2, a splice variant of thrb, identifying changes in function, structure, and behavior in larval and adult zebrafish retinas. Two N-terminus CRISPR mutants were identified. The first is a 6BP+1 insertion deletion frameshift resulting in a truncated protein. The second is a 3BP in frame deletion with intact binding domains. ERG recordings of isolated cone signals showed that the 6BP+1 mutants did not respond to red wavelengths of light while the 3BP mutants did respond. 6BP+1 mutants lacked optomotor and optokinetic responses to red/black and green/black contrasts. Both larval and adult 6BP+1 mutants exhibit a loss of red-cone contribution to the ERG and an increase in UV-cone contribution. Transgenic reporters show loss of cone trβ2 activation in the 6BP+1 mutant but increase in the density of cones with active blue, green, and UV opsin genes. Antibody reactivity for red-cone LWS1 and LWS2 opsin was absent in the 6BP+1 mutant, as was reactivity for arrestin3a. Our results confirm a critical role for trβ2 in long-wavelength cone development. There are four cone photoreceptors responsible for color vision in zebrafish: red, green, blue, and UV. The thyroid hormone receptor trβ2 is localized in the vertebrate retina. We know that it is necessary for the development of cones expressing long-wavelength-sensitive opsins (red cones), but here we investigate the functional alterations that accompany a loss of trβ2. Our work contributes to the ongoing investigations of retinal development and the involvement of thyroid hormone receptors. As suggested by previous morphological findings, fish became red colorblind when trβ2 was knocked out, and the contributions of the other three cone types shifted. Our work highlights the plasticity of photoreceptor patterning as we see changes in opsin peaks and cone sensitivity, increases in contributions of UV cones, and an attempt at a mosaic pattern in the adult retina, all in the absence of trβ2 and red cones. We now have an increased understanding of mechanisms underlying retinal development.
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Affiliation(s)
- Ciana Deveau
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Rockville, Maryland, United States of America
- * E-mail:
| | - Xiaodong Jiao
- National Eye Institute, National Institutes of Health, Rockville, Maryland, United States of America
| | - Sachihiro C. Suzuki
- Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
| | - Asha Krishnakumar
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Rockville, Maryland, United States of America
| | | | - J Fielding Hejtmancik
- National Eye Institute, National Institutes of Health, Rockville, Maryland, United States of America
| | - Ralph F. Nelson
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Rockville, Maryland, United States of America
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29
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Colella M, Cuomo D, Giacco A, Mallardo M, De Felice M, Ambrosino C. Thyroid Hormones and Functional Ovarian Reserve: Systemic vs. Peripheral Dysfunctions. J Clin Med 2020; 9:E1679. [PMID: 32492950 PMCID: PMC7355968 DOI: 10.3390/jcm9061679] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023] Open
Abstract
Thyroid hormones (THs) exert pleiotropic effects in different mammalian organs, including gonads. Genetic and non-genetic factors, such as ageing and environmental stressors (e.g., low-iodine intake, exposure to endocrine disruptors, etc.), can alter T4/T3 synthesis by the thyroid. In any case, peripheral T3, controlled by tissue-specific enzymes (deiodinases), receptors and transporters, ensures organ homeostasis. Conflicting reports suggest that both hypothyroidism and hyperthyroidism, assessed by mean of circulating T4, T3 and Thyroid-Stimulating Hormone (TSH), could affect the functionality of the ovarian reserve determining infertility. The relationship between ovarian T3 level and functional ovarian reserve (FOR) is poorly understood despite that the modifications of local T3 metabolism and signalling have been associated with dysfunctions of several organs. Here, we will summarize the current knowledge on the role of TH signalling and its crosstalk with other pathways in controlling the physiological and premature ovarian ageing and, finally, in preserving FOR. We will consider separately the reports describing the effects of circulating and local THs on the ovarian health to elucidate their role in ovarian dysfunctions.
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Affiliation(s)
- Marco Colella
- Department of Science and Technology, University of Sannio, via De Sanctis, 82100 Benevento, Italy; (M.C.); (A.G.)
- IRGS, Biogem-Scarl, Via Camporeale, Ariano Irpino, 83031 Avellino, Italy
| | - Danila Cuomo
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, TX 77843, USA;
| | - Antonia Giacco
- Department of Science and Technology, University of Sannio, via De Sanctis, 82100 Benevento, Italy; (M.C.); (A.G.)
| | - Massimo Mallardo
- Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, 80131 Naples, Italy;
| | - Mario De Felice
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, TX 77843, USA;
- Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, 80131 Naples, Italy;
- IEOS-CNR, Via Pansini 6, 80131 Naples, Italy
| | - Concetta Ambrosino
- Department of Science and Technology, University of Sannio, via De Sanctis, 82100 Benevento, Italy; (M.C.); (A.G.)
