{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:25:55Z","timestamp":1792805155803,"version":"4.5.0"},"reference-count":52,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,26]],"date-time":"2022-11-26T00:00:00Z","timestamp":1669420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Laboratory of Translational Neuroscience","award":["RRF-2.3.1-21-2022-00011"],"award-info":[{"award-number":["RRF-2.3.1-21-2022-00011"]}]},{"name":"National Laboratory of Translational Neuroscience","award":["K125247"],"award-info":[{"award-number":["K125247"]}]},{"name":"National Research, Development and Innovation Office (NKFIH) of Hungary","award":["RRF-2.3.1-21-2022-00011"],"award-info":[{"award-number":["RRF-2.3.1-21-2022-00011"]}],"id":[{"id":"https:\/\/ror.org\/03g2am276","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Research, Development and Innovation Office (NKFIH) of Hungary","award":["K125247"],"award-info":[{"award-number":["K125247"]}],"id":[{"id":"https:\/\/ror.org\/03g2am276","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thyroid hormone (TH) signaling is a prerequisite of normal tissue function. Environmental pollutants with the potential to disrupt endocrine functions represent an emerging threat to human health and agricultural production. We used our Thyroid Hormone Action Indicator (THAI) mouse model to study the effects of tetrabromobisphenol A (TBBPA; 150 mg\/bwkg\/day orally for 6 days) and diclazuril (10.0 mg\/bwkg\/day orally for 5 days), a known and a potential hormone disruptor, respectively, on local TH economy. Tissue-specific changes of TH action were assessed in 90-day-old THAI mice by measuring the expression of a TH-responsive luciferase reporter in tissue samples and by in vivo imaging (14-day-long treatment accompanied with imaging on day 7, 14 and 21 from the first day of treatment) in live THAI mice. This was followed by promoter assays to elucidate the mechanism of the observed effects. TBBPA and diclazuril impacted TH action differently and tissue-specifically. TBBPA disrupted TH signaling in the bone and small intestine and impaired the global TH economy by decreasing the circulating free T4 levels. In the promoter assays, TBBPA showed a direct stimulatory effect on the hdio3 promoter, indicating a potential mechanism for silencing TH action. In contrast, diclazuril acted as a stimulator of TH action in the liver, skeletal muscle and brown adipose tissue without affecting the Hypothalamo-Pituitary-Thyroid axis. Our data demonstrate distinct and tissue-specific effects of TBBPA and diclazuril on local TH action and prove that the THAI mouse is a novel mammalian model to identify TH disruptors and their tissue-specific effects.<\/jats:p>","DOI":"10.3390\/ijms232314782","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T01:58:46Z","timestamp":1669600726000},"page":"14782","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Tetrabromobisphenol A and Diclazuril Evoke Tissue-Specific Changes of Thyroid Hormone Signaling in Male Thyroid Hormone Action Indicator Mice"],"prefix":"10.3390","volume":"23","author":[{"given":"Rich\u00e1rd","family":"Sink\u00f3","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Cell Metabolism, Institute of Experimental Medicine, H-1083 Budapest, Hungary"},{"name":"J\u00e1nos Szent\u00e1gothai PhD School of Neurosciences, Semmelweis University, H-1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krist\u00f3f","family":"Rada","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cell Metabolism, Institute of Experimental Medicine, H-1083 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Koll\u00e1r","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious Diseases, University of Veterinary Medicine, H-1143 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Moh\u00e1csik","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cell Metabolism, Institute of Experimental Medicine, H-1083 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0399-8147","authenticated-orcid":false,"given":"Mikl\u00f3s","family":"Tenk","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious Diseases, University of Veterinary Medicine, H-1143 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Csaba","family":"Fekete","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, H-1083 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5727-8500","authenticated-orcid":false,"given":"Bal\u00e1zs","family":"Gereben","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cell Metabolism, Institute of Experimental Medicine, H-1083 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,26]]},"reference":[{"key":"ref_1","unstructured":"Wilson, J.D., Foster, D.W., Kronenberg, H.M., and Larsen, P.R. (1998). The Thyroid Gland. Williams Textbook of Endocrinology, W.B. Saunders Co.. [9th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1210\/er.2008-0019","article-title":"Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling","volume":"29","author":"Gereben","year":"2008","journal-title":"Endocr. