Use of Methods Combined with Analysis to Identify Potential Skin Sensitizers in the Tox21 10K Compound Library

Overview

Journal Front Toxicol

Date 2024 Mar 14

PMID 38482198

Authors

Zhengxi Wei

Tuan Xu

Judy Strickland

Li Zhang

Yuhong Fang

Dingyin Tao

Anton Simeonov

Ruili Huang

Nicole C Kleinstreuer

Menghang Xia

Affiliations

Soon will be listed here.

Abstract

Skin sensitization, which leads to allergic contact dermatitis, is a key toxicological endpoint with high occupational and consumer prevalence. This study optimized several assays listed in OECD skin sensitization test guidelines for use on a quantitative high-throughput screening (qHTS) platform and performed model predictions to assess the skin sensitization potential of prioritized compounds from the Tox21 10K compound library. First, we screened the entire Tox21 10K compound library using a qHTS KeratinoSens (KS) assay and built a quantitative structure-activity relationship (QSAR) model based on the KS results. From the qHTS KS screening results, we prioritized 288 compounds to cover a wide range of structural chemotypes and tested them in the solid phase extraction-tandem mass spectrometry (SPE-MS/MS) direct peptide reactivity assay (DPRA), IL-8 homogeneous time-resolved fluorescence (HTRF) assay, CD86 and CD54 surface expression in THP1 cells, and predicted sensitization potential using the OECD QSAR Toolbox (v4.5). Interpreting tiered qHTS datasets using a defined approach showed the effectiveness and efficiency of methods. We selected 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, along with associated tools, and analysis designed to support chemical assessments.

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