通过 perfluorohexane sulfonate 对小鼠和人类过氧体增殖器激活受体-α 的不同肝脏激活
Yahya Khan1,2, Annalee M Schmidt1,2, Kyle J Oldro1,2
1Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, PA 16802, United States.
概括
暴露于 perfluorohexane sulfonate (PFHxS) 会通过激活小鼠PPARα而增加肝脏体重,但不会激活人类PPARα. 构成性安德罗斯坦受体 (CAR) 和孕妇X受体 (PXR) 的激活也会导致PFHxS诱导的肝病巨变.
科学领域:
- 环境毒理学环境毒理学
- 肝病学 肝病学是一种肝病学.
- 核受体信号传递的信号
背景情况:
- perfluorohexane sulfonate (PFHxS) 的暴露与肝脏扩大和脂质积累有关.
- 核受体,包括PPARα,CAR和PXR,是这些效应的潜在媒介.
- 了解物种特异性反应对于风险评估至关重要.
研究的目的:
- 研究PFHxS是否通过激活PPARα,CAR或PXR来诱导肝脏变化.
- 为了确定PFHxS是否在PPARα受体表现出特定物种的活性.
- 为了阐明PFHxS诱导的肝壮病背后的机制.
主要方法:
- 野生型,Ppara-null和PPARA-人性化的小鼠通过饮食暴露于PFHxS7或28天.
- 分析了肝脏重量,血清和肝脏PFHxS度以及向基因表达.
- 对PPARα,CAR和PXR点的基因表达在全基因型中进行了检查.
主要成果:
- 在28天的高剂量后,PFHxS暴露增加了所有基因型的相对肝脏重量.
- 在野生型小鼠中,PFHxS激活的小鼠PPARα向基因,但在Ppara-null或PPARA-人性化小鼠中并非如此.
- 在所有基因型中,PFHxS上调了CAR和PXR目标基因 (Cyp2b10和Cyp3a11).
结论:
- 暴露于PFHxS会导致肝扩大,部分是通过小鼠PPARα的激活,没有观察到人类PPARα的激活.
- 通过PFHxS激活CAR和PXR也导致观察到的肝脏体重增加.
- 这些发现突出了PFHxS对特定物种的核受体激活及其在肝毒性中的作用.
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