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1210\/er.2011-0007","article-title":"Beyond low plasma T3: Local thyroid hormone metabolism during inflammation and infection","volume":"32","author":"Boelen","year":"2011","journal-title":"Endocr. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1210\/er.2013-1087","article-title":"Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions","volume":"35","author":"Fekete","year":"2014","journal-title":"Endocr. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/nrendo.2015.155","article-title":"Scope and limitations of iodothyronine deiodinases in hypothyroidism","volume":"11","author":"Gereben","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1210\/er.2018-00275","article-title":"Paradigms of Dynamic Control of Thyroid Hormone Signaling","volume":"40","author":"Bianco","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1055\/s-0030-1252034","article-title":"The impact of endocrine disruptors on endocrine targets","volume":"42","author":"Palioura","year":"2010","journal-title":"Horm. Metab. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"117475","DOI":"10.1016\/j.envpol.2021.117475","article-title":"Health toxicity effects of brominated flame retardants: From environmental to human exposure","volume":"285","author":"Feiteiro","year":"2021","journal-title":"Environ. Pollut."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Guarnotta, V., Amodei, R., Frasca, F., Aversa, A., and Giordano, C. (2022). Impact of Chemical Endocrine Disruptors and Hormone Modulators on the Endocrine System. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105710"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Dong, M., Li, Y., Zhu, M., Li, J., and Qin, Z. (2021). Tetrabromobisphenol A Disturbs Brain Development in Both Thyroid Hormone-Dependent and -Independent Manners in Xenopus laevis. Molecules, 27.","DOI":"10.3390\/molecules27010249"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.tox.2016.09.014","article-title":"Evaluation of tetrabromobisphenol A effects on human glucocorticoid and androgen receptors: A comparison of results from human- with yeast-based in vitro assays","volume":"370","author":"Beck","year":"2016","journal-title":"Toxicology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"R160","DOI":"10.1530\/EC-18-0029","article-title":"Thyroid-disrupting chemicals and brain development: An update","volume":"7","author":"Mughal","year":"2018","journal-title":"Endocr. Connect."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Li, J., Li, Y., Zhu, M., Song, S., and Qin, Z. (2022). A Multiwell-Based Assay for Screening Thyroid Hormone Signaling Disruptors Using thibz Expression as a Sensitive Endpoint in Xenopus laevis. Molecules, 27.","DOI":"10.3390\/molecules27030798"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6479","DOI":"10.1021\/acs.est.1c06729","article-title":"Preself-Feeding Medaka Fry Provides a Suitable Screening System for in Vivo Assessment of Thyroid Hormone-Disrupting Potential","volume":"56","author":"Myosho","year":"2022","journal-title":"Environ. Sci. Technol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1210\/en.2017-00582","article-title":"A Transgenic Mouse Model for Detection of Tissue-Specific Thyroid Hormone Action","volume":"159","author":"Mohacsik","year":"2018","journal-title":"Endocrinology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3394","DOI":"10.1038\/s41467-022-31154-1","article-title":"Triiodothyronine (T3) promotes brown fat hyperplasia via thyroid hormone receptor alpha mediated adipocyte progenitor cell proliferation","volume":"13","author":"Liu","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Sink\u00f3, R., Moh\u00e1csik, P., K\u0151v\u00e1ri, D., Penksza, V., Wittmann, G., M\u00e1csai, L., Fonseca, T.L., Bianco, A.C., Fekete, C., and Gereben, B. Different hypothalamic mechanisms control decreased circulating thyroid hormone levels in infection and fasting-induced Non-Thyroidal Illness Syndrome in male Thyroid Hormone Action Indicator Mice. Thyroid, 2022. in press.","DOI":"10.1089\/thy.2022.0404"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6257","DOI":"10.1021\/acs.est.5b06265","article-title":"Stimulation of Tetrabromobisphenol A Binding to Soil Humic Substances by Birnessite and the Chemical Structure of the Bound Residues","volume":"50","author":"Tong","year":"2016","journal-title":"Environ. Sci. Technol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"112594","DOI":"10.1016\/j.envres.2021.112594","article-title":"Review of the environmental occurrence, analytical techniques, degradation and toxicity of TBBPA and its derivatives","volume":"206","author":"Sunday","year":"2022","journal-title":"Environ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"131166","DOI":"10.1016\/j.chemosphere.2021.131166","article-title":"Degradation of TBBPA by nZVI activated persulfate in soil systems","volume":"284","author":"Yuan","year":"2021","journal-title":"Chemosphere"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.envint.2014.09.006","article-title":"Human health risk associated with brominated flame-retardants (BFRs)","volume":"74","author":"Lyche","year":"2015","journal-title":"Environ. Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1016\/j.lfs.2004.08.030","article-title":"Anti-thyroid hormonal activity of tetrabromobisphenol A, a flame retardant, and related compounds: Affinity to the mammalian thyroid hormone receptor, and effect on tadpole metamorphosis","volume":"76","author":"Kitamura","year":"2005","journal-title":"Life Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4203","DOI":"10.1021\/acs.est.5b06378","article-title":"Tetrabromobisphenol-A\/S and Nine Novel Analogs in Biological Samples from the Chinese Bohai Sea: Implications for Trophic Transfer","volume":"50","author":"Liu","year":"2016","journal-title":"Environ. Sci. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.scitotenv.2017.03.200","article-title":"Human exposure to HBCD and TBBPA via indoor dust in Korea: Estimation of external exposure and body burden","volume":"593\u2013594","author":"Barghi","year":"2017","journal-title":"Sci. Total Environ."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.chemosphere.2008.07.084","article-title":"Exposure assessment of French women and their newborns to tetrabromobisphenol-A: Occurrence measurements in maternal adipose tissue, serum, breast milk and cord serum","volume":"73","author":"Cariou","year":"2008","journal-title":"Chemosphere"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"146745","DOI":"10.1016\/j.scitotenv.2021.146745","article-title":"Effects of tetrabromobisphenol A (TBBPA) on the reproductive health of male rodents: A systematic review and meta-analysis","volume":"781","author":"Wu","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.mce.2010.04.010","article-title":"Disruption of thyroid hormone-dependent hypothalamic set-points by environmental contaminants","volume":"323","author":"Decherf","year":"2010","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"87170","DOI":"10.1007\/s11356-022-21817-3","article-title":"Associations of bisphenol exposure with thyroid hormones in pregnant women: A prospective birth cohort study in China","volume":"29","author":"Huang","year":"2022","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1289\/ehp.1002883","article-title":"The impact of bisphenol A and triclosan on immune parameters in the U.S. population, NHANES 2003-2006","volume":"119","author":"Clayton","year":"2011","journal-title":"Environ. Health Perspect."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/S0160-4120(03)00107-7","article-title":"Toxic effects of brominated flame retardants in man and in wildlife","volume":"29","author":"Darnerud","year":"2003","journal-title":"Environ. Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/BF00937111","article-title":"Parasitic apicomplexans harbor a chlorophyll a-D1 complex, the potential target for therapeutic triazines","volume":"81","author":"Hackstein","year":"1995","journal-title":"Parasitol. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/jvp.12450","article-title":"Review of triazine antiprotozoal drugs used in veterinary medicine","volume":"41","author":"Stock","year":"2018","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_33","unstructured":"European Medicines Agency, V.M.E.U. (1996). Committee for Veterinary Medicinal Products, Diclazuril. Summary Report (1)."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1080\/01652176.2011.605247","article-title":"Coccidiosis in poultry: Anticoccidial products, vaccines and other prevention strategies","volume":"31","author":"Peek","year":"2011","journal-title":"Vet. Q."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"921","DOI":"10.4236\/ijcm.2014.515124","article-title":"Novel Synergistic Protective Efficacy of Atovaquone and Diclazuril on Fetal-Maternal Toxoplasmosis","volume":"5","author":"Oz","year":"2014","journal-title":"Int. J. Clin. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"117201","DOI":"10.1016\/j.envpol.2021.117201","article-title":"Endocrine disrupting potential of veterinary drugs by in vitro stably transfected human androgen receptor transcriptional activation assays","volume":"286","author":"Park","year":"2021","journal-title":"Environ. Pollut."