- IRGS, Biogem-Scarl, Via Camporeale, Ariano Irpino, 83031 Avellino, Italy
- IEOS-CNR, Via Pansini 6, 80131 Naples, Italy
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Cheng Y, Xu J, Fu Y, He N. Expression and Regulation of pde6h by Thyroid Hormone During Metamorphosis in Paralichthys olivaceus. Front Physiol 2020; 11:244. [PMID: 32300306 PMCID: PMC7144621 DOI: 10.3389/fphys.2020.00244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 03/02/2020] [Indexed: 11/27/2022] Open
Abstract
PDE6H is a cone cell-specific inhibitory subunit that plays a critical role in the adaptation of the photosensitive system to bright and dark phases of the light environment. Thyroid hormone (TH) is one of the most important factors that control development and metabolism in animals, composed mainly of triiodothyronine (T3), and thyroxine (T4). TH also plays a key role in the metamorphosis of the flounder (Paralichthys olivaceus), wherein exogenous TH can accelerate the behavioral changes of larvae from the pelagic to benthic type accompanying changes in the light environment from bright to dark. In this study, transcriptional analysis showed that pde6h is expressed in adult eye, that its expression peaks at the climax of metamorphosis, and that it can be significantly up-regulated to the highest level by exogenous T4 in the early stages of metamorphosis but is inhibited by thiourea (TU). The rescue experiment showed that metamorphic inhibition of larvae and expression inhibition of pde6h gene in TU groups can be rescued by removing TU. Further, dual-luciferase reporter assay indicated the putative regulatory effect of TH on pde6h expression, mediated directly on the gene promoter by the TRαA gene. Together, we speculated that TH may control physiological adaptation of the photosensitive system to light changes during metamorphosis by acting directly on pde6h. This study can help us further study the physiological function of pde6h during flounder metamorphosis in the future.
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Affiliation(s)
- Yuejuan Cheng
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture, Shanghai Ocean University, Shanghai, China.,Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China.,Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, Shanghai Ocean University, Shanghai, China
| | - Jiaqian Xu
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture, Shanghai Ocean University, Shanghai, China.,Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China.,Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, Shanghai Ocean University, Shanghai, China
| | - Yuanshuai Fu
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture, Shanghai Ocean University, Shanghai, China.,Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China.,Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, Shanghai Ocean University, Shanghai, China
| | - Nisha He
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, China
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Affiliation(s)
- Jerome M Hershman
- Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California
| | - Terry F Davies
- Thyroid Research Unit, Icahn School of Medicine at Mount Sinai, and the James J. Peters VA Medical Center, New York, New York
| | - Charles H Emerson
- Department of Medicine, University of Massachusetts School of Medicine, Worcester, Massachusetts
| | - Peter A Kopp
- Division of Endocrinology, Diabetes and Metabolism, University of Lausanne, Lausanne, Switzerland
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Holmberg MO, Malmgren H, Berglund P, Bunketorp-Käll L, Heckemann RA, Johansson B, Klasson N, Olsson E, Skau S, Nystrom Filipsson H. Structural brain changes in hyperthyroid Graves' disease: protocol for an ongoing longitudinal, case-controlled study in Göteborg, Sweden-the CogThy project. BMJ Open 2019; 9:e031168. [PMID: 31685507 PMCID: PMC6858258 DOI: 10.1136/bmjopen-2019-031168] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 10/06/2019] [Accepted: 10/08/2019] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION Cognitive impairment and reduced well-being are common manifestations of Graves' disease (GD). These symptoms are not only prevalent during the active phase of the disease but also often prevail for a long time after hyperthyroidism is considered cured. The pathogenic mechanisms involved in these brain-derived symptoms are currently unknown. The overall aim of the CogThy study is to identify the mechanism behind cognitive impairment to be able to recognise GD patients at risk. METHODS AND ANALYSIS The study is a longitudinal, single-centre, case-controlled study conducted in Göteborg, Sweden on premenopausal women with newly diagnosed GD. The subjects are examined: at referral, at inclusion and then every 3.25 months until 15 months. Examinations include: laboratory measurements; eye evaluation; neuropsychiatric and neuropsychological testing; structural MRI of the whole brain, orbits and medial temporal lobe structures; functional near-infrared spectroscopy of the cerebral prefrontal cortex and self-assessed quality of life questionnaires. The primary outcome measure is the change in medial temporal lobe structure volume. Secondary outcome measures include neuropsychological, neuropsychiatric, hormonal and autoantibody variables. The study opened for inclusion in September 2012 and close for inclusion in October 2019. It will provide novel information on the effect of GD on medial temporal lobe structures and cerebral cortex functionality as well as whether these changes are associated with cognitive and affective impairment, hormonal levels and/or autoantibody levels. It should lead to a broader understanding of the underlying pathogenesis and future treatment perspectives. ETHICS AND DISSEMINATION The study has been reviewed and approved by the Regional Ethical Review Board in Göteborg, Sweden. The results will be actively disseminated through peer-reviewed journals, national and international conference presentations and among patient organisations after an appropriate embargo time. TRIAL REGISTRATION NUMBER 44321 at the public project database for research and development in Västra Götaland County, Sweden (https://www.researchweb.org/is/vgr/project/44321).
