Microgram-order ammonium perfluorooctanoate may activate mouse peroxisome proliferator-activated receptor α, but not human PPARα
Microgram-order ammonium perfluorooctanoate may activate mouse peroxisome proliferator-activated receptor α, but not human PPARα
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DOI：
10.1016/j.tox.2009.09.004
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发表时间：
2009-11-09
期刊：
影响因子：
4.5
通讯作者：
Nakajima, Tamie
中科院分区：
文献类型：
--
作者：
Nakamura, Toshiki;Ito, Yuki;Nakajima, Tamie
全氟辛酸（PFOA）是过氧化物酶体增殖物激活受体（PPAR）α的配体，其在表达和功能方面表现出明显的物种差异，特别是在啮齿动物和人类之间。我们研究了小鼠和人类之间PFOA反应的功能差异，使用人源化的PPARalpha转基因小鼠系。三只基因分型小鼠，129/5v野生型（mPPARa）、Ppar a-缺失小鼠和人源化PPARa（hPPAR α）小鼠（8周龄雄性）分为三组：第一组通过管饲法每天用水处理2周（对照组），其余两组分别通过管饲法用0.1和0.3 mg/kg全氟辛酸铵（APFO）处理2周。所用APFO剂量不影响任何小鼠系的血浆甘油三酯或总胆固醇水平，但高剂量仅增加mPPAR α小鼠的两种肝脏脂质水平。APFO仅在mPPAR α小鼠的肝脏中增加了PPAR α靶基因细胞色素P450 Cyp 4a 10、过氧化物酶体硫解酶和双功能蛋白的mRNA和/或蛋白水平，但在Ppar α-null或hPPAR α小鼠中没有增加。这种化学物质还增加了mPPAR α小鼠肝脏中线粒体极长链酰基辅酶A脱氢酶的表达。总之，当应用相对低剂量时，人类PPAR α对PFOA的反应性可能低于小鼠。这一信息在考虑PFOA是否影响人体脂质代谢方面可能非常有价值。(c)2009爱思唯尔爱尔兰有限公司保留所有权利。
Perfluorooctanoic acid (PFOA) is a ligand for peroxisome proliferator-activated receptor (PPAR)alpha, which exhibits marked species differences in expression and function, especially between rodents and humans. We investigated the functional difference in PFOA response between mice and humans, using a humanized PPAR alpha transgenic mouse line. Three genotyped mice, 129/5v wild-type (mPPAR alpha), Ppar alpha-null mice and humanized PPAR alpha (hPPAR alpha) mice (8-week-old males) were divided into three groups: the first was treated with water daily for 2 weeks by gavage (control group), and the remaining two groups were treated with 0.1 and 0.3 mg/kg ammonium perflurooctanate (APFO), respectively, for 2 weeks by gavage. The APFO dosages used did not influence the plasma triglyceride or total cholesterol levels in any mouse line, but the high dose increased both hepatic lipid levels only in mPPAR alpha mice. APFO increased mRNA and/or protein levels of PPAR alpha target genes cytochrome P450 Cyp4a10, peroxisomal thiolase and bifunctional protein only in the liver of mPPAR alpha mice, but not in Ppar alpha-null or hPPAR alpha mice. This chemical also increased expression of mitochondrial very long chain acyl-CoA dehydrogenase only in the liver of mPPAR alpha mice. Taken together, human PPAR alpha may be less responsive to PFOA than that of mice when a relatively low dose is applied. This information may be very valuable in considering whether PFOA influences the lipid metabolism in humans. (c) 2009 Elsevier Ireland Ltd. All rights reserved.