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在基于转录组学的体外试验中对帕拉的风险评估

Florian Seidel¹, Franziska Kappenberg², Susann Fayyaz³

¹Leibniz Research Centre for Working Environment and Human Factors at the Technical University of Dortmund (IfADo), Ardeystrasse 67, 44139, Dortmund, Germany.

Chemico-biological interactions

|September 10, 2023

概括

这项研究发现,乙基帕拉本和其他帕拉本仅在远远超过人类暴露水平的度下表现出毒性和基因表达变化. 这些发现表明,不需要进行额外的动物研究来评估乙基甲.

科学领域:

毒理学毒理学毒理学
化品科学化品科学
发展生物学发展生物学

背景情况:

烯是化品,药品和食品中广泛使用的防腐剂.
大多数类在2009年和2014年被禁止,只剩下甲基,乙基,基和丁基类.
乙烯缺乏发育和生殖毒性 (DART) 测试,引发了关于进一步动物研究的辩论.

研究的目的:

为了比较四种已批准的帕拉的体外毒性:甲基,乙基,基和丁基帕拉.
评估乙基甲是否需要进行额外的体内DART研究.

主要方法:

使用基于人体诱导多能干细胞 (iPSC) 的体外试验.
在神经外皮分化过程中暴露iPSCs对帕拉本.
确定了细胞毒性EC50值,并分析了全基因组基因表达变化.

主要成果:

细胞毒性随着基链长度的增加而增加:EC50值在906μM (甲基-) 到63μM (丁基-) 之间.
显著的基因表达变化 (差异表达基因 - - DEG) 仅在细胞毒性度或附近发生.
乙烯没有显示出细胞毒性或DEG,其度是报告的人类生物监测水平的1670倍.

结论:

乙基的毒性和基因表达改变发生在明显高于人类暴露的度.
毒性与基链长度相关,基因表达变化与细胞毒性水平有关.
实验室数据不表明,在体内DART研究以乙烯会产生与甲基或甲相比不同的结果.

关键词:

其他测试策略的替代测试策略.发展性和生殖性毒性毒性基因表达基因表达基因表达在体外试验试验诱导的多能干细胞干细胞帕拉本类药物可以毒素基因组学毒素基因组学文字转录学 (Transcriptomics) 是一个学科.

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