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Affiliation(s)
- Mats Olof Holmberg
- ANOVA, Karolinska University Hospital, Stockholm, Sweden
- Institute of Medicine, University of Gothenburg, Sahlgrenska Academy, Göteborg, Sweden
| | - Helge Malmgren
- Institute of Medicine, University of Gothenburg, Sahlgrenska Academy, Göteborg, Sweden
- MedTech West, University of Gothenburg, Sahlgrenska University Hospital, Göteborg, Sweden
| | - Peter Berglund
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg, Sweden
| | - Lina Bunketorp-Käll
- Department of Health and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg, Sweden
| | - Rolf A Heckemann
- Division of Brain Sciences, Department of Medicine, Faculty of Medicine, Imperial College London, London, UK
- Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Academy, Göteborg, Sweden
| | - Birgitta Johansson
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg, Sweden
| | - Niklas Klasson
- MedTech West, University of Gothenburg, Sahlgrenska University Hospital, Göteborg, Sweden
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg, Sweden
| | - Erik Olsson
- Institute of Medicine, University of Gothenburg, Sahlgrenska Academy, Göteborg, Sweden
| | - Simon Skau
- MedTech West, University of Gothenburg, Sahlgrenska University Hospital, Göteborg, Sweden
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg, Sweden
| | - Helena Nystrom Filipsson
- Institute of Medicine, University of Gothenburg, Sahlgrenska Academy, Göteborg, Sweden
- Department of Endocrinology, Sahlgrenska University Hospital, Göteborg, Sweden
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Karkhaneh M, Qorbani M, Ataie-Jafari A, Mohajeri-Tehrani MR, Asayesh H, Hosseini S. Association of thyroid hormones with resting energy expenditure and complement C3 in normal weight high body fat women. Thyroid Res 2019; 12:9. [PMID: 31666810 PMCID: PMC6813955 DOI: 10.1186/s13044-019-0070-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 10/03/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND A high body fat percentage has a specific effect on activation of the hypothalamic-pituitary-thyroid axis. On the other hand, a slight change in thyroid hormones can affect metabolism and body composition as well as immune function. This study aims to examine the relationship between adiposity, thyroid hormone levels and immunity by comparing resting energy expenditure (REE), serum thyroid hormone levels and complement C3 in normal-weight high body fat (normal weight obesity) women and normal-weight normal body fat women. METHODS In this case-control study, 40 women with normal body weight (BMI < 24.9 kg/m2) and body fat mass (FM) ≥ 30% (normal-weight obesity (NWO) group), and 30 non-obese women (BMI < 24.9 kg/m2) and FM < 30% (non-normal weight obesity (non-NWO) group) were recruited from a sport club in Tehran. Body composition was analyzed using bioimpedance analyzer. Blood samples were collected and analyzed for fasting serum concentration of thyroid hormones (including total T3 and total T4), thyroid-stimulating hormone (TSH), and serum complement C3. REE was measured by an indirect calorimetry. RESULTS Serum T3 and T4 and also complement C3 were higher in the NWO group than in the non-NWO group. Body fat percentages had significant positive correlation with T3 (r; 0.344, P < 0.05), T4 (r; 0.294, P < 0.05), and complement C3 (r; 0.417, P < 0.05). Serum T3 and T4 were also positively correlated with C3 concentration (r; 0.417, p < 0.001) and (r; 0.349, p < 0.05); respectively, but there was no significant correlation between TSH and C3. REE was not significantly different between the two groups. REE only had a significant positive correlation with fat-free mass (r; 0.421, P < 0.001). CONCLUSION An increase in body fat even in the presence of a normal body weight can be accompanied by the changes in thyroid function and inflammatory markers such as complement C3.
