In utero exposure to benzo(a)pyrene predisposes offspring to cardiovascular dysfunction in later-life

Abstract

In utero exposure of the fetus to benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon, is thought to dysregulate cardiovascular development. To investigate the effects of in utero B(a)P exposure on cardiovascular development, timed-pregnant Long Evans Hooded (LEH) rats were exposed to diluent or B(a)P (150, 300, 600 and 1200μg/kg/BW) by oral gavage on embryonic (E) days E14 (the metamorphosing embryo stage) through E17 (the 1st fetal stage). There were no significant effects of in utero exposure to B(a)P on the number of pups born per litter or in pre-weaning growth curves. Pre-weaning profiles for B(a)P metabolite generation from cardiovascular tissue were shown to be dose-dependent and elimination of these metabolites was shown to be time-dependent in exposed offspring. Systolic blood pressure on postnatal day P53 in the middle and high exposure groups of offspring were significantly elevated as compared to controls. Microarray and quantitative real-time PCR results were directly relevant to a biological process pathway in animal models for “regulation of blood pressure”. Microarray and quantitative real-time PCR analysis revealed upregulation of mRNA expression for angiotensin (AngII), angiotensinogen (AGT) and endothelial nitric oxide synthase (eNOS) in exposed offspring. Biological network analysis and gene set enrichment analysis subsequently identified potential signaling mechanisms and molecular pathways that might explain the elevated systolic blood pressures observed in B(a)P-exposed offspring. Our findings suggest that in utero exposure to B(a)P predispose offspring to functional deficits in cardiovascular development that may contribute to cardiovascular dysfunction in later life.