MON-174 Early to Mid-Gestational Testosterone Excess Disrupts Cardiac Epigenome of Late Gestational Fetal Sheep

Abstract Disclosure: D. Purswani: None. D. Bernal: None. B. Alkhatib: None. V. Padmanabhan: None. A. Vyas: None. Excess testosterone (T) exposure from early to mid-gestation days (GD) 30-90 leads to intrauterine growth retardation in late gestational fetuses and sexually dimorphic adverse cardiac programming at fetal life culminating in cardiometabolic dysfunction in adult female offspring. We hypothesized that such adverse cardiac programming with prenatal T excess is secondary to cardiac epigenetic modulation during fetal life. Pregnant ewes received 100 mg T propionate intramuscularly twice weekly from GD 30 to 90 (term GD 147). At GD 120 ±5 fetal hearts were harvested, and cardiac left ventricle (LV) from female control (FC) n=5-6, T (FT) n=7-8; Male C (MC) n=6-7, T(MT) n=6-7 were processed for global methylation assay (% 5-methylcytosine, %5-mC) and microRNA (miRNA) analysis. Data was analyzed by two-way ANOVA and Cohen’s effect size (d) analysis. Prenatal T excess led to downregulation of miRNA 150 and upregulation of miRNA 134, 23A, 431 and 668 in both sexes. Of importance, T excess induced significant sexually dimorphic effect in the fetal LV epigenome. LV global methylation profile revealed a decrease in %5-mC in MT vs. MC (0.1732% vs. 0.3024%) but not in female fetal LV. T excess induced sex-specific changes in various miRNA involved in cardiac apoptosis, hypertrophy and inflammation that contribute to cardiac remodeling. A sexually dimorphic effect of T excess was noted in several LV miRNAs: 1) downregulation of miRNA 10A in FT as opposed to upregulation in MT; 2) selective upregulation of miRNA 431, 107, 544 and downregulation in miRNA 10B in FT as opposed to selective downregulation of miRNA 434 in MT. These findings are indicative of early disruption of fetal cardiac epigenome by prenatal T excess that likely underlie the sex specific adverse cardiac programming persisting into adulthood. Presentation: Monday, July 14, 2025