Abstract 4363999: Sex-Specific Cardiac Remodeling, Mitochondrial Dysfunction, and Transcriptomic Changes in Elderly Baboon Offspring Following Prenatal Synthetic Glucocorticoid Exposure

Abstract

The theory of developmental origins of health and disease suggests prenatal stressors, like synthetic glucocorticoids (sGC) administered to enhance fetal lung maturity, may predispose offspring to cardiovascular (CV) disease in later life. To investigate sex-specific CV outcomes, elderly baboon ( Papio spp.) offspring exposed prenatally to sGC (sGC: 4M/4F; ~17 yrs, ~70 human yrs equiv.) were compared to age/sex matched controls (CTR: 8M/5F). Cardiac magnetic resonance imaging (Siemens TIM Trio) assessed left ventricular (LV) structure, function, and myocardial strain. LV mitochondrial electron transport chain (ETC) function and protein expression were quantified, alongside RNA-seq analysis for differential gene expression and alternative splicing. In elderly males, sGC exposure resulted in LV remodeling indicated by increased end-systolic (p=0.027) and end-diastolic (p=0.00013) sphericity indexes and elevated paracardial adipose thickness (152% > CTR, p=0.016). Male sGC baboons showed impaired myocardial strain, including decreased radial (p=0.03) and longitudinal (p=0.041) strains and reduced early longitudinal strain rate (p=0.009). Mitochondrial function in male sGC baboons revealed decreased Complex I-linked respiration (33.5% lower, p=0.002) and Complex I protein subunit NDUFV2 expression (p=0.048). Transcriptomic profiling in males identified 83 differentially expressed genes enriched in pathways involving extracellular matrix remodeling (TGFB2, POSTN), inflammation (IL33), and fibrosis (OGN). Alterations in alternative splicing (38 clusters, primarily exon skipping events) linked RNA-binding proteins (e.g., TIA1, HNRNPC) to cardiac dysfunction. Principal component analysis highlighted distinct sex-specific clustering, reinforcing observed sexual dimorphism. Female sGC-exposed baboons displayed fewer cardiac changes on MRI, limited mitochondrial alterations, minimal gene expression shifts (4 genes), and reduced splicing alterations (16 clusters), suggesting intrinsic cardioprotective mechanisms. Integrative correlation analyses linked transcriptomic and mitochondrial changes to cardiac phenotypes, specifically in males, highlighting potential biomarkers for early detection and targets for therapeutic intervention. These results underscore the importance of sex-specific long-term CV monitoring in individuals prenatally exposed to synthetic glucocorticoids, informing clinical strategies for prevention and management.