对HFPO-DA和原型PPARα,PPARγ和野外类型和PPARα淘汰赛小鼠肝细胞中的细胞毒剂之间的转录组形状的比较
Melissa M Heintz1, William D Klaren1, Alexander W East1
1ToxStrategies LLC, Asheville, North Carolina 28801, USA.
概括
在小鼠肝细胞中,HFPO-DA暴露反映了PPARα激活剂的作用,这表明在动物肝癌中存在共享机制. 使用PPARα淘汰模式证实了这一点,表明了常见的作用模式.
科学领域:
- 毒理学 毒理学 毒理学
- 分子生物学分子生物学
- 肝癌发生是肝癌的产生.
背景情况:
- HFPO-DA是一种短链PFAS,与小鼠的肝脏影响有关.
- 在体内数据表明,HFPO-DA的肝脏效应与PPARα激活剂MOA一致.
- 转录组数据显示,HFPO-DA反应模仿PPARα激动剂,而不是PPARγ激动剂或细胞毒素.
研究的目的:
- 为了确定HFPO-DA在小鼠肝脏中的转录效应是否依赖PPARα.
- 将HFPO-DA的分子信号与已知的PPARα和PPARγ激动剂进行比较.
- 研究PPARα在HFPO-DA的作用模式中的作用.
主要方法:
- 在实验室中对初级小鼠肝细胞 (WT和PPARα KO) 的转录组分析.
- 暴露于HFPO-DA,PPARα激动剂 (GW7647),PPARγ激动剂 (罗斯格利塔) 和细胞毒素 (乙氨基,d-银胺).
- 在12,24小时和72小时对转录基因反应的分析.
主要成果:
- 在WT肝细胞中,HFPO-DA和GW7647显示出高度一致的转录基因反应.
- 在PPARα KO肝细胞中观察到类似的一致性,但反应延迟.
- PPARα KO细胞的延迟是特定于HFPO-DA和GW7647,而不是其他测试剂.
结论:
- HFPO-DA和PPARα激活剂在动物肝癌发生过程中具有共同的作用模式.
- PPARα在调解HFPO-DA的转录基因效应方面发挥着关键作用.
- 在没有PPARα的情况下,补偿机制可能会影响时间反应.
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