Project 5: Pollutant-Particle Systems and Xenobiotic Bioactivation

项目 5：污染物颗粒系统和异生物质生物活化

• 批准号: 8097844
• 负责人: WAYNE L BACKES
• 金额: $ 14.94万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097844
• 关键词: Address; Affect; Airborne Particulate Matter; Biological; Breathing; Cardiovascular system; Chlorinated Hydrocarbons; Complex Mixtures; Cytochrome P450; Devices; Dose; Down-Regulation; Dust; Enzyme Induction; Enzymes; Exposure to; Free Radicals; Generations; Goals; Hazardous Substances; Heart; Human; Hydrogen Peroxide; Hydroxyl Radical; In Vitro; Incineration; Lead; Lung; Measures; Mediating; Metabolism; Metals; Microsomes; Mixed Function Oxygenases; NADP; NF-kappa B; Organism; Particulate Matter; Pharmaceutical Preparations; Population; Process; Production; Rattus; Reaction; Reactive Oxygen Species; Research; Research Personnel; Respiratory physiology; Role; Signal Transduction; Site; Soil; Superfund; Superoxides; System; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Xenobiotics; gene repression; heart function; heme oxygenase-1; novel; oxidant stress; oxidative damage; particle; particle exposure; planetary Atmosphere; pollutant; reconstitution; remediation; response; superfund site; ultrafine particle

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.

超级基金所在地通常含有复杂的污染物混合物，包括氯化烃、金属和其他有毒有机和无机化合物。对这些场地进行补救会导致周围人群暴露于被处理设备排放的有害物质或PM污染的空气传播土壤粉尘。我们的研究人员已经表明，EPFR至少存在于一些受污染的超级基金土壤中，并在有害物质的焚烧和热处理过程中以高浓度形成。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。一旦吸入，它们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，导致肺和心血管损伤。由于我们发现EPFRs与超级基金网站是相对较新的，很少有人知道他们的毒性机制。毒性反应被认为是通过产生活性氧（ROS）介导的，有几项研究表明P450系统参与了这一过程。本研究的目的是检查的作用，P450和HO-1系统在响应EPFR暴露在一个有机体。所提出的假设是，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）降低几种P450酶的表达并增加ROS保护酶（如HO-1）的表达，（3）改变P450依赖的ROS产生。我们将确定P450表达的减少是否是ROS介导的NF κ B表达改变的结果，其中NF κ B活化导致P450的减少和HO-1表达的增加， 用于限制暴露组织中的氧化损伤。总之，这些研究有望提供关于P450和HO-1系统如何响应EPFR暴露和影响EPFR介导的毒性的新信息。