Semi-Volatile PCBs: Sources, Exposures, Toxicities

描述（由申请人提供）：机载多氯联苯是那些具有较高蒸汽压，较低氯化作用，并且是代谢激活的底物的多氯联苯。我们假设低氯化空气中的多氯联苯及其天然亲电代谢物与DNA和DNA相关蛋白相互作用和/或启动氧化事件，改变细胞内氧化还原环境，从而损害细胞结构和功能。我们的数据表明，PCBs是大鼠肝脏的启动剂，PCB3（4-氯联苯）在转基因BigBlue大鼠的肝脏和可能的肺部注射后诱导突变。此外，PCB3代谢物在培养细胞中引起各种化合物特定类型的基因毒性损伤。我们已经证明前列腺素合成酶和髓过氧化物酶可以生物激活二羟基多氯联苯，并且多氯联苯醌可以通过迈克尔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多氯联苯半醌自由基。因此，我们建议将我们的研究扩展到：1)通过比较细胞核和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)研究空气中多氯联苯及其代谢物与端粒和端粒酶的相互作用；3)确定多氯联苯-半醌自由基的反应，以及与硫醇缀合等因素对反应性的影响；4)分析空气中多氯联苯吸入暴露后的遗传毒性，探讨改善或调节这些影响的机制。这些研究共同解释了多氯联苯的遗传毒性，哪些器官、亚细胞结构和大分子是目标，这些反应的机制，以及它们是否破坏了细胞自然环境中微妙的氧化还原平衡。重点放在动力学和吸入暴露于空气中的多氯联苯的后果。这些数据和上一阶段的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，最终目标是保护高暴露个人和人群。

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.