Lung mitochondrial DNA copy number, inflammatory biomarkers, gene transcription and gene methylation in vapers and smokers
Kellie M. Mori,
Joseph P. McElroy,
Daniel Y. Weng,
Sangwoon Chung,
Paolo Fadda,
Sarah A. Reisinger,
Kevin L. Ying,
Theodore M. Brasky,
Mark D. Wewers,
Jo L. Freudenheim,
Peter G. Shields,
Min-Ae Song
Affiliations
Kellie M. Mori
Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, OH, United States
Joseph P. McElroy
Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, OH, United States
Daniel Y. Weng
Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, OH, United States
Sangwoon Chung
Pulmonary and Critical Care Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States
Paolo Fadda
Genomics Shared Resource, The Ohio State University and James Cancer Hospital, Columbus, OH, United States
Sarah A. Reisinger
Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, OH, United States
Kevin L. Ying
Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, OH, United States
Theodore M. Brasky
Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, OH, United States
Mark D. Wewers
Pulmonary and Critical Care Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States
Jo L. Freudenheim
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, United States
Peter G. Shields
Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, OH, United States; Corresponding author at: Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, 460 W. 10th Avenue, 9th Floor, Suite D920, Columbus, OH 43210-1240, United States.
Min-Ae Song
Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, OH, United States; Corresponding author at: College of Public Health, Division of Environmental Health Sciences, 404 Cunz Hall, 1841 Neil Ave. Columbus, OH 43210, United States.
Summary: Background: Mitochondrial DNA copy number (mtCN) maintains cellular function and homeostasis, and is linked to nuclear DNA methylation and gene expression. Increased mtCN in the blood is associated with smoking and respiratory disease, but has received little attention for target organ effects for smoking or electronic cigarette (EC) use. Methods: Bronchoscopy biospecimens from healthy EC users, smokers (SM), and never-smokers (NS) were assessed for associations of mtCN with mtDNA point mutations, immune responses, nuclear DNA methylation and gene expression using linear regression. Ingenuity pathway analysis was used for enriched pathways. GEO and TCGA respiratory disease datasets were used to explore the involvement of mtCN-associated signatures. Findings: mtCN was higher in SM than NS, but EC was not statistically different from either. Overall there was a negative association of mtCN with a point mutation in the D-loop but no difference within groups. Positive associations of mtCN with IL-2 and IL-4 were found in EC only. mtCN was significantly associated with 71,487 CpGs and 321 transcripts. 263 CpGs were correlated with nearby transcripts for genes enriched in the immune system. EC-specific mtCN-associated-CpGs and genes were differentially expressed in respiratory diseases compared to controls, including genes involved in cellular movement, inflammation, metabolism, and airway hyperresponsiveness. Interpretation: Smoking may elicit a lung toxic effect through mtCN. While the impact of EC is less clear, EC-specific associations of mtCN with nuclear biomarkers suggest exposure may not be harmless. Further research is needed to understand the role of smoking and EC-related mtCN on lung disease risks. Funding: The National Cancer Institute, the National Heart, Lung, and Blood Institute, the Food and Drug Administration Center for Tobacco Products, the National Center For Advancing Translational Sciences, and Pelotonia Intramural Research Funds.