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Affiliation(s)
- Maryam Karkhaneh
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mostafa Qorbani
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Asal Ataie-Jafari
- Department of Nutrition, Faculty of Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mohamad Reza Mohajeri-Tehrani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Asayesh
- Department of Medical Emergencies, Qom University of Medical Sciences, Qom, Iran
| | - Saeed Hosseini
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Hojatdost street, Naderi street, Keshavarz Blv, Tehran, Iran
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Talhada D, Santos CRA, Gonçalves I, Ruscher K. Thyroid Hormones in the Brain and Their Impact in Recovery Mechanisms After Stroke. Front Neurol 2019; 10:1103. [PMID: 31681160 PMCID: PMC6814074 DOI: 10.3389/fneur.2019.01103] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 10/02/2019] [Indexed: 12/23/2022] Open
Abstract
Thyroid hormones are of fundamental importance for brain development and essential factors to warrant brain functions throughout life. Their actions are mediated by binding to specific intracellular and membranous receptors regulating genomic and non-genomic mechanisms in neurons and populations of glial cells, respectively. Among others, mechanisms include the regulation of neuronal plasticity processes, stimulation of angiogenesis and neurogenesis as well modulating the dynamics of cytoskeletal elements and intracellular transport processes. These mechanisms overlap with those that have been identified to enhance recovery of lost neurological functions during the first weeks and months after ischemic stroke. Stimulation of thyroid hormone signaling in the postischemic brain might be a promising therapeutic strategy to foster endogenous mechanisms of repair. Several studies have pointed to a significant association between thyroid hormones and outcome after stroke. With this review, we will provide an overview on functions of thyroid hormones in the healthy brain and summarize their mechanisms of action in the developing and adult brain. Also, we compile the major thyroid-modulated molecular pathways in the pathophysiology of ischemic stroke that can enhance recovery, highlighting thyroid hormones as a potential target for therapeutic intervention.
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Affiliation(s)
- Daniela Talhada
- Laboratory for Experimental Brain Research, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden
- CICS-UBI-Health Sciences Research Centre, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Covilha, Portugal
- LUBIN Lab-Lunds Laboratorium för Neurokirurgisk Hjärnskadeforskning, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Cecília Reis Alves Santos
- CICS-UBI-Health Sciences Research Centre, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Covilha, Portugal
| | - Isabel Gonçalves
- CICS-UBI-Health Sciences Research Centre, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Covilha, Portugal
| | - Karsten Ruscher
- Laboratory for Experimental Brain Research, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden
- LUBIN Lab-Lunds Laboratorium för Neurokirurgisk Hjärnskadeforskning, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden
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Silva JF, Ocarino NM, Serakides R. Thyroid hormones and female reproduction. Biol Reprod 2019; 99:907-921. [PMID: 29767691 DOI: 10.1093/biolre/ioy115] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/13/2018] [Indexed: 12/31/2022] Open
Abstract
Thyroid hormones are vital for the proper functioning of the female reproductive system, since they modulate the metabolism and development of ovarian, uterine, and placental tissues. Therefore, hypo- and hyperthyroidism may result in subfertility or infertility in both women and animals. Other well-documented sequelae of maternal thyroid dysfunctions include menstrual/estral irregularity, anovulation, abortion, preterm delivery, preeclampsia, intrauterine growth restriction, postpartum thyroiditis, and mental retardation in children. Several studies have been carried out involving prospective and retrospective studies of women with thyroid dysfunction, as well as in vivo and in vitro assays of hypo- and hyperthyroidism using experimental animal models and/or ovarian, uterine, and placental cell culture. These studies have sought to elucidate the mechanisms by which thyroid hormones influence reproduction to better understand the physiology of the reproductive system and to provide better therapeutic tools for reproductive dysfunctions that originate from thyroid dysfunctions. Therefore, this review aims to summarize and update the available information related to the role of thyroid hormones in the morphophysiology of the ovary, uterus, and placenta in women and animals and the effects of hypo- and hyperthyroidism on the female reproductive system.
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Affiliation(s)
- Juneo F Silva
- Centro de Microscopia Eletrônica, Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, Bahia, Brazil
| | - Natália M Ocarino
- Departamento de Clínica e Cirurgia Veterinárias, Escola de Veterinária, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Rogéria Serakides
- Departamento de Clínica e Cirurgia Veterinárias, Escola de Veterinária, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Sainath SB, André A, Castro LFC, Santos MM. The evolutionary road to invertebrate thyroid hormone signaling: Perspectives for endocrine disruption processes. Comp Biochem Physiol C Toxicol Pharmacol 2019; 223:124-138. [PMID: 31136851 DOI: 10.1016/j.cbpc.2019.05.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 05/23/2019] [Accepted: 05/23/2019] [Indexed: 12/14/2022]
Abstract
Thyroid hormones (THs) are the only iodine-containing hormones that play fundamental roles in chordates and non-chordates. The chemical nature, mode of action and the synthesis of THs are well established in mammals and other vertebrates. Although thyroid-like hormones have been detected in protostomes and non-chordate deuterostomes, TH signaling is poorly understood as compared to vertebrates, particularly in protostomes. Therefore, the central objective of this article is to review TH system components and TH-induced effects in non-vertebrate chordates, non-chordate deuterostomes and protostomes based on available genomes and functional information. To accomplish this task, we integrate here the available knowledge on the THs signaling across non-vertebrate chordates, non-chordate deuterostomes and protostomes by considering studies encompassing TH system components and physiological actions of THs. We also address the possible interactions of thyroid disrupting chemicals and their effects in protostomes and non-chordate deuterostomes. Finally, the perspectives on current and future challenges are discussed.
