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Identification and Profiling of Environmental Chemicals That Inhibit the TGF?/SMAD Signaling Pathway.

ABSTRACT: The transforming growth factor beta (TGF?) superfamily of secreted signaling molecules and their cognate receptors regulate cell fate and behaviors relevant to many developmental and disease processes. Disruption of TGF? 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 TGF? disruptors in the Tox21 10K compound library. From the primary screening we identified several kinase inhibitors, organometallic compounds, and dithiocarbamates (DTCs) that inhibited TGF?1-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 ? receptor (RAR), and sonic hedgehog (SHH). The profiling results from SBE-bla assay identify chemicals that disrupt TGF?/SMAD signaling as part of an integrated qHTS approach for prioritizing putative developmental toxicants.

SUBMITTER: Wei Z

PROVIDER: S-EPMC7341485 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Identification and Profiling of Environmental Chemicals That Inhibit the TGFβ/SMAD Signaling Pathway.

Wei Zhengxi Z Sakamuru Srilatha S Zhang Li L Zhao Jinghua J Huang Ruili R Kleinstreuer Nicole C NC Chen Yanling Y Shu Yan Y Knudsen Thomas B TB Xia Menghang M

Chemical research in toxicology 20191111 12

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 ...[more]

PMID: 31652400

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Project description:BackgroundAdult hippocampal neurogenesis (AHN) is restricted under the pathological conditions of neurodegenerative diseases, especially in Alzheimer's disease (AD). The drop of AHN reduces neural circuit plasticity, resulting in the decrease of the generation of newborn neurons in dentate gyrus (DG), which makes it difficult to recover from learning/memory dysfunction in AD, therefore, it is imperative to find a therapeutic strategy to promote neurogenesis and clarify its underlying mechanism involved.MethodsAmyloid precursor protein/presenilin 1 (APP/PS1) mice were treated with photobiomodulation therapy (PBMT) for 0.1 mW/mm2 per day in the dark for 1 month (10 min for each day). The neural stem cells (NSCs) were isolated from hippocampus of APP/PS1 transgenic mice at E14, and the cells were treated with PBMT for 0.667 mW/mm2 in the dark (5 min for each time).ResultsIn this study, photobiomodulation therapy (PBMT) is found to promote AHN in APP/PS1 mice. The latent transforming growth factor-β1 (LTGFβ1) was activated in vitro and in vivo during PBMT-induced AHN, which promoted the differentiation of hippocampal APP/PS1 NSCs into newborn neurons. In particular, behavioral experiments showed that PBMT enhanced the spatial learning/memory ability of APP/PS1 mice. Mechanistically, PBMT-stimulated reactive oxygen species (ROS) activates TGFβ/Smad signaling pathway to increase the interaction of the transcription factors Smad2/3 with Smad4 and competitively reduce the association of Smad1/5/9 with Smad4, thereby significantly upregulating the expression of doublecortin (Dcx)/neuronal class-III β-tubulin (Tuj1) and downregulating the expression of glial fibrillary acidic protein (GFAP). These in vitro effects were abrogated when eliminating ROS. Furthermore, specific inhibition of TGFβ receptor I (TGFβR I) attenuates the DNA-binding efficiency of Smad2/3 to the Dcx promotor triggered by PBMT.ConclusionOur study demonstrates that PBMT, as a viable therapeutic strategy, directs the adult hippocampal APP/PS1 NSCs differentiate towards neurons, which has great potential value for ameliorating the drop of AHN in Alzheimer's disease mice.

Dataset Information

Identification and Profiling of Environmental Chemicals That Inhibit the TGF?/SMAD Signaling Pathway.

Publications

Identification and Profiling of Environmental Chemicals That Inhibit the TGFβ/SMAD Signaling Pathway.

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