FRI103 Developmental Programming: Sex-specific Differences In Lipid Metabolism Of Newborn Lambs Exposed To Prenatal Testosterone Excess

Abstract

Abstract Disclosure: N. Saadat: None. J.N. Ciarelli: None. B. Pallas: None. V. Padmanabhan: None. A.K. Vyas: None. Gestational hyperandrogenism such as that seen in Polycystic Ovary Syndrome (PCOS), leads to adverse offspring health outcomes in both humans and animals. Prenatal T excess (T) in a sheep model of PCOS phenotype induces peripheral insulin resistance, dyslipidemia, adipocyte defects, liver steatosis, pathological cardiac remodeling and hypertension in the female offspring. Whether these adverse cardiometabolic outcomes evidenced in the female offspring also extends to male offspring needs to be addressed. We hypothesized that prenatal T excess will induce sex-specific disruptions in lipid metabolism of newborn lambs thereby contributing to the aberrant cardiometabolic phenotype. Shotgun Lipidomics was performed on the plasma samples collected at 48 hours after birth from prenatal T treated (100mg T-propionate in corn oil from days 30 to 90 of gestation intramuscularly; Term: 147days) and control (C, vehicle only) lambs (N=26, Female C=4, T=7 and Male C=5, T=10). The data was analyzed by multivariate dimensionality reduction modeling followed by functional enrichment and pathway analyses. Unsupervised 3D principal component analysis and supervised models showed separation between C and T groupings in female and male lambs. Most lipids responsible for this separation were from glycerophospholipids and glycerolipids classes in both sexes. Prenatal T excess led to an increase in cholesterol levels only in female lambs as opposed to a decrease in levels of carnitine species (CAR) CAR 16:1 and CAR 14:1 and phosphatidylcholine species (PC) PC 39:4, PC 39:5 and PC 38:5 in male lambs. To investigate the impact of prenatal T excess on lipid metabolism pathways and active reactions, 738 lipid species were mapped, of which 147 were found to be active in reactions. The active reactions involving conversion of ether linked diglycerides (DG) to ether linked phosphatidylethanolamines (PE, O-DG→O-PE, z-score 3.367, p <0.05) and ether linked PC (O-DG →O-PC, z-score 2.299, p < 0.05) were increased in female lambs. In contrast, the conversion of PE to PC to phosphatidic acids (PA) was suppressed (PE→PC→PA, z-score 2.133, p <0.05) in prenatal T-treated male lambs pointing towards the suppression of Phosphatidylethanolamine N-methyltransferase (PEMT) phosphatidylcholine synthesis pathway. Higher cholesterol levels in T female lambs could contribute toward the adverse cardiometabolic phenotype evidenced earlier in this model, whereas suppressed PEMT pathway could lead to endoplasmic reticulum stress, defects in membrane permeability and lipid transport that may lead to liver steatosis in T male lambs. These novel findings of sex-specific effects of gestational exposure to T excess on lipid metabolism of newborn lamb, a precocial model of translational relevance, may have sex-specific functional outcomes in cardiometabolic systems. Presentation: Friday, June 16, 2023