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Affiliation(s)
- S B Sainath
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal; Department of Biotechnology, Vikrama Simhapuri University, Nellore 524 003, AP, India.
| | - A André
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal
| | - L Filipe C Castro
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal; FCUP - Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal.
| | - M M Santos
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal; FCUP - Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal.
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de Souza JS, Ferreira DR, Herai R, Carromeu C, Torres LB, Araujo BHS, Cugola F, Maciel RMB, Muotri AR, Giannocco G. Altered Gene Expression of Thyroid Hormone Transporters and Deiodinases in iPS MeCP2-Knockout Cells-Derived Neurons. Mol Neurobiol 2019; 56:8277-8295. [DOI: 10.1007/s12035-019-01645-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 05/10/2019] [Indexed: 12/12/2022]
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DuVal MG, Allison WT. Photoreceptor Progenitors Depend Upon Coordination of gdf6a, thrβ, and tbx2b to Generate Precise Populations of Cone Photoreceptor Subtypes. Invest Ophthalmol Vis Sci 2019; 59:6089-6101. [PMID: 30592497 DOI: 10.1167/iovs.18-24461] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose Replacing cone photoreceptors, the units of the retina necessary for daytime vision, depends upon the successful production of a full variety of new cones from, for example, stem cells. Using genetic experiments in a model organism with high cone diversity, zebrafish, we map the intersecting effects of cone development factors gdf6a, tbx2b, and thrβ. Methods We investigated these genes of interest by using genetic combinations of mutants, gene knockdown, and dominant negative gene expression, and then quantified cone subtype outcomes (which normally develop in tightly regulated ratios). Results Gdf6a mutants have reduced blue cones and, discovered here, reduced red cones. In combined gdf6a/tbx2b disruption, the loss of gdf6a in heterozygous tbx2b mutants reduced UV cones. Intriguingly, when we disrupted thrβ in gdf6a mutants by using a thrβ morpholino, their combined early disruption revealed a lamination phenotype. Disrupting thrβ activity via expression of a dominant negative thrβ (dnthrβ) at either early or late retinal development had differential outcomes on red cones (reduced abundance), versus UV and blue cones (increased abundance). By using dnthrβ in gdf6a mutants, we revealed that disrupting thrβ activity did not change gdf6a mutant cone phenotypes. Conclusions Gdf6a loss directly affects blue and red cones and indirectly affects UV cones by increasing sensitivity to additional disruption, such as reduced tbx2b, resulting in fewer UV cones. The effects of thrβ change through photoreceptor development, first promoting red cones and restricting UV cones, and later restricting UV and blue cones. The effects of gdf6a on UV, blue, and red cone development overlap with, but likely supersede, those of thrβ.
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Affiliation(s)
- Michèle G DuVal
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - W Ted Allison
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.,Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.,Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada
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Meroni SB, Galardo MN, Rindone G, Gorga A, Riera MF, Cigorraga SB. Molecular Mechanisms and Signaling Pathways Involved in Sertoli Cell Proliferation. Front Endocrinol (Lausanne) 2019; 10:224. [PMID: 31040821 PMCID: PMC6476933 DOI: 10.3389/fendo.2019.00224] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 03/21/2019] [Indexed: 12/16/2022] Open
Abstract
Sertoli cells are somatic cells present in seminiferous tubules which have essential roles in regulating spermatogenesis. Considering that each Sertoli cell is able to support a limited number of germ cells, the final number of Sertoli cells reached during the proliferative period determines sperm production capacity. Only immature Sertoli cells, which have not established the blood-testis barrier, proliferate. A number of hormonal cues regulate Sertoli cell proliferation. Among them, FSH, the insulin family of growth factors, activin, and cytokines action must be highlighted. It has been demonstrated that cAMP/PKA, ERK1/2, PI3K/Akt, and mTORC1/p70SK6 pathways are the main signal transduction pathways involved in Sertoli cell proliferation. Additionally, c-Myc and hypoxia inducible factor are transcription factors which participate in the induction by FSH of various genes of relevance in cell cycle progression. Cessation of proliferation is a pre-requisite to Sertoli cell maturation accompanied by the establishment of the blood-testis barrier. With respect to this barrier, the participation of androgens, estrogens, thyroid hormones, retinoic acid and opioids has been reported. Additionally, two central enzymes that are involved in sensing cell energy status have been associated with the suppression of Sertoli cell proliferation, namely AMPK and Sirtuin 1 (SIRT1). Among the molecular mechanisms involved in the cessation of proliferation and in the maturation of Sertoli cells, it is worth mentioning the up-regulation of the cell cycle inhibitors p21Cip1, p27Kip, and p19INK4, and of the gap junction protein connexin 43. A decrease in Sertoli cell proliferation due to administration of certain therapeutic drugs and exposure to xenobiotic agents before puberty has been experimentally demonstrated. This review focuses on the hormones, locally produced factors, signal transduction pathways, and molecular mechanisms controlling Sertoli cell proliferation and maturation. The comprehension of how the final number of Sertoli cells in adulthood is established constitutes a pre-requisite to understand the underlying causes responsible for the progressive decrease in sperm production that has been observed during the last 50 years in humans.
