Comparative Evaluation of hiPSC-Derived Brain Organoids as Platforms for Assessing Thyroid Hormone System Disrupting Chemicals.

Overview

1. Core Unit Pluripotent Stem Cells and Organoids, Berlin Institute of Health, Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
2. Center for Stroke Research Berlin, Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; (L.H.)
3. Department of Neurology with Experimental Neurology, Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
4. Institut für Experimentelle Endokrinologie, Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; (E.R.); (N.v.K.); (R.S.); (J.K.)
5. Core Unit Bioinformatics, Berlin Institute of Health, Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
6. Department for Paediatric Endocrinology and Diabetology, Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; (R.O.); (P.K.)
7. German Center for Child and Adolescent Health (DZKJ), Partner Site Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
8. Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK

Abstract

Highlights: What are the main findings?

T3-responsive gene expression, T3 metabolism, and SOX2-positive progenitor populations are informative endpoints for detecting THSDC effects in hiPSC-derived brain organoids, as shown by altered T3-dependent responses to silychristin and iopanoic acid, particularly under chronic exposure.

Differentiation-stage quality control improves the interpretability, reproducibility, and assay readiness of distinct hiPSC-derived brain organoid platforms.

What are the implications of the main findings?

hiPSC-derived brain organoids have potential as human-relevant NAMs to study thyroid hormone system disruption during early brain development.

Standardized workflows with defined QC checkpoints are essential for advancing brain organoid models toward reproducible toxicology testing and future regulatory applications.

Abstract: Thyroid hormones (THs) are essential regulators of human brain development, and disrupted TH availability during pregnancy or early life is linked to adverse neurodevelopmental outcomes. 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–MS/MS, we show that exogenous T3 is depleted from culture media and metabolized to 3,3′-T2 and 3′-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—linking TH handling, transcriptomic responsiveness, and scalable phenotypic readouts—as a necessary step toward model validation and implementation of brain organoids in THSDC risk assessment pipelines.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• zenodo:13927681, at Zenodo; found in the references

2.18. Data Availability

RNA-sequencing data discussed in this publication is deposited in BioStudies, ArrayExpress from EMBL-EBI. Accession number: ArrayExpress accession E-MTAB-17066.

Reproduced under the paper's license (CC BY), from the paper cited above.

Data Availability Statement

RNA-sequencing data discussed in this publication will be deposited in BioStudies, ArrayExpress from EMBL-EBI upon final acceptance of the manuscript.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 5 keywords, 9 MeSH terms, 6 funders, 58 references.

Cite

This paper

Fernandez Vallone, V., Hellwig, L., Rijntjes, E., von Kügelgen, N., Sane, R., Opitz, R., Kühnen, P., Köhrle, J., Mergenthaler, P., & Stachelscheid, H. (2026). Comparative Evaluation of hiPSC-Derived Brain Organoids as Platforms for Assessing Thyroid Hormone System Disrupting Chemicals. Cells, 15(11), 963. https://doi.org/10.3390/cells15110963

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