Project 5: Pollutant-Particle Systems and Xenobiotic Bioactivation

超级基金网站通常包含复杂的污染物混合物，包括氯代烃、金属和其他有毒的有机和无机化合物。这些场地的修复会导致周围人口暴露在空气中的土壤粉尘中，这些粉尘受到处理设备排放的有害物质或PM的污染。我们的研究人员已经证明，EPFR至少存在于一些受污染的超级基金土壤中，并在焚烧和热处理危险物质时形成高浓度的EPFR。这些与PM相关的EPFR在大气中存在数天，并可能在受污染的土壤中持续形成。一旦被吸入，它们就会启动并参与催化链循环，产生ROS，并在生物介质中持续足够长的时间，导致肺和心血管损害。由于我们发现与超级基金网站相关的EPFR是相对较新的，因此对它们的毒性机制知之甚少。毒性反应被认为是通过产生活性氧物种(ROS)来调节的，一些研究表明P450系统参与了这一过程。这项研究的目的是研究P450和HO-1系统在有机体内对EPFR暴露的反应中的作用。提出的假设是，与超细颗粒相关的EPFR(1)直接抑制细胞色素P450介导的活性，(2)减少几种P450酶的表达，增加ROS保护酶(如HO-1)的表达，以及(3)改变依赖P450的ROS产生。我们将确定P450的表达减少是否是ROS介导的NFkB表达改变的结果，其中NFkB的激活导致P450的减少和HO-1的表达增加， 用于限制暴露组织中的氧化损伤。综上所述，这些研究有望提供有关P450和HO-1系统如何对EPFR暴露做出反应并影响EPFR介导的毒性的新信息。

Superfund sites typically contain complex mixtures of pollutants including chlorinated hydrocarbons, metals, and other toxic organic and inorganic compounds. Remediation of these sites results in some exposure of the surrounding population to airborne soil dust contaminated with hazardous substances or PM emitted from the treatment devices. Our researchers have shown EPFRs are present in at least some contaminated Superfund soils and formed in high concentration during incineration and thermal treatment of hazardous substances. These PM-associated EPFRs exist for days in the atmosphere and may continually form in contaminated soils. Once inhaled, they initiate and participate in catalytic chain cycles generating ROS and persist in biological media long enough to lead to pulmonary and cardiovascular damage. Since our discovery of EPFRs associated with Superfund sites is relatively recent, little is known about their mechanisms of toxicity. The toxic responses are thought to be mediated through the generation of reactive oxygen species (ROS), with several studies implicating the P450 system in this process. The goal of this study is to examine the roles of the P450 and HO-1 systems in the response to EPFR exposure within an organism. The hypothesis being addressed is that EPFRs associated with ultrafine particles (1) directly inhibit cytochrome P450-mediated activities, (2) decrease the expression of several P450 enzymes and increase the expression of ROS-protective enzymes (such as HO-1), and (3) alter P450-dependent ROS production. We will determine if decrease in P450 expression is the result of a ROS-mediated alteration in NFkB expression, where NFkB activation leads to decreases in P450 and increases in HO-1 expression that serve to limit oxidative damage in exposed tissues. Taken together, these studies are expected to provide novel information regarding how the P450 and HO-1 systems respond to EPFR exposure and affect EPFR-mediated toxicity.