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Stepien BK, Huttner WB. Transport, Metabolism, and Function of Thyroid Hormones in the Developing Mammalian Brain. Front Endocrinol (Lausanne) 2019; 10:209. [PMID: 31001205 PMCID: PMC6456649 DOI: 10.3389/fendo.2019.00209] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 03/14/2019] [Indexed: 12/22/2022] Open
Abstract
Ever since the discovery of thyroid hormone deficiency as the primary cause of cretinism in the second half of the 19th century, the crucial role of thyroid hormone (TH) signaling in embryonic brain development has been established. However, the biological understanding of TH function in brain formation is far from complete, despite advances in treating thyroid function deficiency disorders. The pleiotropic nature of TH action makes it difficult to identify and study discrete roles of TH in various aspect of embryogenesis, including neurogenesis and brain maturation. These challenges notwithstanding, enormous progress has been achieved in understanding TH production and its regulation, their conversions and routes of entry into the developing mammalian brain. The endocrine environment has to adjust when an embryo ceases to rely solely on maternal source of hormones as its own thyroid gland develops and starts to produce endogenous TH. A number of mechanisms are in place to secure the proper delivery and action of TH with placenta, blood-brain interface, and choroid plexus as barriers of entry that need to selectively transport and modify these hormones thus controlling their active levels. Additionally, target cells also possess mechanisms to import, modify and bind TH to further fine-tune their action. A complex picture of a tightly regulated network of transport proteins, modifying enzymes, and receptors has emerged from the past studies. TH have been implicated in multiple processes related to brain formation in mammals-neuronal progenitor proliferation, neuronal migration, functional maturation, and survival-with their exact roles changing over developmental time. Given the plethora of effects thyroid hormones exert on various cell types at different developmental periods, the precise spatiotemporal regulation of their action is of crucial importance. In this review we summarize the current knowledge about TH delivery, conversions, and function in the developing mammalian brain. We also discuss their potential role in vertebrate brain evolution and offer future directions for research aimed at elucidating TH signaling in nervous system development.
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Benchmark dose analysis of multiple thyroid toxicity endpoints in ovariectomized rats exposed to propylthiouracil. Regul Toxicol Pharmacol 2018; 97:120-126. [PMID: 29928935 DOI: 10.1016/j.yrtph.2018.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 06/11/2018] [Accepted: 06/16/2018] [Indexed: 11/21/2022]
Abstract
Benchmark dose (BMD) analysis is generally recognized superior to generate a point of departure (PoD) to conduct risk assessment on environmental toxicants, comparing with the traditionally employed no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL) methods. However, only a few studies compared the two on producing PoD of thyroid toxicity caused by environmental chemicals. Here, we presented BMD analyses on several thyroid toxicity endpoints caused by a model chemical - propylthiouracil (PTU). Adult female rats underwent ovariectomy were randomly assigned into groups receiving different doses of PTU (0, 0.1, 0.5, 1.0, and 5.0 mg/kg bw) through gavage for 8 days. Results show that PTU induces significant dose-dependent changes of serum total thyroxine (tT4), total triiodothyronine (tT3), thyroid stimulating hormones, liver type I 5'-deiodinonase (5'-DI) and malic enzyme (ME) activity with profound histopathological exacerbation. BMD and BMDL results (0.03 and 0.01 mg/kg bw respectively) from Hill model of liver 5'-DI activity were accepted based on selection criteria in the benchmark dose analysis. In summary, BMD analysis results in much lower PoD (0.01 mg/kg bw) than LOAEL (0.1 mg/kg bw) in PTU induced thyroid toxicity.
