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

项目摘要 多氯联苯（PCBs）是一组由209种单独的同系物组成的化合物，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多氯联苯的影响上， 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、挥发性较强的联苯， 室内和室外空气对某些人群来说可能非常高。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效应我们假设空气中的多氯联苯 细胞和组织的氧化还原状态和大分子功能的不适当变化， 不同的，独特的机制，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。 我们在前几个资助期内的发现从根本上改变了人们对 PCBs的毒性我们的数据为将多氯联苯重新分类为第1组（人类）提供了关键信息。 致癌物，由国际癌症研究机构（IARC）我们的新发现提供了 为本次更新申请中提出的研究奠定了基础。为了解决项目1的假设，我们 将研究空气中最常见的多氯联苯及其代谢物，以：1）提供对 细胞的氧化还原网络、氧化还原环境和基本能量代谢-呼吸的破坏， 2）确定活性同系物/代谢物，以阐明结构-活性关系 （基因）毒性，按其重要性和对人类健康的潜在后果排列; 3）确定敏感的 靶组织，分析器官特异性，并确定阈值水平和毒性; 4）检查潜在的 预防或减轻毒性的饮食方法;和5）评估具有已知 多氯联苯和代谢物的身体负担，以开发接触和影响的生物标志物，并确定潜在的 易感亚群 我们的主要目标是获得新的知识，使数据驱动的风险评估，以及化疗， 防止或减轻多氯联苯和其他有害物质的有害影响的保护和治疗方法 有毒物质我们的方法是综合和多样化的，从基础物理化学，到详细的 在“每个细胞的分子”一级分析影响，剖析不同同源物之间的相互作用 多氯联苯的影响、微量营养素的影响以及分析人体样本以确定接触的后果。 这个研究项目明确地聚焦于我们的目标，非常好地完成了超级基金的使命 研究计划，推动科学的界限，着眼于未来的有效危害 管理和健康保护。

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.