Environmental Exposure and DNA Damage

环境暴露和 DNA 损伤

• 批准号: 7169677
• 负责人: JACK A TAYLOR
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7169677
• 关键词: Environmental; Exposure; DNA; Damage

Summary: This area of my research tests the hypothesis that environmental exposures produce patterns of DNA damage. Such patterns can be used both to identify target genes and to suggest mutational mechanisms by which an environmental agent causes cancer. If specific carcinogens produce characteristic patterns of gene mutation in tumors, the detection of those patterns would be a powerful tool in studies of environmental risk and for use in prevention, early diagnosis, and prognosis. We are exploring this concept in our ongoing molecular epidemiologic and clinical studies designed to look at DNA damage in small biopsies of preneoplastic and normal tissue from target tissues and in normal lymphocytes. A long term goal is to develop a quantitative measure of the level of DNA mutation in normal tissue or "somatic mutational load". Such a metric could provide a tissue specific measure of lifetime environmental exposure, integrated across diet, genetic susceptibility, and repair, and might offer a more precise estimate of risk for cancer, neurologic, reproductive, and other diseases where DNA damage plays a role. Fluorescence Bronchoscopy and Molecular Characterization of Abnormal Bronchial Lesions (LIFE Study): We have established a prospective study of people at high risk for developing lung cancer that is designed to test whether molecular changes in normal and preneoplastic bronchial epithelium are correlated with exposure or neoplastic progression. We are using the Lung Imaging Fluorescent Endoscope (LIFE), a bronchoscopy technique that is a sensitive method for detecting premalignant lesions and carcinoma in situ (CIS) to detect, biopsy, and follow preneneoplastic lesions in a prospective manner over time. Multiple biopsies of each individual lesion are collected over time, allowing us to identify mutational patterns related to exposure and to provide better estimates of lung cancer risk, progression, and prognosis. Colon Cell DNA Damage Study: Dietary exposures have been implicated in colorectal cancer risk. Such agents may act to increase risk by causing DNA damage or may decrease risk by protecting against DNA damage. For example, heterocyclic aromatic amines, which are formed in meat that is cooked at high temperature, particularly by pan-frying, induce DNA damage and mutations in vitro, increase tumor formation in rodents, and may increase the risk of colorectal adenomas and cancer in humans11,12. Other dietary components have been identified as inhibitors of heterocyclic amine-induced genotoxicity, including cruciferous vegetables, chlorophyllin, and yogurt13-15. However, the effect of exposure to these compounds in causing or preventing DNA damage has not been directly assessed in colon tissues in humans. Based on the results of previous animal and human studies, we hypothesize that daily exposure in humans to well-done, pan-fried meat in a controlled feeding study will result in measurable increases in DNA damage in colon cells, and that such damage can be inhibited in subjects who consume cruciferous vegetables, chlorophyllin tables, and yogurt along with the well-done meat. As a preliminary step toward investigating these hypotheses, we have undertaken a pilot study of dietary factors and DNA damage, involving 16 healthy volunteers in a four-week controlled feeding study. Our aims in this pilot study were to determine 1) the magnitude of effects on DNA damage in colon cells and lymphocytes after ingestion of fried meat and these putative inhibitors, and 2) the length of time these diets must be consumed in order for these effects to be detected. The results of this study will be used to determine the feasibility and design of a larger study.

概括： 我的研究领域检验了以下假设：环境暴露会产生DNA损伤模式。这种模式既可以用来识别靶基因，又提出了环境剂引起癌症的突变机制。如果特定的致癌物在肿瘤中产生基因突变的特征模式，那么对这些模式的检测将是研究环境风险以及用于预防，早期诊断和预后的强大工具。我们正在正在进行的分子流行病学和临床研究中探索这一概念，旨在研究靶组织和正常淋巴细胞中的肿瘤和正常组织的小活检中的DNA损伤。一个长期目标是制定正常组织中DNA突变水平或“体细胞突变负荷”的定量度量。这样的度量可以提供组织特定的终生环境暴露，跨饮食，遗传敏感性和修复的整合，并可能对DNA损害起作用的癌症，神经系统，生殖和其他疾病的风险进行更精确的估计。 荧光支气管镜检查和异常支气管病变的分子表征（生命研究）： 我们已经建立了一项前瞻性研究，该研究旨在测试正常和肿瘤支气管支气管上皮的分子变化是否与暴露或肿瘤进展相关。我们正在使用肺成像荧光内窥镜（LIFE），这是一种支气管镜技术，是一种敏感方法，用于检测原位病变和癌症（CIS）来检测，活检，并随着时间的推移以前瞻性方式遵循前层状病变。随着时间的推移，收集了每个单个病变的多次活检，使我们能够确定与暴露有关的突变模式，并更好地估计肺癌风险，进展和预后。 结肠细胞DNA损伤研究： 饮食暴露与大肠癌风险有关。此类药物可以通过造成DNA损伤或通过防止DNA损伤来降低风险来增加风险。例如，在高温下煮熟的肉中形成的杂环芳香胺，尤其是通过泛粉，在体外诱导DNA损伤和突变，增加啮齿动物的肿瘤形成，并可能增加人类腺瘤和癌症的风险。其他饮食成分已被确定为杂环胺诱导的遗传毒性的抑制剂，包括十字花科蔬菜，叶绿素蛋白和酸奶13-15。但是，在人类的结肠组织中，未直接评估这些化合物在引起或预防DNA损伤中暴露的影响。根据先前的动物和人类研究的结果，我们假设在受控喂养研究中，人类每天暴露于人类身上，泛滥的肉会导致结肠细胞中DNA损伤的可测量增加，并且可以抑制这种损害的受试者，这些受试者在消耗十字中的蔬菜，叶绿素tables和Yogurt以及Yogurt以及良好的食物中。作为研究这些假设的初步步骤，我们对饮食因素和DNA损害进行了试点研究，涉及为期四周的受控喂养研究，涉及16名健康志愿者。我们在这项试验研究中的目的是确定1）摄入油炸肉和这些假定抑制剂后结肠细胞和淋巴细胞中对DNA损伤的影响的大小，以及2）必须消耗这些饮食的时间，以便检测到这些作用。这项研究的结果将用于确定较大研究的可行性和设计。