DNA Adducts as Biomarkers of Exposure and Effect - Biomedical

DNA 加合物作为暴露和效应的生物标志物 - 生物医学

• 批准号: 7067245
• 负责人: JAMES A SWENBERG
• 金额: $ 31.85万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067245
• 关键词: DNA damage; DNA repair; adduct; animal tissue; biomarker; carbopolycyclic compound; dioxins; environmental exposure; halobiphenyl /halotriphenyl compound; hazardous substances; oxidative stress; toxicant screening; water pollution

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.

本项目的研究将利用新开发的氧化应激生物标志物来评估超级基金场地重要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）芘（DBF），RGBs和二恶英。这些研究将分析来自两项最大和最具特征的致癌性生物测定的速冻组织：关于大鼠体内多氯联苯和二恶英的NTP毒性等效因子研究;以及关于虹鳟鱼的艾德（0.1）DBF研究。我们假设氧化应激是毒性和致癌作用的重要模式。这些研究将通过比较氧化DNA损伤的一系列全面的生物标志物来完成，包括通过长和短补丁碱基切除修复和利用不同的糖基化酶去除的损伤，以及通过 核苷酸切除修复。这些研究将检查氧化性DNA损伤的剂量-反应关系，并将其与P450诱导，细胞增殖以及DBF，32 P-后标记的大体积DNA加合物研究进行比较。此外，它还将对来自哈德逊河和污染较轻的水道的鱼类进行类似的研究，这些河流暴露于不同的多环芳烃、多氯联苯和二恶英混合物和数量。与纽约大学SBRP合作，将进行实验室暴露于类似的危险化学品混合物，以调查对多氯联苯毒性的抵抗力的发展以及生命阶段对这些物质敏感性的差异。最后，我们将继续我们对氧化DNA的基础研究 损伤和修复，以促进我们对DNA损伤和修复的生物学的理解，及其对环境健康和个体易感性的影响。长期目标是深入了解这些化学品如何引起毒性以及在何种条件下引起反应。这些数据将填补将影响低剂量外推基础的知识方面的关键空白，并改进风险评估和补救标准制定的科学基础。我们将通过进行生物标志物分析，提供数据或确定各种有害化学物质或其代谢产物引起氧化DNA损伤的能力，与该计划的其他科学项目进行互动。该研究还将大量使用化学和分析核心以及数学和统计分析和建模核心。