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High-Throughput Screening Platform for Nanoparticle-Mediated Alterations of DNA Repair Capacity
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    High-Throughput Screening Platform for Nanoparticle-Mediated Alterations of DNA Repair Capacity
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    • Sneh M. Toprani
      Sneh M. Toprani
      John B. Little Center of Radiation Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, United States
    • Dimitrios Bitounis
      Dimitrios Bitounis
      Center for Nanotechnology and Nanotoxicology, Department of Environmental Health, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, Massachusetts 02115, United States
    • Qiansheng Huang
      Qiansheng Huang
      Center for Nanotechnology and Nanotoxicology, Department of Environmental Health, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, Massachusetts 02115, United States
      Center for Excellence in Regional Atmospheric Environment, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
    • Nathalia Oliveira
      Nathalia Oliveira
      Center for Nanotechnology and Nanotoxicology, Department of Environmental Health, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, Massachusetts 02115, United States
    • Kee Woei Ng
      Kee Woei Ng
      Center for Nanotechnology and Nanotoxicology, Department of Environmental Health, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, Massachusetts 02115, United States
      School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore
      Environmental Chemistry and Materials Centre, Nanyang Environment and Water Research Institution, 1 Cleantech Loop, CleanTech One, Singapore 637141, Singapore
      More by Kee Woei Ng
    • Chor Yong Tay
      Chor Yong Tay
      School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore
      School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
    • Zachary D. Nagel*
      Zachary D. Nagel
      John B. Little Center of Radiation Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, United States
      *Email: [email protected]
    • Philip Demokritou*
      Philip Demokritou
      Center for Nanotechnology and Nanotoxicology, Department of Environmental Health, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, Massachusetts 02115, United States
      *Email: [email protected]. Tel: +1 617-432-3481.
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    ACS Nano

    Cite this: ACS Nano 2021, 15, 3, 4728–4746
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    https://doi.org/10.1021/acsnano.0c09254
    Published March 12, 2021
    Copyright © 2021 American Chemical Society

    Abstract

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    The potential genotoxic effects of engineered nanomaterials (ENMs) may occur through the induction of DNA damage or the disruption of DNA repair processes. Inefficient DNA repair may lead to the accumulation of DNA lesions and has been linked to various diseases, including cancer. Most studies so far have focused on understanding the nanogenotoxicity of ENM-induced damages to DNA, whereas the effects on DNA repair have been widely overlooked. The recently developed fluorescence multiplex–host-cell reactivation (FM-HCR) assay allows for the direct quantification of multiple DNA repair pathways in living cells and offers a great opportunity to address this methodological gap. Herein an FM-HCR-based method is developed to screen the impact of ENMs on six major DNA repair pathways using suspended or adherent cells. The sensitivity and efficiency of this DNA repair screening method were demonstrated in case studies using primary human small airway epithelial cells and TK6 cells exposed to various model ENMs (CuO, ZnO, and Ga2O3) at subcytotoxic doses. It was shown that ENMs may inhibit nucleotide-excision repair, base-excision repair, and the repair of oxidative damage by DNA glycosylases in TK6 cells, even in the absence of significant genomic DNA damage. It is of note that the DNA repair capacity was increased by some ENMs, whereas it was suppressed by others. Overall, this method can be part of a multitier, in vitro hazard assessment of ENMs as a functional, high-throughput platform that provides insights into the interplay of the properties of ENMs, the DNA repair efficiency, and the genomic stability.

    Copyright © 2021 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.0c09254.

    • Figure S1: Transmission electron micrographs of CuO, Ga2O3, and ZnO ENMs used in this study. Figure S2: Colloidal characterization and dosimetric analysis of CuO, Ga2O3, and ZnO ENMs in DI H2O and SAGM. Figure S3. Cytotoxicity data of SAEC cells exposed to Ga2O3, CuO, or ZnO ENMs. Figure S4. Cytotoxicity data of TK6 cells exposed to Ga2O3, CuO, or ZnO ENMs. Figure S5. Optimization of transfection and flow parameters of SAECs for the FM-HCR assay. Figure S6. Quality check for TK6 cells treated with ENMs for the FM-HCR assay. Figure S7. Assessing the difference in reporter expression upon shifting of gate. Figure S8. Representative pictures of flow cytometry analysis with final gating for reporter expression for each color (PDF)

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    ACS Nano

    Cite this: ACS Nano 2021, 15, 3, 4728–4746
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsnano.0c09254
    Published March 12, 2021
    Copyright © 2021 American Chemical Society

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