Abstract：
:The transforming growth factor beta (TGFβ) superfamily of secreted signaling molecules and their cognate receptors regulate cell fate and behaviors relevant to many developmental and disease processes. Disruption of TGFβ signaling during embryonic development can, for example, affect morphogenesis and differentiation through complex pathways that may be SMAD (Small Mothers Against Decapentaplegic) dependent or SMAD independent. In the present study, the SMAD Binding Element (SBE)-beta lactamase (bla) HEK 293T cell line, which responds to the activation of the SMAD2/3/4 complex, was used in a quantitative high-throughput screening (qHTS) assay to identify potential TGFβ disruptors in the Tox21 10K compound library. From the primary screening we identified several kinase inhibitors, organometallic compounds, and dithiocarbamates (DTCs) that inhibited TGFβ1-induced SMAD signaling of reporter gene activation independent of cytotoxicity. Counterscreen of SBE antagonists on human embryonic neural stem cells demonstrated cytotoxicity, providing additional evidence to support evaluation of these compounds for developmental toxicity. We profiled the inhibitory patterns of putative SBE antagonists toward other developmental signaling pathways, including wingless-related integration site (WNT), retinoic acid α receptor (RAR), and sonic hedgehog (SHH). The profiling results from SBE-bla assay identify chemicals that disrupt TGFβ/SMAD signaling as part of an integrated qHTS approach for prioritizing putative developmental toxicants.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Wei Z,Sakamuru S,Zhang L,Zhao J,Huang R,Kleinstreuer NC,Chen Y,Shu Y,Knudsen TB,Xia Mdoi
10.1021/acs.chemrestox.9b00228subject
Has Abstractpub_date
2019-12-16 00:00:00pages
2433-2444issue
12eissn
0893-228Xissn
1520-5010journal_volume
32pub_type
杂志文章abstract：:The urine from mice exposed to styrene vapors (600 and 1200 mg/m(3), 6 h) was analyzed for ring-oxidized metabolites of styrene. To facilitate the identification of metabolites in urine, the following potential metabolites were prepared: 2-, 3-, and 4-vinylphenol (2-, 3-, and 4-VP), 4-vinylpyrocatechol, and 2-, 3-, an...
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pub_type： 杂志文章
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journal_title：Chemical research in toxicology
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pub_type： 杂志文章
doi：10.1021/acs.chemrestox.0c00104
更新日期：2020-08-17 00:00:00
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更新日期：1998-10-01 00:00:00
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journal_title：Chemical research in toxicology
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journal_title：Chemical research in toxicology
pub_type： 杂志文章
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