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： 我的这一研究领域检验了环境暴露会产生 DNA 损伤模式的假设。这种模式既可以用来识别靶基因，也可以用来提示环境因素导致癌症的突变机制。如果特定的致癌物在肿瘤中产生特征性的基因突变模式，那么对这些模式的检测将成为环境风险研究以及预防、早期诊断和预后的有力工具。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，这些研究旨在观察来自靶组织的癌前组织和正常组织以及正常淋巴细胞的小活检中的 DNA 损伤。长期目标是开发一种定量测量正常组织中 DNA 突变水平或“体细胞突变负荷”的方法。这样的指标可以提供一生中环境暴露的组织特异性测量，整合饮食、遗传易感性和修复，并且可以更精确地估计癌症、神经系统疾病、生殖疾病和其他 DNA 损伤发挥作用的疾病的风险。 荧光支气管镜检查和异常支气管病变的分子特征（LIFE 研究）： 我们针对肺癌高危人群开展了一项前瞻性研究，旨在测试正常和癌前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)，这是一种支气管镜检查技术，是检测癌前病变和原位癌 (CIS) 的敏感方法，可随着时间的推移以前瞻性方式检测、活检和跟踪癌前病变。随着时间的推移，对每个单独病变进行多次活检，使我们能够识别与暴露相关的突变模式，并更好地估计肺癌风险、进展和预后。 结肠细胞 DNA 损伤研究： 饮食暴露与结直肠癌风险有关。此类试剂可能会通过引起 DNA 损伤来增加风险，或者可能会通过防止 DNA 损伤来降低风险。例如，在高温烹饪（特别是煎炸）的肉类中形成的杂环芳香胺会在体外诱导 DNA 损伤和突变，增加啮齿动物的肿瘤形成，并可能增加人类患结直肠腺瘤和癌症的风险。人类11,12。其他膳食成分已被确定为杂环胺诱导的基因毒性的抑制剂，包括十字花科蔬菜、叶绿素和酸奶13-15。然而，尚未在人类结肠组织中直接评估接触这些化合物对造成或预防 DNA 损伤的影响。根据之前的动物和人类研究结果，我们假设，在一项受控喂养研究中，人类每天接触全熟的煎肉会导致结肠细胞 DNA 损伤显着增加，并且这种损伤可能是由在食用十字花科蔬菜、叶绿素片、酸奶以及熟肉的受试者中，这种作用受到抑制。作为调查这些假设的初步步骤，我们对饮食因素和 DNA 损伤进行了一项试点研究，其中 16 名健康志愿者参与了为期 4 周的控制喂养研究。我们在这项试点研究中的目的是确定 1) 摄入炸肉和这些假定的抑制剂后对结肠细胞和淋巴细胞 DNA 损伤的影响程度，以及 2) 为了产生这些影响，必须食用这些饮食的时间长度被检测到。这项研究的结果将用于确定更大规模研究的可行性和设计。