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.

项目概要 多氯联苯 (PCB) 是一组 209 种同系物，它们的毒性作用差异很大 和毒性机制。大多数研究都集中在高氯化 PCB 的影响上，因为 它们会生物累积。然而，通过受污染的环境接触氯化程度较低、挥发性较高的联苯 对于某些人群来说，室内和室外空气可能会非常高。这些空气中的多氯联苯很容易被生物激​​活 并表现出各自独特的毒性作用谱。我们假设空气中的多氯联苯可以带来 细胞和组织的氧化还原状态和大分子功能的不适当改变 不同的、不同的机制，导致对健康的有害影响，并且通过 了解这些机制后，就可以设计改善这些健康影响的策略。 我们在之前的资助期间取得的发现从根本上改变了人们对 PCB 的毒性。我们的数据为将多氯联苯重新分类为第一组（人类）提供了关键信息 致癌物，由国际癌症研究机构 (IARC) 确定。我们的新发现提供了 为本次更新申请中拟议的研究奠定了基础。为了解决项目 1 的假设，我们 将研究空气中最常见的 PCB 及其代谢物，以：1) 提供深入的分析 氧化还原网络、氧化还原环境和细胞基本能量代谢-呼吸的破坏 接触后的组织； 2) 识别活性同源物/代谢物以阐明结构-活性关系 （基因）毒性，对它们的重要性和对人类健康的潜在后果进行排序； 3）识别敏感 目标组织，分析器官特异性，并确定阈值水平和毒性； 4）考察潜力 预防或减轻毒性的饮食方法； 5）用已知的方法评估人类母子样本 PCB 和代谢物的身体负担，以开发暴露和影响的生物标志物，并识别潜在的 易感亚人群。 我们的主要目标是获得新知识，从而实现数据驱动的风险评估以及化疗 预防或改善多氯联苯和其他物质有害影响的保护和治疗方法 有毒物质。我们的方法是综合性和多样化的，从基础物理化学到详细的 在“每个细胞的分子”水平上分析效应，剖析不同同类物之间的相互作用 PCB 的含量、微量营养素的影响以及对人体样本进行分析以确定接触的后果。 该研究计划明确关注我们的目标，非常好地履行了超级基金的使命 研究计划，突破科学界限，着眼于未来有效的危害 管理和健康保护。