{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:55:57Z","timestamp":1771808157094,"version":"3.50.1"},"reference-count":85,"publisher":"Oxford University Press (OUP)","issue":"2","funder":[{"DOI":"10.13039\/100000139","name":"US Environmental Protection Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000139","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The US Environmental Protection Agency has evaluated thousands of environmental chemicals within the ToxCast and Toxicology in the 21st Century (Tox21) programs using high-throughput screening (HTS) assays for molecular targets across the hypothalamic\u2013pituitary\u2013thyroid axis. The thyroid stimulating hormone receptor (TSHR) is a critical regulator of thyroid development and function and essential for thyroid hormone synthesis. Hundreds of chemicals have been identified as potential modulators of the TSHR in a Tox21 HTS assay, but the mechanistic and biological relevance to humans is uncertain. The objectives of this study were to select a subset of active chemicals from the Tox21 TSHR assay, screen for agonist or antagonist activity in human primary thyrocyte assays to evaluate mechanistic effects on the native TSHR, and then extend screening to assess functional effects on thyroid hormone synthesis in human thyroid microtissues. A total of 72 (agonist mode) and 64 (antagonist mode) chemicals were selected for screening. A conventional two-dimensional screening assay was implemented as a primary screening strategy to evaluate thyroglobulin protein production as a biomarker for TSHR-dependent bioactivity in primary thyrocytes. Active chemicals were triaged for secondary screening in three-dimensional thyroid microtissue assays to evaluate the functional relevance to thyroid hormone synthesis. Final results revealed 2 agonist and 13 antagonist chemicals that demonstrated concordant activity across the 2 assay formats. The results support a strategic tiered testing paradigm whereby chemicals flagged for hazard potential from targeted HTS assays are evaluated in assays with enhanced biological relevance to the target tissue of interest to inform hazard characterization for putative thyroid-disrupting chemicals in humans.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf102","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T17:07:30Z","timestamp":1753117650000},"page":"415-434","source":"Crossref","is-referenced-by-count":1,"title":["Orthogonal screening for thyroid stimulating hormone receptor modulators in human thyroid assays"],"prefix":"10.1093","volume":"207","author":[{"given":"Briana","family":"Foley","sequence":"first","affiliation":[{"name":"Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency , Research Triangle Park, NC 27711,","place":["United 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