Environmental Exposure and DNA Damage

荧光支气管镜检查和异常支气管病变的分子特征(LIFE研究)： 我们已经完成了一项针对肺癌高危人群的前瞻性研究的临床部分，该研究旨在测试正常和癌前病变支气管上皮的分子变化是否与暴露或肿瘤进展有关。我们使用了肺成像荧光内窥镜(LIFE)，这是一种检测癌前病变和原位癌(CIS)的敏感方法，随着时间的推移，我们以前瞻性的方式检测、活检和跟踪癌前病变。随着时间的推移，我们收集了每个单独病变的多次活检，使我们能够识别与暴露相关的突变模式，并对肺癌风险、进展和预后提供更好的估计。杂合性丢失的数据分析仍在继续。 结肠细胞DNA损伤研究： 饮食暴露与结直肠癌风险有关。这类制剂可能会造成DNA损伤，从而增加风险，或者可能会通过防止DNA损伤来降低风险。例如，在高温下烹调的肉类中形成的杂环芳胺，特别是通过平底锅煎炸，在体外会导致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。其他饮食成分已被确定为杂环胺引起的遗传毒性的抑制剂，包括十字花科蔬菜、叶绿素和酸奶。然而，暴露在这些化合物中导致或防止DNA损伤的影响尚未在人类的结肠组织中直接评估。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，人类每天接触熟肉、平底锅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、叶绿素桌子和酸奶以及熟肉的受试者中得到抑制。作为研究这些假说的初步步骤，我们已经完成了一项关于饮食因素和DNA损伤的初步研究，16名健康志愿者参与了为期四周的受控喂养研究。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假定的抑制剂后对结肠细胞和淋巴细胞DNA损伤的影响的程度，以及2)为了检测到这些影响必须消费这些饮食的时间长度。这项研究的数据分析仍在继续。

Fluorescence Bronchoscopy and Molecular Characterization of Abnormal Bronchial Lesions (LIFE Study): We have completed the clinical portion of 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 used 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 were collected over time, allowing us to identify mutational patterns related to exposure and to provide better estimates of lung cancer risk, progression, and prognosis. Data analysis for loss of heterozygosity is continuing. 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 humans. Other dietary components have been identified as inhibitors of heterocyclic amine-induced genotoxicity, including cruciferous vegetables, chlorophyllin, and yogurt. 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 completed 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. Data analysis for this study is continuing.