The impact of nicotine exposure and cigarette smoking on gene expression and behavior from a translational perspective

Open Access
- Author:
- Silva Gallardo, Constanza Paulina
- Graduate Program:
- Biobehavioral Health
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 24, 2021
- Committee Members:
- Dajiang Liu, Outside Unit Member
David Vandenbergh, Major Field Member
Steven Branstetter, Outside Field Member
Helen Kamens, Chair & Dissertation Advisor
Thomas Gould, Program Head/Chair - Keywords:
- gene expression
genomics
smoking
nicotine
translational
cigarette smoking
reduced nicotine-content cigarettes
RNA-Seq
DNA methylation
sex differences - Abstract:
- Worldwide, smoking remains a threat to public health, causing preventable diseases and premature mortality. Combustible cigarettes create dependence since tobacco contains nicotine, a highly addictive chemical compound. Cigarette smoke is a potent inducer of DNA methylation and gene expression alterations. Changes in these genomic marks are valuable tools to understand how the genome interacts with environmental exposures, leading to physiological responses, behavioral alterations, and disease states. However, nicotine exposure and cigarette smoking occur at multiple developmental stages, have different durations, as well as varying doses (depending on the cigarette yield). Little is known about nicotine and cigarette smoking effects on genomic marks in these different scenarios. Thus, this dissertation aimed to identify nicotine- and cigarette smoking-induced alterations on genomic marks under different exposure scenarios. I included different developmental stages (adolescence and adulthood), tissues (brain and blood), duration span (acute and chronic), and nicotine doses. The studies in this dissertation were conceived from a translational approach, being laid out to mimic how nicotine and cigarette smoke exposure commonly occur throughout life: initiation during adolescence, persistent smoking during adulthood, and attempts to decrease cigarette-smoking associated risks using reduced nicotine content (RNC) cigarettes. First, I focused on determining the mechanisms by which nicotine exposure during adolescence can alter neurodevelopment and subsequent alcohol intake using female mice (Chapter 2). I found that prior nicotine exposure increases alcohol consumption and resulting alcohol concentrations in blood (BEC, mg%). These behavioral responses could be mediated by changes in brain gene expression and biological pathways associated with corticotrophin-releasing hormone signaling, neurogenesis (Arc, Nr4a1, and Fos), anorectic effects (Pomc), or stress-induced neuronal activation (Avp). Second, I collated genes reported to be both differentially expressed and methylated among smokers (Chapter 3). I showed that frequently reported differentially expressed genes (DEG) that contained methylated sites in smokers are associated with cell growth, cell differentiation, inflammation, and immune responses (AHRR, CYP1B1, TNF, RARA, E2F1, GFI1, and RUNX3). Finally, I presented the dose-dependent effects of nicotine exposure on blood gene expression in smokers. For this, I used Spectrum research cigarettes with either a High (10.9 mg/cig), Medium (3.2 mg/cig), or Very Low (0.2 mg/cig) nicotine content (Chapter 4). Here, I reported that DEG were cigarette- and sex-specific. Specifically, sex-specific mechanisms underlay common physiological responses to cigarette smoking, including nicotine metabolism (NOS2, SULT1C2, NOS1, CYP19A1, and SULT1A3/SULT1A4) and stress-related responses (LHB, NOS2, and NOS1). Overall, these findings show that gene expression is a useful proxy to understand the mechanism by which nicotine and cigarette smoke exposure can lead to physiological responses, behavioral changes, and disease states. Moreover, this approach allowed me to unveil sex-specific mechanisms that underlaid shared physiological responses to cigarette smoking. These results provide additional evidence regarding the importance of considering developmental stages and sex differences in prevention and intervention programs aiming to reduce the impact of cigarette smoking.