DNA Adducts as Biomarkers of Exposure and Effect - Biomedical

该项目的研究将利用新开发的氧化应激生物标志物来评估对超级基金地点具有重要意义的危险化学品的作用模式和剂量反应。我们的研究将主要针对多卤代和多环芳烃的影响，包括二苯并(a，L)并(DBF)、RGB和二恶英。这些研究将分析来自两个规模最大、特征最好的致癌性生物测试的快速冷冻组织：关于大鼠的多氯联苯和二恶英的NTP毒性当量因子研究；以及关于彩虹鲑鱼的ED(0.1)DBF研究。我们假设氧化应激是毒性和致癌的重要作用方式。这些研究将通过比较氧化dna损伤的一系列全面的生物标记物来完成，这些生物标记物包括通过长和短斑块碱基切除修复和利用不同的糖基酶以及通过 核苷酸切除修复。这些研究将检验氧化DNA损伤的剂量-反应关系，并将其与P450诱导、细胞增殖以及在DBF的情况下，大量DNA加合物的32P-后标记研究进行比较。此外，它还将对哈德逊河和污染较少的水道中暴露于不同混合物和数量的多环芳烃、多氯联苯和二恶英的鱼类进行类似的研究。将与纽约大学SBRP合作，在实验室中暴露于类似的危险化学品混合物中，以调查对多氯联苯毒性的抗性发展以及生命阶段对这些制剂的敏感性差异。最后，我们将继续我们对氧化DNA的基础研究 损伤和修复，以加深我们对DNA损伤和修复的生物学及其对环境健康和个人易感性的影响的理解。长期目标将是深入了解这些化学品是如何造成毒性的，以及它们在什么条件下会引起反应。这些数据将填补将影响低剂量外推基础的关键知识空白，并改善风险评估和制定补救标准的科学基础。我们将通过进行生物标记物分析、提供数据或确定各种环境化学物质或其代谢产物造成DNA氧化损伤的能力，与该计划的其他科学项目进行互动。这项研究还将大量使用化学和分析核心以及数学和统计分析与建模核心。

The research of this project will utilize newly developed biomarkers of oxidative stress to evaluate the mode of action and dose response of hazardous chemicals of importance to Superfund sites. Our studies will primarily address effects of polyhalogenated and polycyclic aromatic hydrocarbons including dibenzo(a,l)pyrene (DBF), RGBs and dioxin. These studies will analyze snap frozen tissues from two of the largest and best characterized carcinogenicity bioassays: the NTP Toxic Equivalency Factor studies on PCBs and dioxin in rats; and the ED(0.1) DBF study in rainbow trout. We hypothesize that oxidative stress is an important mode of action for toxicity and carcinogenesis. These studies will be accomplished by comparing a comprehensive series of biomarkers for oxidative DNA damage that includes lesions removed by long and short patch base excision repair and utilizes different glycosylases, as well as by nucleotide excision repair. The studies will examine dose-response relationships for oxidative DNA damage and compare this with P450 induction, cell proliferation, and in the case of DBF, 32P-postlabeling studies of bulky DNA adducts. In addition, it will conduct similar research on fish from the Hudson River and less polluted waterways that have exposures to different mixtures and amounts of PAHs, PCBs and dioxins. In collaboration with the NYU SBRP, laboratory exposures to similar mixtures of hazardous chemicals will be conducted to investigate the development of resistance to PCBs toxicity and differences in life stage susceptibility to these agents. Finally, we will continue our basic research on oxidative DNA damage and repair to further our understanding of the biology of DNA damage and repair, and its implications for environmental health and individual susceptibility. The long term goals will be to develop an in-depth understanding of how these chemicals cause toxicity and under what conditions they elicit responses. These data will fill critical gaps in knowledge that will impact the basis of low dose extrapolation and improve the scientific basis of risk assessment and the setting of remediation standards. We will interact with each of the other scientific projects of this program by performing biomarker analyses, providing data or determining the ability of various environ-mental chemicals or their metabolites to cause oxidative DNA damage. The research will also make heavy use of both the Chemistry and Analytical Core and the Mathematical and Statistical Analysis and Modeling Core.