Identification and profiling of environmental chemicals that inhibit the TGFβ/SMAD signaling pathway

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 specifically 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. Counter-screen of SBE antagonists on human embryonic neura...