Project 1: PCBs: Metabolism, Genotoxicity and Gene Expression in Vivo

项目 1：PCB：体内代谢、遗传毒性和基因表达

• 批准号: 9249562
• 负责人: LARRY W ROBERTSON
• 金额: $ 35.79万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-12 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9249562
• 关键词: Address; Air; Animal Model; Antioxidants; Biochemistry; Biological; Biological Markers; Biology; Blood; Blood specimen; Body Burden; Breathing; Carcinogens; Cell Respiration; Cell physiology; Cells; Chemopreventive Agent; Chemoprotection; Chemoprotective Agent; Chicago; Child; Chronic; Collaborations; Communities; Consumption; DNA; DNA Damage; Data; Development; Dissection; Energy Metabolism; Environment; Environmental Exposure; Environmental Pollutants; Enzymes; Excision; Exhibits; Exposure to; Family; Fertilization; Foundations; Funding; Future; Gene Expression; Gene Expression Profile; Glutathione Disulfide; Glycolysis; Goals; Grant; Hazard Management; Health; Health protection; Homeostasis; Human; Hydrogen Peroxide; Individual; Industrialization; International Agency for Research on Cancer; Iowa; Kinetics; Knowledge; Laboratories; Liver; Location; Lung; Malignant Neoplasms; Mammals; Metabolic; Metabolic Diseases; Metabolism; Metallothionein; Metals; Methods; Micronutrients; Minerals; Mission; Mitochondria; Mothers; Organ; Organ Specificity; Organelles; Oxidation-Reduction; Oxidative Stress; Paint; Pathway interactions; Physical Chemistry; Plants; Point Mutation; Polychlorinated Biphenyls; Population; Prevalence; Progress Reports; Quinones; Recruitment Activity; Reference Values; Research; Respiration; Risk Assessment; Route; Rural; SOD2 gene; Sampling; Science; Scientist; Seminal; Source; Structure of parenchyma of lung; Structure-Activity Relationship; Sulfhydryl Compounds; Superfund; Techniques; Teenagers; Therapeutic; Tissues; Toxic effect; Translational Research; Translations; Unspecified or Sulfate Ion Sulfates; Urine; Vacuum; Vitamins; Xenobiotics; antioxidant enzyme; base; cohort; copper zinc superoxide dismutase; design; dietary approach; dietary supplements; diphenyl; gender difference; genome-wide; genotoxicity; in vivo; interest; macromolecule; oxidation; potential biomarker; prevent; programs; response; semiquinone; small molecule; sound; success; telomere; tissue respiration; toxicant; transcriptome sequencing

PROJECT SUMMARY Polychlorinated biphenyls (PCBs) are a group of 209 individual congeners that differ widely in their toxic effects and mechanisms of toxicity. Most research has focused on the effects of higher chlorinated PCBs because they bioaccumulate. However, exposure to lower chlorinated, more volatile biphenyls through contaminated indoor and outdoor air can be very high for some populations. These airborne PCBs are readily bio-activated and exhibit their own, distinct spectra of toxic effects. We hypothesize that airborne PCBs can bring about inappropriate changes in the redox status and macromolecule function of cells and tissues through different, distinct mechanisms, leading to detrimental effects on health, and that through understanding these mechanisms, strategies to ameliorate these health effects can be designed. The discoveries we have made in the previous funding periods have fundamentally changed views on the toxicity of PCBs. Our data provided key information for the reclassification of PCBs to Group 1, human carcinogens, by the International Agency of Research on Cancer (IARC). Our new discoveries supply the foundation for the proposed research in this renewal application. To address the hypothesis of Project 1, we will study PCBs occurring most often in air, and their metabolites, to: 1) provide an in-depth analysis of the disruptions in the redox networks, redox environment, and basic energy metabolism-respiration of cells and tissues upon exposure; 2) identify the active congeners/metabolites to elucidate structure-activity relationships of (geno)toxicity, ranking them in importance and potential consequences to human health; 3) identify sensitive target tissues, analyze organ specificity, and determine threshold levels and toxicity; 4) examine the potential of dietary approaches to prevent or ameliorate toxicity; and 5) assess human mother-child samples with known PCB and metabolite body burdens to develop biomarkers of exposure and effects, and to identify potential susceptible subpopulations. Our principal goal is to gain new knowledge that will enable data-driven risk assessment, as well as chemo- protective and therapeutic methods to prevent or ameliorate the detrimental effects of PCBs and other toxicants. Our approach is integrative and diverse, ranging from fundamental physical chemistry, to detailed analysis of effects at the `molecule per cell' level, to dissection of the interactions between different congeners of PCBs, effects of micronutrients, and analysis of human samples to determine consequences of exposure. With a clear focus on our goals, this research program meets exceptionally well the mission of the Superfund Research Program, pushing the boundaries of science with a view to the future for effective hazard management and health protection.

项目摘要 多氯联苯（PCB）是一组209个单个同类物，其毒性作用差异很大 和毒性机制。大多数研究都集中在较高氯化PCB的影响上，因为 他们生物蓄积。但是，暴露于较低的氯化，通过受污染的挥发性二苯基 对于某些人群，室内和室外空气可能很高。这些机载PCB很容易生物激活 并展示自己的有毒作用的独特光谱。我们假设机载PCB可以带来 通过细胞和组织的氧化还原状态和大分子功能的不当变化通过 不同的，不同的机制，导致对健康的有害影响，并通过 了解这些机制，可以设计改善这些健康影响的策略。 我们在前几个资金期间的发现从根本上改变了看法 PCB的毒性。我们的数据提供了将PCB重新分类为第1组的关键信息， 致癌物，国际癌症研究机构（IARC）。我们的新发现提供了 在此更新应用中提议的研究基金会。为了解决项目1的假设，我们 将研究最常在空气中发生的PCB及其代谢物，至：1）对 氧化还原网络的破坏，氧化还原环境和基本能量代谢的细胞和基本能量代谢和 暴露时组织； 2）确定活跃的同源物/代谢物以阐明结构活性关系 （Geno）毒性的重要性和对人类健康的潜在后果的排名； 3）确定敏感 靶组织，分析器官特异性并确定阈值水平和毒性； 4）检查潜力 预防或改善毒性的饮食方法； 5）评估人类的母子样本 PCB和代谢物体重负担，以发展暴露和影响的生物标志物，并确定潜力 易感亚群。 我们的主要目标是获得新知识，以实现数据驱动的风险评估以及化学 防止或改善PCB和其他的有害影响的保护性和治疗方法 有毒物质。我们的方法是综合性和多样的，从基本的物理化学到详细 分析在“每个细胞分子”水平上的效应，以解剖不同同类物之间的相互作用 PCB的影响，微量营养素的作用以及人类样品的分析以确定暴露的后果。 明确关注我们的目标，该研究计划非常符合超级基金的使命 研究计划，推动科学的界限，以期为未来有效危害 管理和健康保护。