AUTHOR=Wei Zhengxi , Xu Tuan , Strickland Judy , Zhang Li , Fang Yuhong , Tao Dingyin , Simeonov Anton , Huang Ruili , Kleinstreuer Nicole C. , Xia Menghang 

TITLE=Use of in vitro methods combined with in silico analysis to identify potential skin sensitizers in the Tox21 10K compound library

JOURNAL=Frontiers in Toxicology

VOLUME=Volume 6 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2024.1321857

DOI=10.3389/ftox.2024.1321857

ISSN=2673-3080

ABSTRACT=Skin sensitization, leading to allergic contact dermatitis, is a key toxicological endpoint with high occupational and consumer prevalence. This study optimized several in vitro assays listed in OECD skin sensitization test guidelines to quantitative high throughput screening (qHTS) and performed in silico model predictions to assess skin sensitization potential of prioritized compounds from the Tox21 10K compound library. Firstly, we screened the entire Tox21 10K compound library using a qHTS KeratinoSens TM assay (KS), and built a quantitative structure activity relationship (QSAR) model based on the KS results. From the qHTS KS screen results, we prioritized 288 compounds to cover a wide range of structural chemotypes, and tested them in the solid phase extractiontandem mass spectrometry (SPE-MS/MS) direct peptide reactivity assay (DPRA), IL-8 homogeneous time resolved fluorescence (HTRF) assay, CD 86 and CD 54 surface expression in THP1 cells, and predicted in silico sensitization potential using the OECD QSAR Toolbox (v4.5). Interpreting tiered qHTS datasets using a defined approach showed the effectiveness and efficiency of in vitro methods. We select structural chemotypes to present this diverse chemical collection and to explore previously unidentified structural contributions to sensitization potential. Here we provide a skin sensitization dataset of unprecedented size, associated tools and analysis designed to support chemical assessments.