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

项目1：多氯联苯：体内代谢、遗传毒性和基因表达

• 批准号: 8659475
• 负责人: LARRY W ROBERTSON
• 金额: $ 43.38万
• 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 2015-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8659475
• 关键词: Acetylcysteine; Affect; Aftercare; Air; Antibodies; Aroclor 1254; Attention; Behavior; Binding; Biological; Blood; Breathing; Carcinogens; Cell Nucleus; Cell physiology; Cells; Cellular Structures; Chemicals; Chicago; Chlorine; Chromosomal Breaks; Chromosomal Stability; Chromosomes; Copper; Covalent Interaction; Cytoplasm; DNA; DNA Adduction; Data; Diet; Dietary Factors; Environment; Enzymes; Equilibrium; Event; Exposure to; Food; Frequencies; Gene Expression; Gene Expression Regulation; Gene Mutation; Genetic Transcription; Goals; Health; Human; In Vitro; Individual; Induced Mutation; Ingestion; Inhalation Exposure; Injection of therapeutic agent; Kinetics; Laboratories; Lead; Length; Light; Liver; Location; Lung; Mediating; Metabolic; Metabolic Activation; Metabolism; Metals; Mitochondria; Mitochondrial DNA; Mutagens; Mutation; Mutation Spectra; Normal Cell; Nuclear; Nucleic Acids; Oral; Organ; Organ Specificity; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Pattern; Peptides; Peroxidases; Plasma; Polychlorinated Biphenyls; Population; Prevalence; Production; Progress Reports; Proliferating; Prostaglandin-Endoperoxide Synthase; Protein Analysis; Proteins; Publications; Quinones; RNA-Directed DNA Polymerase; Rattus; Reaction; Reactive Oxygen Species; Reporting; Research; Ribonucleoproteins; Risk; Risk Assessment; Role; Sampling; Selenium; Source; Structure; Structure-Activity Relationship; Subcellular structure; Sulfhydryl Compounds; Superoxides; Telomerase; Telomere Shortening; Testing; Time; Tissues; Toxic effect; Transgenic Organisms; Triad Acrylic Resin; Tubulin; Umbilical Cord Blood; Work; adduct; base; carcinogenesis; carcinogenicity; chlorination; chromosome loss; dechlorination; dietary antioxidant; genotoxicity; human TERT protein; in vivo; macromolecule; novel; pressure; semiquinone; semiquinone radicals; senescence; telomere; tool; tumor; uptake; vapor

Airborne PCBs are those that have higher vapor pressures, lower chlorination, and are substrates for metabolic activation. We hypothesize that lower chlorinated airborne PCBs and their natural electrophilic metabolites interact with DNA and DNA-associated proteins and/or initiate oxidative events that alter the intracellular redox environment, thereby compromising cellular structures and functions. Our data show that PCBs are initiators in rat liver and that PCB3 (4-chlorobiphenyl) induces mutations in the liver and possibly lung of transgenic BigBlue rats after ip injection. Also, PCB3 metabolites cause various, compound-specific types of genotoxic damage in cells in culture. We have shown that prostaglandin synthase and myeloperoxidase bioactivate dihydroxy-PCBs and that the PCB-quinones can react with nucleophiles like GSH by Michael addition or a substitution reaction with dechlorination. We have also observed, for the first time, a PCB semiquinone radical in cells. We therefore propose to extend our studies to: 1) Examine the mechanisms of PCB genotoxicity by comparing nuclear vs. mitochondrial effects and elucidating PCB interactions with DNA-associated protein; 2) Investigate interactions of airborne PCBs and their metabolites with telomeres and telomerase; 3) Determine the reactions of PCB-semiquinone radicals and how factors, such as conjugation with thiols, affect this reactivity; 4) Analyze the genotoxicity of airborne PCBs after inhalation exposure and explore mechanisms to ameliorate/mediate against those effects. Jointly these studies may explain which and how PCBs are genotoxic, which organs, subcellular structures, and macromolecules are the targets, the mechanisms of these reactions, and whether these upset the delicate redox balance of the natural environment of the cell. Emphasis is placed on the kinetics and consequences of inhalation exposure to airborne PCBs. These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations.

空气中的多氯联苯具有较高的蒸汽压，较低的氯化作用，是代谢活化的底物。我们假设，较低的氯化空气中的多氯联苯和它们的天然亲电代谢产物与DNA和DNA相关蛋白相互作用和/或启动氧化事件，改变细胞内的氧化还原环境，从而损害细胞的结构和功能。 我们的数据表明，多氯联苯在大鼠肝脏和PCB 3（4-氯联苯）诱导突变的肝脏和可能的肺转基因BigBlue大鼠后，ip注射。此外，多氯联苯3代谢物在培养的细胞中引起各种特定化合物类型的遗传毒性损害。我们已经表明，前列腺素合酶和髓过氧化物酶生物激活二羟基-PCB和PCB-醌类可以与亲核试剂如GSH通过迈克尔加成或取代反应与脱氯反应。我们还 首次观察到细胞中的PCB半醌自由基。 因此，我们建议将我们的研究扩展到：1）通过比较核与线粒体效应以及阐明PCB与DNA相关蛋白的相互作用来研究PCB的遗传毒性机制; 2）研究空气中PCB及其代谢物与端粒和端粒酶的相互作用; 3）确定PCB-半醌自由基的反应以及诸如与硫醇结合等因素如何影响这种反应性; 4）分析吸入暴露后空气中多氯联苯的遗传毒性，并探索改善/介导这些影响的机制。 联合这些研究可以解释哪些以及如何多氯联苯是遗传毒性，哪些器官，亚细胞结构和大分子是目标，这些反应的机制，以及这些是否破坏了细胞自然环境的微妙氧化还原平衡。重点放在动力学和吸入暴露于空气中的多氯联苯的后果。上一个目标中的这些数据和饮食研究将为风险评估提供科学依据，并为利益攸关方提供建议，最终目标是保护高度暴露的个人和人群。