Key issues in the role of peroxisome proliferator-activated receptor agonism and cell signaling in trichloroethylene toxicity.
Key issues in the role of peroxisome proliferator-activated receptor agonism and cell signaling in trichloroethylene toxicity.
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DOI：
10.1289/ehp.8693
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发表时间：
2006-09
影响因子：
10.4
通讯作者：
Caldwell JC
中科院分区：
文献类型：
--
作者：
Keshava N;Caldwell JC
过氧化物酶体增殖物激活受体α(PPARα)被认为与多种不同的疾病、毒性反应和受体通路有关。美国环境保护局2001年起草的三氯乙烯(TCE)风险评估得出结论，尽管PPAR可能在肝脏肿瘤的诱发中发挥作用，但其激活的作用和对肿瘤发生至关重要的后续事件的序列尚未得到很好的定义，特别是由于有关过氧化体外影响的不确定性。这篇文章是关于三氯乙烯健康风险评估中关键问题的迷你专著的一部分，在本文中，我们总结了自那时以来发表的一些关于PPARα的影响和行动的科学文献，这些文献有助于告知和说明与三氯乙烯风险评估相关的关键科学问题。最近对PPARα在三氯乙烯及其代谢产物引起的基因表达变化中的作用的分析只提供了有限的数据来与其他PPARα激动剂进行比较，特别是考虑到涉及PPARα基因敲除小鼠的结果很难解释。此外，过去5年有关PPARα激动剂的数据增加，呈现了一系列更复杂的过氧体外效应和作用，这表明PPARα可能不仅参与肝脏肿瘤的作用模式(MOA)，而且还参与TCE及其代谢物的其他影响。综上所述，最近的研究支持这样的结论，即确定三氯乙烯诱导的效应与PPARα相关多器官功能障碍(S)的相关性和易感性不能依赖于对过氧化体增殖本身的推断，而需要更好地了解PPARα激动剂后过氧体外事件的相互作用。
Peroxisome proliferator–activated receptor α (PPARα) is thought to be involved in several different diseases, toxic responses, and receptor pathways. The U.S. Environmental Protection Agency 2001 draft trichloroethylene (TCE) risk assessment concluded that although PPAR may play a role in liver tumor induction, the role of its activation and the sequence of subsequent events important to tumorigenesis are not well defined, particularly because of uncertainties concerning the extraperoxisomal effects. In this article, which is part of a mini-monograph on key issues in the health risk assessment of TCE, we summarize some of the scientific literature published since that time on the effects and actions of PPARα that help inform and illustrate the key scientific questions relevant to TCE risk assessment. Recent analyses of the role of PPARα in gene expression changes caused by TCE and its metabolites provide only limited data for comparison with other PPARα agonists, particularly given the difficulties in interpreting results involving PPARα knockout mice. Moreover, the increase in data over the last 5 years from the broader literature on PPARα agonists presents a more complex array of extraperoxisomal effects and actions, suggesting the possibility that PPARα may be involved in modes of action (MOAs) not only for liver tumors but also for other effects of TCE and its metabolites. In summary, recent studies support the conclusion that determinations of the human relevance and susceptibility to PPARα-related MOA(s) of TCE-induced effects cannot rely on inferences regarding peroxisome proliferation per se and require a better understanding of the interplay of extraperoxisomal events after PPARα agonism.
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影响因子：
5.4
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