对代谢物介导的神经毒性的测试策略
Julian Suess1, Moritz Reinmoeller1, Viktoria Magel1
1In Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany.
International journal of molecular sciences
|September 13, 2025
概括
为了改进下一代风险评估 (NGRA),本研究将新陈代谢纳入发展神经毒性测试的新方法方法 (NAMs). 这一策略解决了缺乏代谢活动的试验的假阴性,提高了对人类的危险预测.
科学领域:
- 毒理学 毒理学 毒理学
- 发育神经毒性 发育神经毒性
- 在体外检测中进行检测.
背景情况:
- 在风险评估中,代谢依赖的毒性挑战了当前的非动物新方法 (NAMs).
- 现有的NAM通常缺乏代谢活性,可能导致对人类健康危害的错误负面预测.
- 评估代谢物中介毒性对于准确的发育神经毒性 (DNT) 评估至关重要.
研究的目的:
- 开发和评估将代谢活动整合到DNT NAM中的策略.
- 确定适合的与代谢物相关的神经毒性的阳性对照.
- 提高NAM的预测能力,以准确评估化学风险.
主要方法:
- 利用肝脏的线粒体后分数 (S9) 来产生代谢物混合物.
- 应用于NAM的代谢物混合物,包括MitoMet (UKN4b) 和cMINC (UKN2) 的测定.
- 与母化合物相比,评估了代谢产物对神经元健康的毒性.
主要成果:
- 证明一些代谢物比它们的原始化合物具有更高的神经毒性.
- 成功地将使用S9分数的"代谢模块"集成到DNT NAM中.
- 展示了综合方法在不同NAM中的适用性和可转移性.
结论:
- 开发的战略有效地解决了DNT NAM中代谢物介导的毒性.
- 将代谢能力整合到NAM中对于强大的下一代风险评估 (NGRA) 至关重要.
- 为了在监管科学中更广泛地实施这种方法,需要进一步讨论.
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