FRI115 Sex-specific Programming Of The Late Gestational Fetal Heart With Prenatal T Excess

Abstract

Abstract Disclosure: B.G. Alkhatib: None. M. Jabari: None. P. Kurup: None. S. Domke: None. J.N. Ciarelli: None. B. Pallas: None. O. Nicholas: None. V. Padmanabhan: None. A.K. Vyas: None. Excess testosterone (T) exposure from early to mid-gestation (days 30-90) leads to sexually dimorphic adverse cardiac programming at fetal day 90 (term 147 days). Whether this is direct effect of T or reprogramming that persists is unknown. We hypothesized that gestational T excess leads to sex specific cardiac reprogramming that persists into late gestation and neonatal period. Pregnant ewes were injected 100 T propionate in corn oil or vehicle (C), twice weekly (day 30 to 90). At day 120 ±5 gestation, fetal body weight (BW) and heart weights were recorded, and left ventricles (LV) processed for molecular analysis (Female C (FC) n=5-6, T (FT) n=7-8; Male C (MC) n=6-7, T(MT) n=6). Neonatal echocardiograms were performed in a second study (Female C n=2, T n=7, Male C n=5, T n=10). Prenatal T excess reduced BW in both sexes compared to C (male: 3.38±0.15 vs.2.68±0.14, p=0.001, Cohen’s effect size: d=1.29; female: 3.27±0.21 vs. 2.72±0.11, p=0.03, d=1.08). LV/BW ratio (3.62±0.15 vs 3.15± 0.11, p=0.04, d=0.81) was increased in MT compared to MC and not in females suggestive of sex specific programming. Prenatal T excess had no impact on insulin, estrogen or androgen receptor expression at day 120 in both sexes. However, downstream protein expression of pAKT/Total AKT protein ratio was significantly downregulated in MT compared to MC fetuses (MT-0.36±0.10 vs MC 0.47±0.11, p=0.03, d=1.34) with a non-significant moderate magnitude decrease in FT (FT-0.34±0.08 vs FC 0.50±0.14, d=0.63). A non-significant large magnitude downregulation of mTORC1 (0.86±0.05 vs 1.00±0.01, d=0.87), a non-significant moderate magnitude decrease in SERCA (0.85±0.07 vs 1.03±0.12, p=0.2, d=0.7), and a significant large magnitude decrease in Col1A1 (0.71±0.28 vs 1.02±0.09, p=0.02, d=1.48) gene expression were evident in MT compared to MC as opposed to no differences in females. A large magnitude decrease in Cytochrome C and PERK (mitochondrial metabolism genes) expression were seen in FT compared to FC (0.76±0.08 vs 1.02±0.09, p=0.07, d=1.07 and 0.81±0.10 vs 1.01±0.08, p=0.17 d=0.79 respectively) but not in males. Neonatal echocardiogram analysis demonstrated a significant increase LV area in diastole (LVAD) (5.35±0.11 vs 4.08±0.15, p=0.04, d=0.92), LV internal dimension in diastole (LVIDd) (2.54±0.02 vs 2.22±0.03, p=0.03, 0.92), and in LVID in systole (1.75±0.01 vs 1.55±0.02, p=0.04, d=0.84) in T treated offspring compared to control. In a sub analysis of only males fetuses there was a non-significant medium to large magnitude increases in LV area in diastole (LVAD) (7.6±0.36 vs 4.18±0.53, p=0.07, d=2.8), LV internal dimension in diastole (2.54±0.13 vs 2.2±0.13, p=0.14, d=0.9), and LV internal dimension in systole (1.73±0.09 vs 1.54±0.08, p=0.11, d=0.74) in MT compared to MC. Altogether, these results support persistence of sex specific adverse programming of prenatal T excess into late gestation and neonatal life. Presentation: Friday, June 16, 2023