{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T03:10:57Z","timestamp":1794107457878,"version":"4.8.0"},"reference-count":45,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,1,15]],"date-time":"2022-01-15T00:00:00Z","timestamp":1642204800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Tetrabromobisphenol A (TBBPA), a derivative of BPA, is a ubiquitous environmental contaminant with weak estrogenic properties. In women, uterine fibroids are highly prevalent estrogen\u2010responsive tumors often with excessive accumulation of extracellular matrix (ECM) and may be the target of environmental estrogens. We have found that BPA has profibrotic effects in vitro, in addition to previous reports of the in vivo fibrotic effects of BPA in mouse uterus. However, the role of TBBPA in fibrosis is unclear. To investigate the effects of TBBPA on uterine fibrosis, we developed a 3D human uterine leiomyoma (ht\u2010UtLM) spheroid culture model. Cell proliferation was evaluated in 3D ht\u2010UtLM spheroids following TBBPA (10\n                    <jats:sup>\u22126<\/jats:sup>\n                    \u2013200\u00a0\u00b5M) administration at 48\u00a0h. Fibrosis was assessed using a Masson's Trichrome stain and light microscopy at 7\u00a0days of TBBPA (10\n                    <jats:sup>\u22123<\/jats:sup>\n                    \u00a0\u00b5M) treatment. Differential expression of ECM and fibrosis genes were determined using RT\u00b2 Profiler\u2122 PCR arrays. Network and pathway analyses were conducted using Ingenuity Pathway Analysis. The activation of pathway proteins was analyzed by a transforming growth factor\u2010beta (TGFB) protein array. We found that TBBPA increased cell proliferation and promoted fibrosis in 3D ht\u2010UtLM spheroids with increased deposition of collagens. TBBPA upregulated the expression of profibrotic genes and corresponding proteins associated with the TGFB pathway. TBBPA activated TGFB signaling through phosphorylation of TGFBR1 and downstream effectors\u2014small mothers against decapentaplegic \u20102 and \u20103 proteins (SMAD2 and SMAD3). The 3D ht\u2010UtLM spheroid model is an effective system for studying environmental agents on human uterine fibrosis. TBBPA can promote fibrosis in uterine fibroid through TGFB\/SMAD signaling.\n                  <\/jats:p>","DOI":"10.1096\/fj.202101262r","type":"journal-article","created":{"date-parts":[[2022,1,15]],"date-time":"2022-01-15T11:55:12Z","timestamp":1642247712000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Short\u2010term tetrabromobisphenol A exposure promotes fibrosis of human uterine fibroid cells in a 3D culture system through TGF\u2010beta signaling"],"prefix":"10.1096","volume":"36","author":[{"given":"Jingli","family":"Liu","sequence":"first","affiliation":[{"name":"Mechanistic Toxicology Branch (MTB) Division of the National Toxicology Program (DNTP) National Institute of Environmental Health Sciences (NIEHS), NIH  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Yu","sequence":"additional","affiliation":[{"name":"Mechanistic 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P.","family":"Clayton","sequence":"additional","affiliation":[{"name":"Cellular &amp; Molecular Pathogenesis Branch DNTP NIEHS, NIH  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Bushel","sequence":"additional","affiliation":[{"name":"Biostatistics &amp; Computational Biology Branch, Division of Intramural Research (DIR) NIEHS, NIH  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norris D.","family":"Flagler","sequence":"additional","affiliation":[{"name":"Cellular &amp; Molecular Pathogenesis Branch DNTP NIEHS, NIH  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Scappini","sequence":"additional","affiliation":[{"name":"Signal Transduction Laboratory, DIR NIEHS, NIH  Research Triangle Park North Carolina 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