Abstract 19654: Cardiac Epigenetic and Transcriptional Responses to In Utero Diesel Exposure
Introduction: We have previously shown, in a mouse model, that gestational exposure to diesel exhaust causes placental inflammation, as well as increased cardiac hypertrophy, fibrosis and susceptibility to heart failure in the adult offspring following transverse aortic constriction (TAC). We have also found that the hearts of the in utero diesel exhaust (DE) exposed mice show an increased rate of apoptosis following TAC, and that neonatal cardiomyocytes from in utero exposed mice are more susceptible to apoptosis to hydrogen peroxide, suggesting an alteration of the cardiomyocytes that increases sensitivity to apoptotic triggers. The basis for this susceptibility is unknown.
Hypothesis: We hypothesize that in utero exposure to DE alters DNA methylation at specific loci in cardiomyocytes and also alters transcriptional profiles to promote susceptibility to injury.
Methods: We performed reduced representation bisulfite sequencing and RNA sequencing on neonatal cardiomyocytes isolated from p0 pups exposed to DE or filtered air (FA) in utero.
Results: Analysis of CpG-enriched DNA from exposed neonatal cardiomyocytes showed not only global hypomethylation in DE exposed animals, but also 63 specific differentially methylated regions (DRMs). Ingenuity pathway analysis indicates hypomethylation of DRMs associated with genes involved in pathways important for cardiac hypertrophy, beta-adrenergic and GPCR signaling. RNA sequencing showed signficantly dysregulated transcription of 300 genes involved in pathways such as mitochondrial carnitine shuttling, fatty acid oxidation, AMPK signaling, and cell cycle regulation.
Conclusions: In utero exposure to diesel exhaust leads to profound changes in cardiomyocyte DNA methylation and RNA transcription that likely alter beta-adrenergic signaling, cellular energetics and cell cycle regulation. These alterations likely have downstream effects that promote susceptibility to adult injury. Understanding how exposure changes gene expression through dysregulation of DNA methylation or other mechanisms will be vital for identifying therapeutic interventions for air pollution-related heart failure.
Author Disclosures: J.M. Goodson: None. J.W. MacDonald: None. T.K. Bammler: None. Y. Liu: None. M.T. Chin: Ownership Interest; Significant; Founder and CEO of TransCellular Therapeutics.
- © 2016 by American Heart Association, Inc.