Exposure to adverse environmental factors early in development can lead to poor birth outcomes and higher risk for the development of diseases later in life in accordance with the Developmental Origins of Health and Disease (DOHaD) Hypothesis (Barker 2004). Globally, the leading causes of death are non-communicable diseases (NCDs) (Landrigan et al., 2016), and one reason postulated for this increase in NCD is developmental exposure to pollutants acting as endocrine-disrupting chemicals (EDCs) (Kumar et al., 2020). One such EDC is bisphenol A (BPA), which is used in polycarbonate plastics and epoxy resins that are used in many common commercial products, including beverage and food containers, medical equipment, thermal paper, and myriad non-food related items (Geens et al., 2012; Almeida et al., 2018). Multiple studies have documented that more than 90% of individuals living in the U.S. have detectable levels of BPA, highlighting the ubiquitous and widespread nature of BPA exposure (Corrales, Kristofco et al. 2015Corrales et al., 2015; Tait et al., 2021; Tschersich, Murawski et al. 2021Tschersich et al., 2021). As a prototypical EDC, BPA has been extensively studied for many years (Fenichel et al., 2013; Beausoleil et al., 2018; vom Saal and Vandenberg, 2021), with studies documenting both estrogenic (Dodds and Lawson 1936, Ishida et al., 2023; Yuan et al., 2023) and antiandrogenic activity (Sohoni and Sumpter 1998, Lee et al., 2003; Huang et al., 2019). In studies of developmental programming, prenatal BPA exposure has been found to disrupt thyroid function (Ahmed 2016) and alter energy metabolism (Le Magueresse-Battistoni et al., 2018; Akash et al., 2020; Abulehia et al., 2022). Population-based studies have documented associations between BPA exposure and type 2 diabetes mellitus (T2DM) (Lang 2008; Hwang et al., 2018; Sargis and Simmons 2019); these data implicate BPA as an underappreciated T2DM risk factor (Pérez-Bermejo et al., 2021). This is of notable concern because of the large and increasing number of adults living with diabetes worldwide, currently estimated to be 537 million individuals (Sun et al., 2022).

In addition to these epidemiologic associations, numerous animal studies have found that developmental BPA exposure disrupts glucose homeostasis (Alonso-Magdalena et al., 2010; García-Arevalo et al., 2014) and leads to cardiometabolic disruptions (Shu et al., 2019; Akash et al., 2020; Abulehia et al., 2022). For instance, our studies in sheep, a precocial model with human translational relevance, found that gestational BPA exposure leads to peripheral insulin resistance with compensatory hyperinsulinemia and disruptions in adipose tissue biology (Veiga-Lopez et al., 2016) as well as lipotoxicity and increased markers of inflammation and oxidative stress in both liver and muscle (Puttabyatappa et al., 2019). Because most studies of BPA's programming effects on the pancreas have been conducted in rodents and because sheep are a unique model with particular translational relevance, we undertook an exploratory analysis of gestational BPA exposure effects on the endocrine pancreas in female fetuses and the adult offspring of exposed pregnant ewes that could explain our observation of BPA-induced hyperinsulinemia using this novel model.