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Genotoxic effects of alternative tobacco products & alcohol

Institution: Beckman Research Institute of the City of Hope
Investigator(s): Timothy O'Connor, Ph.D.
Award Cycle: 2019 (Cycle 28) Grant #: 28IR-0050 Award: $1,297,500
Subject Area: Environmental Exposure/Toxicology
Award Type: High Impact Research Project Award

Initial Award Abstract

Overwhelming evidence that cigarette smoke causes cancer as well as other serious illnesses and subsequent falling sales of traditional tobacco products has led tobacco companies to develop electronic cigarettes (e-cigs)and other alternative products. E-cigs are more socially acceptable compared to smoking cigarettes and perceived as less toxic, so there may be advantages to using e-cigs, but users could “vape” for 30-50 years. However, the long-term health effects of e-cigs remain undefined. In addition to vaping, alcohol is an extremely popular recreational drug. Alcohol use by smokers increases cancer risk more than does the use of either drug alone. Similarly, combined e-cig and alcohol use could potentially increase the user’s danger of developing cancers. Despite that possibility, only limited research has been done on long-term health risks of e-cigs and alternatives, much less on the popular combination of e-cigs and alcohol. Thus, there is a need to evaluate the cancer risks from combined e-cig and alcohol use. Although cancers generally develop in normal cells that survive exposure to chemicals or radiation, these surviving cells often have changes in their DNA that make them become cancerous. Determining how likely a product, such as e-cigs, is to cause DNA changes (also known as genotoxicity) is one way to predict if a chemical can cause cancer. Evaluating genotoxicity is a better predictor of cancer risk, but complementary to ways that focus on measuring cell survival after exposure to a chemical. Genotoxicity can be subdivided into changes in a single DNA position (e.g., a G becoming an A) and large changes in chromosomes (in which large pieces of DNA are lost or moved to incorrect locations). Both types of genotoxicity increase the chances that cells will become cancerous, and therefore, both types of changes must be evaluated. Our goal in this proposal is to develop methods to evaluate both types of genotoxicity for e-cigs, and thus document the cancer risks that e-cigs present to humans. We will develop methods that evaluate the genotoxicity of e-cigs and their e-liquids in combination with alcohol and compare those to genotoxicity of tobacco with alcohol. For our proposed studies, we will focus on a single brand of e-cig that is popular and has a refillable reservoir. Our studies will also provide mechanistic information on the ways that incorrect DNA changes can be fixed by DNA repair pathways. In human cells, there are currently nine known ways that cells can fix DNA changes caused by different compounds found in the environment. We will eliminate each of those DNA repair systems to determine which protect cells against compounds in e-cigs to identify possible ways to eliminate or protect against harmful DNA changes. We will also determine the genotoxicity of e-cigs and alcohol in human cells grown in a flask. We will also evaluate risks in mice exposed to e-cigs, a new tobacco alternative heat-not-burn cigarettes, or tobacco smoke and alcohol as a controlled model for human exposure. Finally, we will survey a group of volunteers about their use of e-cigs and/or alcohol and associate this use with genotoxicity indicators in the individuals. Thus, our results will be directly applicable to human health by providing the first information about the genotoxicity of e-cigs and alcohol use. Our findings will also establish a basis for further human studies on risks and use of e-cigs and alcohol by yielding an estimate of the mutation risk posed to humans by e-cigs and alcohol. Ultimately, our methods and the information we gain on mechanism and genotoxicity will improve our ability to assess the potential human health impact of e-cigs and alcohol and could potentially improve early diagnosis by identifying early indicators of cancer. Furthermore, we will leverage our established relationships within the community to ensure broad dissemination of our results. These discoveries will enable policymakers and health care professionals to inform the public in a responsible manner and guide both public policy and personal decisions.