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.

超级基金场地通常含有复杂的污染物混合物，包括氯化碳氢化合物、金属和其他有毒有机和无机化合物。对这些场地的修复会导致周围人群部分接触到被处理设备排放的有害物质或 PM 污染的空气中的土壤灰尘。我们的研究人员表明，EPFR 至少存在于一些受污染的 Superfund 土壤中，并且在危险物质的焚烧和热处理过程中形成高浓度。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，产生活性氧，并在生物介质中持续存在足够长的时间，从而导致肺部和心血管损伤。由于我们与超级基金网站相关的 EPFR 的发现相对较新，因此对其毒性机制知之甚少。毒性反应被认为是通过活性氧 (ROS) 的产生来介导的，多项研究表明 P450 系统参与了这一过程。本研究的目的是检查 P450 和 HO-1 系统在生物体内对 EPFR 暴露的反应中的作用。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（例如 HO-1）的表达，以及 (3) 改变 P450 依赖性 ROS 的产生。我们将确定 P450 表达的减少是否是 ROS 介导的 NFkB 表达改变的结果，其中 NFkB 激活导致 P450 的减少和 HO-1 表达的增加，从而 用于限制暴露组织的氧化损伤。总而言之，这些研究预计将提供有关 P450 和 HO-1 系统如何响应 EPFR 暴露并影响 EPFR 介导的毒性的新信息。