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. 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. In 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. We 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.

中文翻译：

---

子宫内暴露于柴油机尾气与新生儿心肌细胞转录、DNA 甲基化和代谢扰动的改变有关


发育过程中接触颗粒物空气污染对心血管健康有害，但人们对这种接触介导心脏病易感性的机制知之甚少。我们之前在小鼠模型中表明，妊娠期暴露于柴油机尾气（DE）会导致成年后代在横主动脉缩窄后心脏肥大、纤维化和心力衰竭的易感性增加。在这项研究中，我们通过 RNA 测序分析了妊娠暴露后新生儿心肌细胞的基因表达，并确定了 300 个失调的基因，其中包括许多与心脏代谢有关的基因。我们随后确定，通过海马细胞外通量分析测量，这些心肌细胞表现出代谢活性降低。我们还使用简化代表性亚硫酸氢盐测序调查了全球监管区域 DNA 甲基化的修饰，发现从子宫内暴露于 DE 的新生儿中分离出的新生儿心肌细胞中 DNA 低甲基化。我们已经证明，在子宫内暴露于柴油尾气会改变新生儿心肌细胞的转录和表观遗传景观，以及这些细胞的代谢能力。了解暴露如何通过基因表达、代谢和 DNA 甲基化失调来改变发育中的心脏，对于确定空气污染相关心力衰竭的治疗干预措施至关重要。