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Overview of Cadmium Thyroid Disrupting Effects and Mechanisms. Int J Mol Sci 2018; 19:ijms19051501. [PMID: 29772829 PMCID: PMC5983752 DOI: 10.3390/ijms19051501] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 05/08/2018] [Accepted: 05/14/2018] [Indexed: 01/01/2023] Open
Abstract
Humans are exposed to a significant number of chemicals that are suspected to produce disturbances in hormone homeostasis. Hence, in recent decades, there has been a growing interest in endocrine disruptive chemicals. One of the alleged thyroid disrupting substances is cadmium (Cd), a ubiquitous toxic metal shown to act as a thyroid disruptor and carcinogen in both animals and humans. Multiple PubMed searches with core keywords were performed to identify and evaluate appropriate studies which revealed literature suggesting evidence for the link between exposure to Cd and histological and metabolic changes in the thyroid gland. Furthermore, Cd influence on thyroid homeostasis at the peripheral level has also been hypothesized. Both in vivo and in vitro studies revealed that a Cd exposure at environmentally relevant concentrations results in biphasic Cd dose-thyroid response relationships. Development of thyroid tumors following exposure to Cd has been studied mainly using in vitro methodologies. In the thyroid, Cd has been shown to activate or stimulate the activity of various factors, leading to increased cell proliferation and a reduction in normal apoptotic activity. Evidence establishing the association between Cd and thyroid disruption remains ambiguous, with further studies needed to elucidate the issue and improve our understanding of Cd-mediated effects on the thyroid gland.
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Siderova M, Hristozov K, Tsukeva A. TSH-receptor antibodies may prevent bone loss in pre- and postmenopausal women with Graves' disease and Graves' orbitopathy. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2018; 62:221-226. [PMID: 29768627 PMCID: PMC10118993 DOI: 10.20945/2359-3997000000027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 12/23/2016] [Indexed: 11/23/2022]
Abstract
OBJECTIVE Thyrotoxicosis is established risk factor for osteoporosis due to increased bone turnover. Glucocorticoids often administered for Graves' orbitopathy (GO) have additional negative effect on bone mineral density (BMD). Our aim was to examine the influence of thyroid hormones, TSH, TSH-receptor antibodies (TRAb) and glucocorticoid treatment on bone in women with Graves' thyrotoxicosis and Graves' orbitopathy (GO). SUBJECTS AND METHODS Forty seven women with Graves' disease, mean age 55.6 ± 12.8 (23 women with thyrotoxicosis and 24 hyperthyroid with concomitant GO and glucocorticoid therapy) and 40 age-matched healthy female controls were enrolled in the study. We analyzed clinical features, TSH, FT4, FT3, TRAb, TPO antibodies. BMD of lumbar spine and hip was measured by DEXA and 10-year fracture risk was calculated with FRAX tool. RESULTS The study showed significantly lower spine and femoral BMD (g/cm2) in patients with and without GO compared to controls, as well as significantly higher fracture risk. Comparison between hyperthyroid patients without and with orbitopathy found out significantly lower spine BMD in the first group (p = 0.0049). Negative correlations between FT3 and femoral neck BMD (p = 0.0001), between FT4 and BMD (p = 0.049) and positive between TSH and BMD (p = 0.0001), TRAb and BMD (p = 0.026) were observed. Fracture risk for major fractures and TRAb were negatively associated (p = 0.05). We found negative correlation of BMD to duration of thyrotoxicosis and cumulative steroid dose. CONCLUSIONS Our results confirm the negative effect of hyperthyroid status on BMD. TRAb, often in high titers in patients with GO, may have protective role for the bone, but further research is needed.
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Abstract
Thyroid hormones have many cardioprotective actions expressed mainly through the action of T3 on thyroid receptors α1 and β1. They are procontractile anti-apoptotic, anti-inflammatory, and anti-fibrotic, promote angiogenesis and regeneration, and have beneficial effects on microRNA profiles. They have proven to be anti-remodeling in numerous animal studies, mostly in rodents; a specific action on the border zone has been described. Studies in humans with DIPTA have been in conclusion. Remodeling can be defined as an increase of ≥20 % of the end-diastolic or end-systolic volume, together with a return to the fetal phenotype. An overview of animal and clinical studies is given.
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Sun N, Wang H, Ju Z, Zhao H. Effects of chronic cadmium exposure on metamorphosis, skeletal development, and thyroid endocrine disruption in Chinese toad Bufo gargarizans tadpoles. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 2018; 37:213-223. [PMID: 28799665 DOI: 10.1002/etc.3947] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 05/22/2017] [Accepted: 08/09/2017] [Indexed: 06/07/2023]
Abstract
The present study examined the effects of chronic cadmium (Cd) exposure on metamorphosis, body size, thyroid gland, and skeletal development of Chinese toad (Bufo gargarizans) tadpoles. Tadpoles were exposed to Cd concentrations at 0, 5, 10, 50, 100, and 500 μg/L from Gosner stages 26 to 46 of completion of metamorphosis. Our results showed that 100 and 500 μg/L of Cd concentrations increased mortality and decelerated metamorphosis rate. In addition, significant body size reduction at Gosner stage 42 was observed at 100 and 500 μg/L of Cd treatments (p < 0.01). Average body length and hind-limb length were significantly decreased in the 500 μg/L of Cd group (p < 0.05) but body mass was not significantly different at Gosner stage 46. Moreover, bone formation was delayed in high Cd concentration treatments (50, 100, and 500 μg/L) at both Gosner stage 42 and 46. Histopathological changes of the thyroid gland showed that follicular cell hyperplasia and malformation were induced by high Cd concentrations (50, 100, and 500 μg/L). Furthermore, real-time polymerase chain reaction analysis suggested that the larvae exposed to high-dose Cd exhibited a significant decrease in deiodinase (Dio2) and thyroid hormone receptor (TRβ) mRNA levels at Gosner stage 42 and 46. Our investigation indicated that high-dose Cd caused metamorphic deceleration, body size reduction, and delayed skeletal development through disrupting the thyroid system in B. gargarizans larvae. Environ Toxicol Chem 2018;37:213-223. © 2017 SETAC.
