Abstract
BackgroundDevelopmental exposure to particulate matter air pollution is harmful to cardiovascular health, but the mechanisms by which this exposure mediates susceptibility to heart disease is poorly understood. We have previously shown, in a mouse model, that gestational exposure to diesel exhaust (DE) results in increased cardiac hypertrophy, fibrosis and susceptibility to heart failure in the adult offspring following transverse aortic constriction.ResultsIn this study, we have analyzed gene expression in neonatal cardiomyocytes after gestational exposure by RNA-sequencing and have identified 300 genes that are dysregulated, including many involved in cardiac metabolism. We subsequently determined that these cardiomyocytes exhibit reduced metabolic activity as measured by Seahorse extracellular flux analysis. We also surveyed for modifications in DNA methylation at global regulatory regions using reduced representation bisulfite sequencing and found hypomethylation of DNA in neonatal cardiomyocytes isolated from in utero DE exposed neonates.ConclusionWe have demonstrated that in utero exposure to diesel exhaust alters the neonatal cardiomyocyte transcriptional and epigenetic landscapes, as well as the metabolic capability of these cells. Understanding how exposure alters the developing heart through dysregulation of gene expression, metabolism and DNA methylation is vital for identifying therapeutic interventions for air pollution-related heart failure.
Highlights
Developmental exposure to particulate matter air pollution is harmful to cardiovascular health, but the mechanisms by which this exposure mediates susceptibility to heart disease is poorly understood
In utero exposure to DE results in altered gene expression To assess alterations in transcription due to in utero exposure to DE (dams were exposed to a time weighted hourly average of 53 μg/m3 diesel exhaust-created PM2.5, 5 days a week from embryonic day 0.5 (E0.5) to E17.5), RNA-seq was performed on isolated neonatal cardiomyocyte (NCM) from filtered air (FA) and DE postnatal day 0 (PND0) offspring
We can see a clear link between exposure and altered transcription of genes that affect cellular metabolism, showing a consistent decrease in expression in the DE NCMs
Summary
Developmental exposure to particulate matter air pollution is harmful to cardiovascular health, but the mechanisms by which this exposure mediates susceptibility to heart disease is poorly understood. In a mouse model, that gestational exposure to diesel exhaust (DE) results in increased cardiac hypertrophy, fibrosis and susceptibility to heart failure in the adult offspring following transverse aortic constriction. Exposure to particulate matter air pollution has been associated with increased incidence of cardiovascular disease [1,2,3], including arrhythmias [4], myocardial infarction [3] and heart failure [5]. Prenatal and early-life exposure to PM2.5 and PM10 is associated with deleterious effects, such as decreased placental mitochondrial DNA [6], decreased fetal growth [7], reduced birth weight [8] and increased newborn systolic blood pressure [9]. We have previously shown hypomethylation in exon 1 of GM6307 in neonatal cardiomyocytes (NCMs) resulting from in utero exposure to DE, which correlates with dysregulation of the contiguous miR133a-2 gene [22]
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