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在体外到体内外推算建模,以促进转录组学数据纳入基因毒性评估中的整合

Anouck Thienpont¹, Eunnara Cho², Andrew Williams²

¹Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium; Department of Chemical and Physical Health Risks, Sciensano, Brussels 1050, Belgium.

|April 27, 2025

概括

使用GENOMARK和TGx-DDI生物标志物的标准化体外转录组为体内基因毒性提供了保护性估计. 这项研究开发了转录学起点 (tPoDs) 和体外到体外抽取的方法,从而推进了监管科学.

科学领域:

毒理学和药理学毒理学和药理学
基因组学和生物信息学
监管科学监管科学

背景情况:

实验室转录组学为基因毒性评估提供高通量,与人类相关的数据.
缺乏用于监管整合的标准化方法,特别是用于导出转录组出发点 (tPoDs) 和体外到体内外推算 (IVIVE).
像GENOMARK和TGx-DDI这样的转录组生物标志物有助于分析复杂的转录组数据.

研究的目的:

调查从体外转录组数据计算tPoDs的不同方法.
应用IVIVE来估计基因毒剂的给予等效剂量 (AED).
将转录基因衍生的AED与体内起点 (PoD) 和其他新方法方法 (NAM) 进行比较.

主要方法:

人类HepaRG细胞暴露于已知的10种体内基因毒性物质.
用TempO-Seq®人类S1500+基因面板生成基因表达数据.
基准度 (BMC) 建模用于推导tPoDs (tPoD_{生物标志物}和tPoD_S1500+).
高通量毒动力学模型估计了人类的AED,以与体内数据进行比较.

主要成果:

GENOMARK和TGx-DDI生物标志物正确识别了所有参考基因毒素.
发现通用AED比基因毒性特定生物标志物AED更为保守.
对于九种基因毒剂中的六种,转录组AED低于体内PoD,这表明保护性估计.

结论:

来自HepaRG细胞的体外转录学数据提供了对体内基因毒性度的保护性估计.
为tPoD衍生和IVIVE开发的方法支持转录学的监管应用.
进一步完善运动模型可能会提高 in vitro-to-in vivo 预测的准确性.

关键词:

基准剂量建模的基准剂量.基因毒性基因毒性在体外到体内抽象的抽象.新方法方法论新方法方法论这就是TempO-Seq®.文字转录学 (Transcriptomics) 是一个学科.

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