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Epigenetic Biomarkers of Tobacco Smoke Exposure

Principal Investigator: Douglas Bell

Funding Mechanism: National Institutes of Health-Intramural

ID number: 251945

Award Date: 10/1/2012

Institution: National Institute of Environmental Health Sciences (NIEHS)

In previous research, the investigators used genomic arrays to identify specific DNA methylation changes associated with maternal smoking; they have identified a set of epigenetic biomarkers as well as mechanistic pathways for transplacental and adult smoking-associated diseases. The goal of the study is to extend these findings by examining the dose, time course, and persistence of the epigenetic changes spurred by tobacco product use, identifying the target cells for epigenetic-mediated change, and characterizing toxic effects at the molecular and cellular level. Study aims are: (1) to test the previously-developed methylation biomarker profile in DNA samples from 230 adult subjects with well-characterized smoking histories including measurements of cotinine, chromosome aberrations, somatic gene mutations, and genetic polymorphisms; (2) to conduct a prospective cohort study (including approximately 500 subjects with smoking-induced bladder cancer and 500 controls) to test the relationship between tobacco exposure, methylation biomarkers, and risk of developing tobacco-induced bladder cancer in order to evaluate the biomarkers’ predictive value; (3) to test the methylation biomarker in blood and other tissues from newly-recruited tobacco product users in order to determine the best tissue for regulatory-related population monitoring, assess profiles of DNA methylation and identify biomarkers that are shared by or unique to a specific tobacco exposure, and examine samples from recent quitters to determine the persistence of biomarkers; subjects will include never smokers, light smokers (<1pack day),="" heavy="" smokers="" (="">1 pack day), ex-smokers (6-12 months), menthol smokers, smokeless tobacco users, and e-cigarette users; and (4) to determine target cell types in blood (i.e., lymphoid, granulocytes, erythroid, and CD34+ cells) and compare the relationship between exposure, methylation, and gene expression to improve accuracy and sensitivity of the tobacco exposure biomarker. This study will reveal important epigenetic biomarker effects related to tobacco use, particularly with regard to the specific cell types affected, and will make connections between epigenetic biomarkers of effect, intermediate molecular phenotypes and tobacco-induced disease outcomes that could support regulatory review of the biomarker.

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