PEROXISOME PROLIFERATOR CARCINOGENESIS--GENE MODULATION

人类广泛接触过氧化物酶体增殖物（PP）外源性物质 如降胆固醇药物、增塑剂和除草剂， 因为许多PP是啮齿动物肝癌原。 争议 关于健康风险的程度存在，因为有限的研究， 数据表明，人类肝细胞对这种现象不太敏感， 过氧化物酶体细胞器的增殖。 然而， 致癌作用是未知的，可能与过氧化物酶体增殖无关。 这项建议的广泛和长期目标是改善 通过定义一个子集估计与PP暴露相关的人类风险 导致PP诱导的啮齿动物肝脏肿瘤的分子事件。 的 PP不是基因突变，最近的研究表明，大多数，如果不是全部， 它们的作用是通过一种特定的PP激活受体介导的， 过氧化物酶体增殖物激活受体（α）。 结构同源的PPARs存在于许多哺乳动物中， 物种，包括人类。 该提案旨在测试 PP通过肝基因特异性改变诱发肿瘤假说 通过激活的过氧化物酶体增殖物激活受体（α）调节表达。 研究设计 包括使用nRNA差异显示技术来分析基因 正常肝细胞和肝细胞中mRNA表达的差异 肿瘤的mRNA。 一个连续的过程将识别PP调制的 通过PPAR（α）调节mRNA表达的变化。 的 这项工作的结果将提供一个明确的框架，比较人类 和啮齿动物基因表达，可用于预测PP- 诱发啮齿动物肿瘤，用于人类危害表征。

The widespread human exposure to peroxisome proliferator (PP) xenobiotics such as cholesterol-lowering drugs, plasticizers, and herbicides is a health concern because many PP are rodent hepatocarcinogens. Controversy exists regarding the degree of health risk because the limited studies to date indicate that human hepatocytes are less susceptible to the phenomenon of peroxisomal organelle proliferation. However, the mechanism of carcinogenesis is unknown and may independent of peroxisomal proliferation. The broad, long-term objective of this proposal is to improve the estimation of human risk associated with PP exposure by defining a subset of he molecular events leading to PP induced rodent livers tumors. The PP are not genotixic, and recent work indicates that most, if not all, of their effects are mediated through a specific PP-activated receptor, the PPAR (alpha). Structurally homologous PPARs are present in many mammalian species, including humans. This proposal is designed to test the hypothesis that PP induce cancer through specific changes in hepatic gene expression modulated via an activated PPAR (alpha). The research design involves using an nRNA differential display technique to analyze gene expression differences between normal hepatic m RNA and hepatocellular tumor mRNA in rodents. A sequential process will identify PP-modulated changes in MRNA expression that are regulated via the PPAR (alpha). The results of this work will provide a defined framework for comparing human and rodent gene expression that can be used to predict the relevance of PP- induced rodent tumors for human hazard characterization.