Hyperandrogenic disorders such as polycystic ovary syndrome (PCOS) are often accompanied by metabolic dysfunction (Manzano-Nunez et al., 2023; Azziz, 2018; Joham and Teede, 2022). A majority of women with PCOS manifest metabolic abnormalities, including insulin resistance and compensatory hyperinsulinemia (Diamanti-Kandarakis and Dunaif, 2012; Marshall and Dunaif, 2012). Emerging evidence points to a developmental contribution of androgen excess to the origins of this disease (Dumesic et al., 2007). Animal models of gestational hyperandrogenism using rodents (Walters et al., 2012), primates (Abbott et al., 2013), and sheep (Padmanabhan and Veiga-Lopez, 2013) recapitulate metabolic phenotypes similar to those seen in women with PCOS, including insulin resistance and hyperinsulinemia. In our own model, female sheep exposed prenatally to testosterone (T) from gestational day (GD) 30–90 also exhibit insulin resistance, insulin signaling defects in target tissues (Padmanabhan et al., 2010; Puttabyatappa et al., 2017; Lu et al., 2016) and hyperinsulinemia (Padmanabhan et al., 2010; Recabarren et al., 2005). Indeed, this model provides a unique resource to address the developmental origins of perturbations in metabolic homeostasis.

Prenatal T-induced increases in insulin secretion may result from an increase in beta-cell number or increased capacity of beta-cells to produce insulin. The studies we have previously undertaken with GD 90 T-treated female fetuses (the end of the treatment window) indicate prenatal T-treatment decreases pancreatic weight and increases beta-cell apoptosis in the endocrine pancreas (Jackson et al., 2020). Whether these pancreatic changes are activational effects of T treatment or organizational consequences that persist after cessation of T-treatment is unclear. If organizational, the underlying mechanisms and mediators that contribute to this altered programming are unknown. In this context, GD 30–90 in sheep is the sexually dimorphic window of development, where male fetuses naturally see elevated levels of T (Robinson et al., 2002; Veiga-Lopez et al., 2011). Thus, exposure of females to levels of T that males naturally experience during this window may masculinize the female pancreas to a more male-like phenotype. If this premise is correct, increased T exposure during the sexually dimorphic window will induce pancreatic changes at the molecular or structural level in females that may render them comparable to control (C) males.

Genome-wide transcriptomic analysis offers an approach to identify molecular signatures and gene pathways impacted by gestational hyperandrogenism during the sexually dimorphic window that can illuminate the mechanisms of adverse pancreatic reprogramming that contribute to morphological and functional changes while also helping reveal potential biomarkers of prenatal androgen exposure. Therefore, we hypothesize that prenatal T-induced transcriptional changes contribute to pancreatic compromise in females, and that this arises from a programming event that persists after the cessation of treatment and induces a phenotype in T-treated female fetuses that is similar to male fetuses.