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.

总结： 我的这一研究领域验证了环境暴露会产生DNA损伤模式的假设。这种模式既可用于识别靶基因，也可用于提示环境因子导致癌症的突变机制。如果特定的致癌物在肿瘤中产生基因突变的特征模式，那么这些模式的检测将是环境风险研究以及用于预防、早期诊断和预后的有力工具。我们正在我们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。长期目标是开发正常组织中DNA突变水平或“体细胞突变负荷”的定量测量。这种度量可以提供终生环境暴露的组织特异性测量，整合饮食，遗传易感性和修复，并可能提供癌症，神经系统，生殖和其他疾病的风险更精确的估计，其中DNA损伤起作用。 荧光支气管镜检查和异常支气管病变的分子表征（LIFE研究）： 我们已经建立了一个前瞻性研究的人在高风险发展为肺癌，旨在测试是否在正常和癌前支气管上皮细胞的分子变化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，是一种检测癌前病变和原位癌（CIS）的敏感方法，可以随着时间的推移以前瞻性的方式检测、活检和随访癌前病变。随着时间的推移，每个单独病变的多个活检被收集，使我们能够识别与暴露相关的突变模式，并提供更好的肺癌风险，进展和预后估计。 结肠细胞DNA损伤研究： 饮食暴露与结直肠癌风险有关。这类药物可能通过引起DNA损伤来增加风险，或通过保护免受DNA损伤来降低风险。例如，在高温下烹饪的肉类中形成的杂环芳香胺，特别是通过平底锅油炸，在体外诱导DNA损伤和突变，增加啮齿动物的肿瘤形成，并可能增加人类结直肠腺瘤和癌症的风险11，12。其他膳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、叶绿酸和酸奶13 -15。然而，尚未在人类结肠组织中直接评估暴露于这些化合物引起或预防DNA损伤的效果。基于先前的动物和人类研究结果，我们假设在一项控制喂养研究中，人类每天接触熟透的煎肉将导致结肠细胞DNA损伤的可测量增加，并且这种损伤可以在食用十字花科蔬菜，叶绿酸表和酸奶沿着熟透的肉的受试者中得到抑制。作为调查这些假设的初步步骤，我们进行了一项饮食因素和DNA损伤的初步研究，涉及16名健康志愿者，进行为期四周的控制喂养研究。我们在这项初步研究中的目的是确定1）摄入油炸肉类和这些推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）为了检测这些影响，必须食用这些饮食的时间长度。本研究的结果将用于确定更大规模研究的可行性和设计。