Effects of in utero Diesel Exhaust Exposure on Development of Atherosclerosis in Hyperlipidemic Mice

Abstract

Coronary artery disease, commonly manifested as atherosclerosis, is a leading cause of death in western countries. There is substantial evidence of the detrimental effect of particulate matter (PM) exposure on cardiovascular morbidity, and diesel exhaust (DE) is a substantial contributor to urban atmospheric PM levels. However, there is little evidence of the impact of in utero exposure to PM on long-term health effects. It is hypothesized that in utero exposures could permanently affect fetus health through an epigenetic phenomenon termed "fetal programming," in which fetal exposures alter gene expression through adulthood. The current study aims to elucidate the effect of in utero DE exposure on atherosclerosis development in adulthood in hyperlipidemic Apo E -/- mice. The study consisted of three treatment groups: a control group in which pregnant mice were exposed to filtered air (FA) during pregnancy and the pups were exposed to FA post-birth (FA/FA); a group in which pregnant mice were exposed to DE during pregnancy and the pups were exposed to FA post-birth (DE/FA); and a group in which pregnant mice were exposed to DE during pregnancy and the pups were exposed to DE post-birth until weaning, at which point they were switched back to FA (DE/DE). Thoracic aortas were analyzed for RNA sequencing in male mice at 4 weeks of age. Histologic analysis of atherosclerotic plaque development (lesion area) in the aortic sinus was conducted at 16 weeks of age. A significant increase in week 1 body weight was observed in the DE/DE group compared to the DE/FA and FA/FA groups. The DE/DE group was also associated with a significant increase in HDLs when compared to the DE/FA and FA/FA groups. Histological results showed no significant impact of in utero DE exposure on atherosclerotic lesion area. RNA sequencing studies indicated downregulation of 137 genes and upregulation of 15 genes due specifically to in utero DE exposure when compared to the FA/FA group. Overall results of the impact of in utero DE exposure were inconclusive and further studies should be conducted in order to fully elucidate the effect of in utero DE exposure on atherosclerotic progression.