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Concerns that environmental chemicals interfere with TH signalling have increased the need for human-relevant in vitro systems to identify thyroid hormone system-disrupting chemicals (THSDCs) for risk assessment. Here, we compared two human-induced pluripotent stem cell (hiPSC)-derived brain organoid models for THSDC assessment: (i) human cortical organoids (COs) generated by unguided differentiation, offering higher architectural complexity but lower throughput; and (ii) neural stem cell-derived organoids (NSCOs), designed for scalability with reduced cellular diversity. Both models expressed key TH handling components, including the transporter SLC16A2 (MCT8) and the inactivating enzyme DIO3. Using LC\u2013MS\/MS, we show that exogenous T3 is depleted from culture media and metabolized to 3,3\u2032-T2 and 3\u2032-T1 in both models, alongside upregulation of T3-responsive genes (HR, KLF9, DIO3, SEMA3C). Pulse and chronic co-exposures to reference disruptors iopanoic acid (IA, deiodinase inhibitor) and silychristin (SC, MCT8 inhibitor) altered T3 metabolism and modulated T3-responsive transcriptional endpoints. In NSCOs, high-content imaging revealed treatment-associated changes in cell composition, with chronic T3 reducing the SOX2-positive progenitor pool and THSDCs blocking this effect. Together, these findings provide a framework for organoid qualification\u2014linking TH handling, transcriptomic responsiveness, and scalable phenotypic readouts\u2014as a necessary step toward model validation and implementation of brain organoids in THSDC risk assessment pipelines.<\/jats:p>","DOI":"10.3390\/cells15110963","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T15:05:08Z","timestamp":1779721508000},"page":"963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative Evaluation of hiPSC-Derived Brain Organoids as Platforms for Assessing Thyroid Hormone System Disrupting Chemicals"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3875-9170","authenticated-orcid":false,"given":"Valeria","family":"Fernandez Vallone","sequence":"first","affiliation":[{"name":"Core Unit Pluripotent Stem Cells and Organoids, Berlin Institute of Health, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4430-8384","authenticated-orcid":false,"given":"Lina","family":"Hellwig","sequence":"additional","affiliation":[{"name":"Center for Stroke Research Berlin, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"},{"name":"Department of Neurology with Experimental Neurology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8870-8545","authenticated-orcid":false,"given":"Eddy","family":"Rijntjes","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Experimentelle Endokrinologie, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8116-9032","authenticated-orcid":false,"given":"Nicolai","family":"von K\u00fcgelgen","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Experimentelle Endokrinologie, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"},{"name":"Core Unit Bioinformatics, Berlin Institute of Health, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajas","family":"Sane","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Experimentelle Endokrinologie, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3143-0997","authenticated-orcid":false,"given":"Robert","family":"Opitz","sequence":"additional","affiliation":[{"name":"Department for Paediatric Endocrinology and Diabetology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"K\u00fchnen","sequence":"additional","affiliation":[{"name":"Department for Paediatric Endocrinology and Diabetology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"},{"name":"German Center for Child and Adolescent Health (DZKJ), Partner Site Berlin, Augustenburger Platz 1, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9187-9078","authenticated-orcid":false,"given":"Josef","family":"K\u00f6hrle","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Experimentelle Endokrinologie, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9753-6711","authenticated-orcid":false,"given":"Philipp","family":"Mergenthaler","sequence":"additional","affiliation":[{"name":"Center for Stroke Research Berlin, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"},{"name":"Department of Neurology with Experimental Neurology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"},{"name":"Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9283-4605","authenticated-orcid":false,"given":"Harald","family":"Stachelscheid","sequence":"additional","affiliation":[{"name":"Core Unit Pluripotent Stem Cells and Organoids, Berlin Institute of Health, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"bqaa106","DOI":"10.1210\/endocr\/bqaa106","article-title":"Regulation of Thyroid-disrupting Chemicals to Protect the Developing Brain","volume":"161","author":"Gilbert","year":"2020","journal-title":"Endocrinology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/ncpendmet0424","article-title":"Thyroid hormone receptors in brain development and 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