Sex-specific perturbation of systemic lipidomic profile in newborn lambs impacted by prenatal testosterone excess.

Gestational hyperandrogenism adversely impacts offspring health. Using an ovine model, we found prenatal testosterone (T) excess adversely affects growth and cardiometabolic outcomes in female offspring and sex-specific effects on fetal myocardium. Since lipids are essential to cardiometabolic function, we hypothesized that prenatal T excess will lead to sex-specific disruptions in lipid metabolism at birth. Shotgun lipidomics was performed on the plasma samples collected 48 hours after birth from female (F) and male (M) lambs of control (C) and (T) sheep (CF=4, TF=7, CM=5, TM=10) and data analyzed by univariate analysis, multivariate dimensionality reduction modeling followed by functional enrichment and pathway analyses. Biosynthesis of phosphatidylserine was the major pathway responsible for sex differences in controls. Unsupervised and supervised models showed separation between C and T in both sexes with glycerophospholipids and glycerolipids classes being responsible for the sex differences between C and T. T excess increased cholesterol in females while decreasing phosphatidylcholine levels in male lambs. Specifically, T excess: 1) suppressed phosphatidylethanolamine N-methyltransferase (PEMT) phosphatidylcholine synthesis pathway overall and in TM lambs as opposed to suppression of carnitine levels overall and TF lambs and 2) activated biosynthesis of PE-O and PC-O from DG-O overall and in TF lambs. Higher cholesterol levels could underlie adverse cardiometabolic outcomes in TF lambs, whereas suppressed PEMT pathway in TM lambs could lead to endoplasmic reticulum stress and defect in lipid transport. These novel findings point to sex-specific effects of prenatal T excess on lipid metabolism of newborn lamb, a precocial ovine model of translational relevance.