Doctoral Dissertations: Jamie Goodson
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University of Washington
- Faculty Sponsor
Transcriptional, metabolic and epigenetic changes associated with in utero diesel exhaust particulate exposure
Epidemiological studies have demonstrated that exposure to particulate matter air pollution is harmful to cardiovascular health, and recent work has shown that exposure during development can affect fetal outcomes in humans, such as decreased newborn weight and increased blood pressure. We have previously shown, in a mouse model, that gestational exposure to diesel exhaust (DE) causes placental inflammation, as well as increased cardiac hypertrophy, fibrosis and susceptibility to heart failure in the adult offspring following transverse aortic constriction (TAC). To identify potential transcriptional effects that mediate this susceptibility, we have performed RNA‐seq analysis on neonatal cardiomyocytes from mice exposed to diesel exhaust in utero, as well as on adult hearts that have undergone transverse aortic constriction. We have identified a neonatal cardiomyocyte dysregulation of 300 genes, including many involved in cardiac metabolism. In the adult hearts, we have identified three target genes, Mir133a‐2, Ptprf and Pamr1, which demonstrate dysregulation after exposure and aortic constriction. These target genes in the heart are the first to be identified that likely play an important role in mediating DE‐related adult sensitivity to heart failure. We followed up on the identified neonatal transcriptional dysregulation by determining whether cardiomyocytes from mice exposed in utero to diesel exhaust have impaired metabolic activity, and observed that the neonatal cardiomyocytes exhibit reduced metabolic activity as measured by pyruvate/glutamate‐fueled oxygen consumption. Due to the delay between exposure and phenotype, alterations in DNA methylation were also examined, and we found hypomethylation both globally at CpG‐rich regions and in the first exon of GM6307, the gene miR133a‐2 is intronically embedded in. Identifying dysregulation of pathways important to normal cardiac function will lead to the pathological cellular alterations that cause diesel‐related heart failure. 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.