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"97009","DOI":"10.1289\/EHP5314","article-title":"Limited Chemical Structural Diversity Found to Modulate Thyroid Hormone Receptor in the Tox21 Chemical Library","volume":"127","author":"Martin","year":"2019","journal-title":"Environ. Health Perspect."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1210\/edrv.23.1.0455","article-title":"Biochemistry, cellular and molecular biology and physiological roles of the iodothyronine selenodeiodinases","volume":"23","author":"Bianco","year":"2002","journal-title":"Endo. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1159\/000504668","article-title":"Evidence for Prenatal Exposure to Thyroid Disruptors and Adverse Effects on Brain Development","volume":"8","author":"Demeneix","year":"2019","journal-title":"Eur. Thyroid J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nrendo.2017.123","article-title":"Endocrine disruptors: Flame retardants and increased risk of thyroid cancer","volume":"13","author":"Mughal","year":"2017","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"eabe8244","DOI":"10.1126\/science.abe8244","article-title":"From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures","volume":"375","author":"Caporale","year":"2022","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/bs.apha.2021.05.002","article-title":"Endocrine disrupting chemicals and thyroid hormone action","volume":"92","author":"Zoeller","year":"2021","journal-title":"Adv. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3389\/fncel.2016.00149","article-title":"Long-Term Estrogen Receptor Beta Agonist Treatment Modifies the Hippocampal Transcriptome in Middle-Aged Ovariectomized Rats","volume":"10","author":"Sarvari","year":"2016","journal-title":"Front. Cell Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"530","DOI":"10.2460\/ajvr.1994.55.04.530","article-title":"Activity of diclazuril against Toxoplasma gondii in cultured cells and mice","volume":"55","author":"Lindsay","year":"1994","journal-title":"Am. J. Vet. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.tox.2014.08.007","article-title":"Toxicogenomic analysis of the ability of brominated flame retardants TBBPA and BDE-209 to disrupt thyroid hormone signaling in neural cells","volume":"325","author":"Guyot","year":"2014","journal-title":"Toxicology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.tox.2014.12.013","article-title":"A reproductive, developmental and neurobehavioral study following oral exposure of tetrabromobisphenol A on Sprague-Dawley rats","volume":"329","author":"Cope","year":"2015","journal-title":"Toxicology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41574-019-0273-8","article-title":"Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification","volume":"16","author":"Vandenberg","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jchromb.2019.04.042","article-title":"Determination of residual enantiomers of diclazuril in chicken edible tissues by high performance liquid chromatography","volume":"1118\u20131119","author":"Zhang","year":"2019","journal-title":"J. Chromatogr. B Analyt. Technol. Biomed. Life Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s00726-021-02953-5","article-title":"In vivo emergence of beige-like fat in chickens as physiological adaptation to cold environments","volume":"53","author":"Sotome","year":"2021","journal-title":"Amino Acids"},{"key":"ref_50","first-page":"189","article-title":"Growth performance parameters in chicken experimental coccidiosis treated with Diclazuril and Clopidol: The need for assessing new anticoccidial resources","volume":"9","author":"Youssefi","year":"2015","journal-title":"Iran. J. Vet. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"14466","DOI":"10.1073\/pnas.0706754104","article-title":"Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes","volume":"104","author":"Dentice","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2356","DOI":"10.1210\/en.2016-1043","article-title":"Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Regulates the Hypothalamo-Pituitary-Thyroid (HPT) Axis via Type 2 Deiodinase in Male Mice","volume":"157","author":"Egri","year":"2016","journal-title":"Endocrinology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/23\/14782\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:27:14Z","timestamp":1760146034000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/23\/14782"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,26]]},"references-count":52,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232314782"],"URL":"https:\/\/doi.org\/10.3390\/ijms232314782","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,26]]}}}