Environmental Exposure and DNA Damage

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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.