In utero exposure to diesel exhaust particulates is associated with an altered cardiac transcriptional response to transverse aortic constriction and altered DNA methylation.. Mus musculus

In utero exposure to diesel exhaust particulates has been associated with increased adult susceptibility to heart failure in mice but the mechanisms by which this exposure promotes susceptibility are poorly understood. To identify potential transcriptional effects that mediate this susceptibility, we have performed RNA-seq analysis on adult hearts from mice exposed to diesel exhaust in utero and that have subsequently undergone transverse aortic constriction. We identified three target genes, Mir133a-2, Ptprf and Pamr1, which demonstrate dysregulation after exposure and aortic constriction. Examination of expression patterns in human heart tissue indicate a correlation between expression and heart failure. We subsequently examined for DNA methylation modifications at these candidate loci in neonatal cultured cardiac myocytes after in utero exposure to diesel exhaust and found that the promoter for Mir133a-2 is differentially methylated. Overall design: Female mice were paired with male mice for timed mating in filtered air (FA). After observation of a vaginal plug, pregnant mice were put into FA or diesel exhaust (DE) with exposures beginning at E0.5 and lasting until E17.5. Neonates were used for neonatal cardiomyocyte preparation or saved for adult surgery. Offspring were raised in FA until 11 weeks, at which time they underwent baseline echocardiography and transverse aortic constriction at 12 weeks using a 27-gauge needle. Hearts from these mice were harvested at 15 weeks, rapidly frozen in liquid nitrogen and stored at -80C prior to RNA isolation.