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Affiliation(s)
- Nailiang Sun
- College of Life Sciences, Shaanxi Normal University, Shaanxi, China
| | - Hongyuan Wang
- College of Life Sciences, Shaanxi Normal University, Shaanxi, China
| | - Zongqi Ju
- College of Life Sciences, Shaanxi Normal University, Shaanxi, China
| | - Hongfeng Zhao
- College of Life Sciences, Shaanxi Normal University, Shaanxi, China
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Little AG. Local Regulation of Thyroid Hormone Signaling. VITAMINS AND HORMONES 2018; 106:1-17. [DOI: 10.1016/bs.vh.2017.06.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Calzà L, Baldassarro VA, Fernandez M, Giuliani A, Lorenzini L, Giardino L. Thyroid Hormone and the White Matter of the Central Nervous System: From Development to Repair. VITAMINS AND HORMONES 2018; 106:253-281. [DOI: 10.1016/bs.vh.2017.04.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Fanibunda SE, Desouza LA, Kapoor R, Vaidya RA, Vaidya VA. Thyroid Hormone Regulation of Adult Neurogenesis. VITAMINS AND HORMONES 2018; 106:211-251. [DOI: 10.1016/bs.vh.2017.04.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Wrutniak-Cabello C, Casas F, Cabello G. Thyroid Hormone Action: The p43 Mitochondrial Pathway. Methods Mol Biol 2018; 1801:163-181. [PMID: 29892824 DOI: 10.1007/978-1-4939-7902-8_14] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The possibility that several pathways are involved in the multiplicity of thyroid hormone physiological influences led to searches for the occurrence of T3 extra nuclear receptors. The existence of a direct T3 mitochondrial pathway is now well established. The demonstration that TRα1 mRNA encodes not only a nuclear thyroid hormone receptor but also two proteins imported into mitochondria with molecular masses of 43 and 28 kDa has provided new clues to understand the pleiotropic influence of iodinated hormones.The use of a T3 photo affinity label derivative (T3-PAL) allowed detecting two mitochondrial T3 binding proteins. In association with western blots using antibodies raised against the T3 nuclear receptor TRα1, mitochondrial T3 receptors were identified as truncated TRα1 forms. Import and in organello transcription experiments performed in isolated mitochondria led to the conclusion that p43 is a transcription factor of the mitochondrial genome, inducing changes in the mitochondrial/nuclear crosstalk. In vitro experiments indicated that this T3 mitochondrial pathway affects cell differentiation, apoptosis, and transformation. Generation of transgenic mice demonstrated the involvement of this mitochondrial pathway in the determination of muscle phenotype, glucose metabolism, and thermogenesis.
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Thyroid Hormone Signaling in the Development of the Endochondral Skeleton. VITAMINS AND HORMONES 2018; 106:351-381. [PMID: 29407442 PMCID: PMC9830754 DOI: 10.1016/bs.vh.2017.06.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Thyroid hormone (TH) is an established regulator of skeletal growth and maintenance both in clinical studies and in laboratory models. The clinical consequences of altered thyroid status on the skeleton during development and in adulthood are well known, and genetic mouse models in which elements of the TH signaling axis have been manipulated illuminate the mechanisms which underlie TH regulation of the skeleton. TH is involved in the regulation of the balance between proliferation and differentiation in several skeletal cell types including chondrocytes, osteoblasts, and osteoclasts. The effects of TH are mediated primarily via the thyroid hormone receptors (TRs) α and β, ligand-inducible nuclear receptors which act as transcription factors to regulate target gene expression. Both TRα and TRβ signaling are important for different stages of skeletal development. The molecular mechanisms of TH action in bone are complex and include interaction with a number of growth factor signaling pathways. This review provides an overview of the regulation and mechanisms of TH action in bone, focusing particularly on the role of TH in endochondral bone formation during postnatal growth.
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