Abstract 128: Nicotine Transgenerationally Alters Gene Methylation And Abdominal Aortic Aneurysm Risk

Abstract

Significance: Both smoking and family history are major risk factors for abdominal aortic aneurysm (AAA). Smoking is a powerful modulator of DNA methylation, and nicotine alone can cause heritable epigenetic alterations in animal models and humans. Nicotine also increases aortic stiffness, predisposing towards AAA. We investigated the effects of parental nicotine exposure in mice on their offspring’s risk for experimental AAA and on transgenerational DNA methylation. Methods: Male and female Apo E-/- mice (F0) were exposed to subcutaneous nicotine (25 mg/kg/day) or saline infusion for 28 days. After treatment completion, mice were mated to untreated controls. F1 generation offspring underwent Angiotensin II infusion (1μg/kg/min) to induce AAA at age 10-weeks. Aneurysm growth was tracked via ultrasound over 28 days. Subgroups of F1 mice underwent ex-vivo pressure myography assessment of the abdominal aorta. Germ and aortic tissue from both F0 and F1 were evaluated using RRBS-Seq genome-wide DNA methylation analysis. Results: Parental nicotine augments model AAA formation, incidence, and rupture rates in their offspring. This effect was most significant in male offspring of nicotine-exposed females (vs. saline). Maternal nicotine exposure also increased F1 aortic stiffness. F0 nicotine exposure altered DNA methylation in multiple tissues, and led to numerous significant differentially methylated regions (DMRs) in their F1 offspring, many precisely conserved. Nicotine caused global DNA hypermethylation, altered maternally imprinted genes in F0 females, and had variable patterns depending on gender. Nicotine altered aortic methylation patterns in genes known to relate to AAA development, including lncRNAs/miRNAs. DMR pathway analysis revealed enrichment for transcription factors, suggesting that nicotine transgenerationally influences numerous genes through expression modulation. Conclusion: Nicotine exposure can augment experimental AAA growth and aortic stiffness across generations. These effects are accompanied by widespread epigenetic changes in germ tissue and aorta, including several key AAA modulator genes, with enrichment in transcription factors, including many targeting known AAA-related genes.