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结合分析方法用于识别Tox21 10K化合物库中的潜在皮肤致敏剂。

Use of methods combined with analysis to identify potential skin sensitizers in the Tox21 10K compound library.

作者信息

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

机构信息

National Institutes of Health, National Center for Advancing Translational Sciences, Bethesda, MD, United States.

Inotiv, Inc., Research Triangle Park, NC, United States.

出版信息

Front Toxicol. 2024 Feb 28;6:1321857. doi: 10.3389/ftox.2024.1321857. eCollection 2024.

DOI:10.3389/ftox.2024.1321857
PMID:38482198
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10933113/
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.

摘要

皮肤致敏会导致过敏性接触性皮炎，是一个关键的毒理学终点，在职业和消费领域中普遍存在。本研究优化了经合组织皮肤致敏试验指南中列出的几种试验，以用于定量高通量筛选（qHTS）平台，并进行模型预测，以评估来自Tox21 10K化合物库的优先化合物的皮肤致敏潜力。首先，我们使用qHTS角蛋白敏感细胞（KS）试验筛选了整个Tox21 10K化合物库，并基于KS结果建立了定量构效关系（QSAR）模型。根据qHTS KS筛选结果，我们优先选择了288种化合物，以涵盖广泛的结构化学类型，并在固相萃取-串联质谱（SPE-MS/MS）直接肽反应性试验（DPRA）、白细胞介素-8均相时间分辨荧光（HTRF）试验、THP1细胞中CD86和CD54表面表达试验中对它们进行测试，并使用经合组织QSAR工具箱（v4.5）预测致敏潜力。使用定义的方法解释分层qHTS数据集显示了这些方法的有效性和效率。我们选择结构化学类型来展示这个多样化的化学集合，并探索以前未确定的对致敏潜力的结构贡献。在这里，我们提供了一个前所未有的规模的皮肤致敏数据集，以及相关工具和旨在支持化学评估的分析。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20e7/10933113/f2fb42059356/ftox-06-1321857-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20e7/10933113/f2fb42059356/ftox-06-1321857-g008.jpg
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