E-cigarettes Epigenetically Augment Transgenerational Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) disease is a common, morbid and highly lethal disease. Importantly, there are currently no therapeutic strategies that limit the growth of AAAs, due in part to a lack of understanding of the mechanisms of disease and progression. In addition to advanced age, genetic predilection, and male sex, the most crucial risk factor for AAA is a history of smoking, and at present, smoking cessation is considered the most effective approach to decreasing AAA incidence. The recent explosion in popularity of e-cigarette “vaping” has also raised urgent questions as to the short and long-term impacts on vascular disease risk. Published work from our laboratory has shown that both subcutaneous infusion of the major tobacco component, nicotine, and inhaled e-cigarette nicotine vapor, augment experimental AAA. It has been recently appreciated that exposure to tobacco smoke, nicotine, and vaping can cause cellular epigenetic alterations, and that in some cases these effects can be transmitted in a transgenerational fashion - not only in animal models, but also in humans. We have new data showing that both infused nicotine and e-cig vaping in mice augments AAA in their progeny. Additionally, with parental exposure we observed thousands of genome alterations within the blood and tissues of both parents and offspring, including changes to both DNA methylation and accessibility. In particular we find changes in “imprinted” genes, capable of transmitting cardiovascular disease risk epigenetically to subsequent generations. The outlined studies in this proposal will examine the effects of nicotine and e-cigarette vapor on the cellular epigenetic machinery in vitro and in vivo, with a particular emphasis on heritable changes capable of augmenting AAA. In order to verify the specific mechanisms involved, we will also seek to inhibit their impact on transgenerational AAA risk. In Specific Aim 1, we will determine the impact of e-cigarette vapor and infused nicotine on epigenetic patterning and imprinted gene expression in germ cells and evaluate these effects over time in mice using multi-omic high-throughput methods. For Specific Aim 2 we will examine the effects of these epigenetic changes on cellular signaling pathways known to be crucial for AAA pathophysiology. Finally, in Specific Aim 3 we will seek to inhibit e-cigarette-induced DNA alterations, with a view to preventing transgenerational AAA augmentation during a multi-generation in vivo time course. These specific aims will provide key information regarding the potential transgenerational risk of e-cigarette use on vascular disease, and form the basis for advancing future research and clinical translation, including potential screening for high-risk epigenetic changes in humans. Project Number: 1R01HL179076-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: JOSHUA SPIN | Institution: PALO ALTO VETERANS INSTIT FOR RESEARCH, PALO ALTO, CA | Award Amount: $355,000 | Activity Code: R01 | Study Section: Atherosclerosis and Vascular Inflammation Study Section[AVI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17907601