PPAR, hormones, and xenobiotics

三氯乙烯（TCE）、四氯乙烯（PCE）及其相关化学品是一类重要的环境污染物，被称为过氧化物酶体增殖物化学品（PPC）。在职业和环境中接触PPC会对健康产生一系列不良影响，包括肝、肾和中枢神经系统毒性、造血系统恶性肿瘤和生殖毒性。啮齿动物模型系统已经确定，这些毒性中的几种，包括肝癌效应，是由称为PPARalpha的核受体蛋白介导的，PPARalpha是过氧化物酶体增殖物激活受体-α。在过去的项目期间进行的研究表明，通过与激素/精氨酸激活的STAT信号通路的串扰可以抑制PPAR转录活性，但是这种串扰对PPC的毒性和致癌作用的影响以及这类异种化学品致癌性的潜在机制尚不清楚。本提案的具体目标是：1）研究控制细胞因子/激素和PPC之间抑制性串扰的机制，并确定这种串扰对PPC暴露的细胞反应和毒理学结果的影响; 2）阐明这种串扰对PPC暴露的细胞反应和毒理学结果的影响; 2）阐明PPC抑制细胞凋亡的机制，这可能是导致PPC诱导的肿瘤促进和癌变的细胞增殖和细胞死亡之间的失衡的关键因素;和3）使用计算和实验方法来鉴定PPC和其它PPARgamma的环境活化剂，其在多种人体组织中高度表达，并且可能对应于人体中与PPC暴露相关的某些有害作用的重要靶点。总之，这些研究将提供有关PPAR依赖性毒性的潜在机制及其通过内源性激素和细胞因子调节的基本新知识，并可能有助于解释物种，个体和发育期间激素模式的差异如何影响TCE，PCE和其他PPC产生不良健康影响。从这些研究中更全面地了解PPC和PPAR作用的基本机制，将有助于评估人类低水平暴露于一类重要的环境污染物的风险，这类污染物对超级基金的清理工作特别重要。

Trichloroethylene (TCE), perchloroethylene (PCE) and related chemicals constitute an important class of environmental pollutants termed peroxisome proliferator chemicals (PPCs). Occupational and environmental exposure to PPCs is associated with a range of adverse health effects including liver, kidney and central nervous system toxicity, hematopoietic malignancies and reproductive toxicities. Rodent model systems have established that several of these toxicities, including the hepatocarcinogenic effects, are mediated by a nuclear receptor protein termed PPARalpha, peroxisome proliferator-activated receptor-alpha. Studies during the past project period demonstrated that PPAR transcriptional activity can be inhibited through cross-talk with hormone/cytokine-activated STAT signaling pathways, however the impact of this cross talk on the toxic and carcinogenic effects of PPCs, and the underlying mechanism of carcinogenicity of this class of xenochemicals are not known. The specific goals of this proposal are: 1) to investigate the mechanisms that govern the inhibitory cross-talk between cytokines/hormones and PPCs and to establish the impact of this cross-talk on cellular responses to, and the toxicological outcome of, PPC exposure; 2) to elucidate the impact of this cross-talk on cellular responses to, and the toxicological outcome of, PPC exposure; 2) to elucidate the mechanisms that underlie the suppression of apoptosis by PPCs, which is likely to be a key factor in the imbalance between cell proliferation and cell death that leads to PPC-induced tumor promotion and carcinogenesis; and 3) to use computational and experimental methods to identify PPC and other environmental activators of PPARgamma, which is highly expressed in multiple human tissues and may correspond to an important target in humans for some of the deleterious effects associated with PPC exposure. Together, these studies will provide fundamental new knowledge on the underlying mechanisms of PPAR-dependent toxicities and their modulation by endogenous hormones and cytokines, and may help explain how differences in hormone patterns between species, individuals and during development affect how TCE, PCE and other PPCs produce adverse health effects. The more complete understanding of the basic mechanisms of PPC and PPAR action that will derive from these studies will aid in the assessment of human risk of low-level exposure to an important class of environmental contaminants that is of special interest to Superfund clean-up efforts.