Mechanisms for the adverse effects of late gestational increases in maternal cortisol on the heart revealed by transcriptomic analyses of the fetal septum

Abstract

We have previously shown in sheep that 10 days of modest chronic increase in maternal cortisol resulting from maternal infusion of cortisol (1 mg/kg/day) caused fetal heart enlargement and Purkinje cell apoptosis. In subsequent studies we extended the cortisol infusion to term, finding a dramatic incidence of stillbirth in the pregnancies with chronically increased cortisol. To investigate effects of maternal cortisol on the heart, we performed transcriptomic analyses on the septa using ovine microarrays and Webgestalt and Cytoscape programs for pathway inference. Analyses of the transcriptomic effects of maternal cortisol infusion for 10 days (130 day cortisol vs 130 day control), or ∼25 days (140 day cortisol vs 140 day control) and of normal maturation (140 day control vs 130 day control) were performed. Gene ontology terms related to immune function and cytokine actions were significantly overrepresented as genes altered by both cortisol and maturation in the septa. After 10 days of cortisol, growth factor and muscle cell apoptosis pathways were significantly overrepresented, consistent with our previous histologic findings. In the term fetuses (∼25 days of cortisol) nutrient pathways were significantly overrepresented, consistent with altered metabolism and reduced mitochondria. Analysis of mitochondrial number by mitochondrial DNA expression confirmed a significant decrease in mitochondria. The metabolic pathways modeled as altered by cortisol treatment to term were different from those modeled during maturation of the heart to term, and thus changes in gene expression in these metabolic pathways may be indicative of the fetal heart pathophysiologies seen in pregnancies complicated by stillbirth, including gestational diabetes, Cushing's disease and chronic stress.