使用高通量转录组学和来自50名捐赠者的原始人类肝细胞绘制毒动力学个体间变异的映射
Marije Niemeijer1, Witold Więcek2, Shuai Fu2
1Division of Drug Discovery and Safety, LACDR, Leiden University, Leiden, The Netherlands.
Environmental health perspectives
|March 18, 2024
概括
了解人类的毒动力学变异性对于化学品安全至关重要. 这项研究揭示了细胞应激反应的显著个体间差异,为不同人群提供了更好的风险评估和安全因素.
科学领域:
- 毒理学和药理学的毒理学和药理学.
- 基因组学和转录基因组学
- 人口健康和风险评估.
背景情况:
- 毒力学反应的个体间变异性影响化学品风险评估.
- 细胞应激反应途径是化学诱导毒性的早期指标.
- 了解这种变化是建立全人口安全因素的关键.
研究的目的:
- 在一个大型的原发性人肝细胞 (PHHs) 面板上绘制细胞应激反应激活的变异性.
- 量化毒动力学个体间的变异性,用于推导安全不确定性因素.
- 评估PHH小组大小对变化估计的影响.
主要方法:
- 来自50名PHH捐赠者的8000多个样本的高通量转录组学.
- 暴露于四种毒理刺激物:尼卡米辛 (UPR),二甲基酸盐 (OSR),西斯 (DDR) 和TNFα (NF-κB).
- 种群混合效应建模以分析基准度 (BMC) 和基因表达变异性.
主要成果:
- 在UPR (864倍),OSR (13倍),DDR (13倍) 和NF-κB (259倍) 的BMC中存在显著的个体间变异.
- 小小的PHH小组规模导致低估了差异和不准确的人口变异性估计.
- 估计的毒动力学变化因子在1.6至6.3之间.
结论:
- 高通量转录组学和人口建模增强了对压力通路激活中的个人间变异性的理解.
- 这种方法提高了对不良反应,特别是肝毒性在体外基预测的信心.
- 这些发现有助于对不同的人群进行更准确的风险评估.
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