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

项目总结 多氯联苯(多氯联苯)是一组209个独立的同系物，它们的毒性作用大不相同。 和毒性机制。大多数研究都集中在氯化程度较高的多氯联苯的影响上，因为 它们会在生物上积累。然而，由于受到污染，接触氯化程度较低、挥发性更强的联苯 对于一些人群来说，室内和室外空气可能非常高。这些空气中的多氯联苯很容易被生物激活。 并表现出自己独特的毒害效应光谱。我们假设空气中的多氯联苯可以带来 细胞和组织氧化还原状态和大分子功能的不适当变化 不同的、不同的机制，导致对健康的有害影响，并通过 了解了这些机制，就可以设计出改善这些健康影响的策略。 我们在前几个资助期的发现从根本上改变了人们对 多氯联苯的毒性。我们的数据为多氯联苯的重新分类提供了关键信息 致癌物，由国际癌症研究机构(IARC)提供。我们的新发现为 为本次续展申请中的拟议研究奠定基础。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 氧化还原网络、氧化还原环境和基本能量代谢的破坏--细胞和 2)鉴定活性同系物/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)确定敏感性 靶向组织，分析器官特异性，并确定阈值水平和毒性；4)检查潜在的 预防或改善毒性的饮食方法；以及5)评估人类母婴样本 多氯联苯和代谢产物的身体负荷，以开发暴露和影响的生物标记物，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学- 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 毒药。我们的方法是综合的和多样化的，从基础物理化学到详细的 在“每个细胞的分子”水平上的效应分析，以剖析不同同系物之间的相互作用 多氯联苯的影响，微量营养素的影响，以及对人体样本的分析，以确定暴露的后果。 明确我们的目标，这项研究计划非常符合超级基金的使命 研究计划，推动科学的边界，着眼于有效危险的未来 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.