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.

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重要性化学物质对超级基金地点的危险化学物质的作用方式和剂量反应。我们的研究将主要解决多面化和多环芳族烃的影响，包括二苯并（a，l）pyrene（dbf），RGB和二恶英。这些研究将分析来自两个最大，最佳的致癌性生物测定的快照冷冻组织：大鼠PCB和二恶英的NTP毒性等效因子研究；以及彩虹鳟鱼中的ED（0.1）DBF研究。我们假设氧化应激是毒性和致癌作用的重要作用方式。这些研究将通过比较一系列用于氧化DNA损伤的综合生物标志物来完成，其中包括通过长和短斑块碱基切除修复去除的病变，并利用不同的糖基化酶以及通过 核苷酸切除修复。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，细胞增殖以及在DBF的32p Postlabeling研究中进行比较。此外，它将对哈德逊河的鱼类以及污染较少的水道进行类似的研究，这些水域暴露于不同的混合物和数量的PAH，PCB和二恶英。将与NYU SBRP合作，将进行实验室暴露于类似的危险化学物质混合物，以研究对PCB的毒性抗性的发展，以及生命阶段对这些药物的敏感性的差异。最后，我们将继续有关氧化DNA的基础研究 损坏和维修，以进一步了解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。长期目标将是对这些化学物质如何引起毒性以及在什么条件下引起反应的深入了解。这些数据将填补知识的关键空白，这将影响低剂量外推的基础，并改善风险评估的科学基础和修复标准的设定。我们将通过执行生物标志物分析，提供数据或确定各种环境化学物质或其代谢产生氧化DNA损伤的能力，与该程序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。