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Effects of side stream tobacco smoke on DNA deletions

Institution: University of California, Los Angeles
Investigator(s): Mitsuko Yamamoto, B.S.
Award Cycle: 2005 (Cycle 14) Grant #: 14DT-0121 Award: $58,876
Subject Area: Cancer
Award Type: Dissertation Awards

Initial Award Abstract
Secondhand smoke can be thought of as harmful on many levels such as damaging small molecules like DNA, or causing oxidative stress to cells, resulting in diseases such as cancer and heart disease. In addition, secondhand smoke is difficult to reproduce in a laboratory setting, so often side stream tobacco smoke (SSTS) is used, which makes up about 85% of secondhand smoke. Studying the effects of secondhand smoke has been difficult, however in part because animals used in research have not responded to secondhand smoke in the same way as humans. To facilitate the response of animals to SSTS exposure, I am proposing to use mice which are deficient in the repair of DNA, specifically DNA in which oxygen atoms have been added (oxidized DNA), altering its properties. Tobacco smoke is thought to cause such an alteration in DNA, thus these animals should be more sensitive to exposure. To study the effects of SSTS on mice, I will look at the frequency of DNA deletions which occur in a specific section of DNA. The deletion of DNA is an indication of genetic instability, or that the DNA is being damaged. Damaged or altered DNA is often the first step in how cancer starts. Since being able to see where DNA may have been deleted in a sequence of DNA is difficult, I will be using mice in which the occurrence of a DNA can be visually quantified. The assay can be used to score the frequency of DNA deletions in a specific sequence of DNA. A valuable analysis to assess a cause and effect relationship is to use increasing amounts of a chemical, drug or toxin to induce an increasing effect, which is called a dose-response curve. In this research project, I am proposing to find a dose-response relationship between SSTS concentration and the frequency of deletions. Because I will also be using mice which lack certain enzymes required for repairing DNA, the results of this study will also give insight into mechanisms of cancer predisposition. For example, if mice deficient in the repair of oxidized DNA have an increase in DNA deletions compared to normal mice, it can be inferred that humans deficient in the repair of oxidized DNA may also be more susceptible. Results from this study may also suggest treatments to prevent DNA from becoming damaged like anti-oxidant supplementation. Finally, if the mice used in this study show a dose-response association to SSTS, they may be useful as models for further cancer studies.