trans-activation of PPARα and PPARγ by structurally diverse environmental chemicals
trans-activation of PPARα and PPARγ by structurally diverse environmental chemicals
复制标题
DOI：
10.1006/taap.1999.8809
复制
发表时间：
1999-12-01
影响因子：
3.8
通讯作者：
Waxman, DJ
中科院分区：
文献类型：
--
作者：
Maloney, EK;Waxman, DJ
大量工业化学品和环境污染物，包括三氯乙烯（TCE）、邻苯二甲酸二（2-乙基己基）酯（DEHP）、全氟辛酸（PFOA）和各种苯氧乙酸除草剂，是非遗传毒性的啮齿动物肝癌物质，其人类健康风险不确定。啮齿动物模型研究已确定参与这些化学物质的肝毒性和肝癌作用的受体为过氧化物酶体增殖物激活受体α（PPARα），这是一种在肝脏中高表达的核受体。人类对这些过氧化物酶体增殖剂化学物质表现出较弱的反应，部分原因是人类肝脏中 PPAR α 表达水平相对较低。细胞转染研究旨在研究过氧化物酶体增殖剂化学物质与从人和小鼠克隆的 PPAR α 以及 PPAR γ 的相互作用，PPAR γ 是一种在多种人体组织中高表达的 PPAR 亚型，是脂肪生成和造血等生理过程的重要调节剂。对于三种环境化学物质 TCE、全氯乙烯和 DEHP，发现 PPARa 被代谢物激活，但不被母体化学物质激活。与小鼠 PPAR α 相比，某些过氧化物酶体增殖剂（Wy-14,643、PFOA）观察到人 PPAR α 对反式激活的敏感性降低，但其他过氧化物酶体增殖剂（TCE 代谢物、三氯乙酸盐和二氯乙酸盐；以及 DEHP 代谢物、邻苯二甲酸单[2-乙基己基] 酸盐和 2-乙基己酸）则没有。对人类和小鼠 PPAR γ 的研究表明，该受体的转录活性会受到邻苯二甲酸单（2-乙基己基）酯的刺激，邻苯二甲酸单（2-乙基己基）酯是一种 DEHP 代谢物，可诱导啮齿动物的发育和生殖器官毒性。这一发现表明，PPAR γ 在人类脂肪组织中高度表达，许多亲脂性外来化学物质往往在其中积聚，并且在结肠、心脏、肝脏、睾丸、脾脏和造血细胞中也高度表达，它可能是人类细胞中过氧化物酶体增殖剂类工业和环境化学物质子集迄今为止未被识别的靶标。 (C) 1999 年学术出版社。
A large number of industrial chemicals and environmental pollutants, including trichloroethylene (TCE), di(2-ethylhexyl)phthalate (DEHP), perfluorooctanoic acid (PFOA), and various phenoxyacetic acid herbicides, are nongenotoxic rodent hepatocarcinogens whose human health risk is uncertain. Rodent model studies have identified the receptor involved in the hepatotoxic and hepatocarcinogenic actions of these chemicals as peroxisome proliferator-activated receptor alpha (PPAR alpha), a nuclear receptor that is highly expressed in liver. Humans exhibit a weak response to these peroxisome proliferator chemicals, which in part results from the relatively low level of PPAR alpha expression in human liver. Cell transfection studies were carried out to investigate the interactions of peroxisome proliferator chemicals with PPAR alpha, cloned from human and mouse, and with PPAR gamma, a PPAR isoform that is highly expressed in multiple human tissues and is an important regulator of physiological processes such as adipogenesis and hematopoiesis, With three environmental chemicals, TCE, per-chloroethylene, and DEHP, PPARa was found to be activated by metabolites, but not by the parent chemical. A decreased sensitivity of human PPAR alpha compared to mouse PPAR alpha to trans-activation was observed with some (Wy-14,643, PFOA), but not other, peroxisome proliferators (TCE metabolites, trichloroacetate and dichloroacetate; and DEHP metabolites, mono[2-ethylhexyl]phthalate and 2-ethylhexanoic acid). Investigation of human and mouse PPAR gamma revealed the transcriptional activity of this receptor to be stimulated by mono(2-ethylhexyl)phthalate, a DEHP metabolite that induces developmental and reproductive organ toxicities in rodents. This finding suggests that PPAR gamma, which is highly expressed in human adipose tissue, where many lipophilic foreign chemicals tend to accumulate, as well as in colon, heart, liver, testis, spleen, and hematopoietic cells, may be a heretofore unrecognized target in human cells for a subset of industrial and environmental chemicals of the peroxisome proliferator class. (C) 1999 Academic Press.