Sexually dimorphic impact of prenatal hyperandrogenism on offspring growth trajectory in sheep

In a translationally relevant ovine model of gestational hyperandrogenism we have previously reported cardiometabolic disruption in female offspring (males were not extensively studied). We hypothesized that gestational hyperandrogenism would lead to sex-specific disruption in offspring's growth, cytokine and metabolic milieu, potential mediators of cardiometabolic disease (CMD). 100 mg Testosterone propionate (T) or vehicle (C) was administered intramuscularly twice weekly between gestational days (GD) 30-90. Two cohorts of offspring were generated, including both males and females. Fetal weight and systemic metabolomics were analyzed in the fetal cohort (GD120). Growth trajectory, systemic cytokines, and metabolomics were analyzed in the postnatal cohort. Data was analyzed using mixed model ANOVA, student T-test, and Cohen D (d) analysis. T excess led to (1) a reduction in fetal weight at GD 120 in both sexes and sex-specific perturbations in the fetal metabolome, (2) T-Female had a growth trajectory similar to males and significantly different from C-Females (age x treatment interaction p = 0.028) and (3) sex-specific alterations in cytokine milieu at birth and metabolome in the pre-pubertal period. Altered sex-specific postnatal metabolic milieu and growth trajectory, notable for catch-up growth in T-Female, could have implications for sex-specific impact on the cardiometabolic function in the lambs.