Semi-Volatile PCBs: Sources, Exposures, Toxicities

半挥发性多氯联苯：来源、暴露、毒性

• 批准号: 7813124
• 负责人: LARRY W ROBERTSON
• 金额: $ 305.56万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813124
• 关键词: Semi; Volatile; PCBs; Sources; Exposures

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：空气中的多氯联苯是那些具有较高的蒸汽压，较低的氯化作用，并且是新陈代谢激活的底物。我们假设，较低的氯化空气中的多氯联苯及其天然亲电代谢产物与DNA和DNA相关蛋白相互作用和/或引发氧化事件，改变细胞内的氧化还原环境，从而损害细胞结构和功能。我们的数据表明，多氯联苯是大鼠肝脏的引发剂，IP注射后，PCB3(4-氯联苯)可诱导转基因BigBlue大鼠肝脏和可能的肺发生突变。此外，PCB3代谢物在培养的细胞中会引起各种特定类型的遗传毒性损伤。我们已经证明了前列腺素合成酶和髓过氧化物酶对二羟基-多氯联苯的生物激活作用，并且多氯联苯对苯二酚可以通过Michael加成或脱氯取代反应与GSH等亲核试剂反应。我们还首次在细胞中观察到了多氯联苯的半喹酮自由基。因此，我们建议将我们的研究扩展到：1)通过比较核效应和线粒体效应，并阐明多氯联苯与DNA相关蛋白的相互作用，来检测多氯联苯的遗传毒性机制；2)研究空气中多氯联苯及其代谢产物与端粒和端粒酶的相互作用；3)确定多氯联苯-半喹自由基的反应以及与硫醇的结合等因素如何影响这种反应；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/调节这些影响的机制。结合这些研究，可以解释哪些多氯联苯具有基因毒性，哪些器官、亚细胞结构和大分子是目标，这些反应的机制，以及这些反应是否破坏了细胞自然环境的微妙氧化还原平衡。重点放在吸入暴露于空气中的多氯联苯的动力学和后果。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。