LBSUN310 Developmental Programming: Gestational Bpa Treatment Leads To Pancreatic Beta Cell Compromise

Abstract Developmental exposure to endocrine disrupting chemicals (EDC) such as bisphenol A (BPA) have been shown to be associated with many metabolic defects in humans. Studies in animals have documented detrimental effects of fetal exposure to BPA on metabolic variables such as insulin resistance, adiposity, and cardiac function. For instance, developmental exposure of sheep to bisphenol A (BPA), a ubiquitously present EDC, causes insulin resistance and compensatory hyperinsulinemia but the underlying mechanism of it is not fully understood. To determine if pancreatic hyperplasia or hypertrophy contributes to the hyperinsulinemic status and the ontogeny of these effects, pregnant Suffolk sheep were administered daily subcutaneous injections of BPA (0. 05, 0 .5 or 5 mg/Kg BW) in corn oil from days (D) 30-90 of gestation (term 147 days). Controls received corn oil during the same period. Pancreas were taken at Day 65 and 90 of gestation from control and 0.5mg/kg BPA (environmental exposure level)-treated female fetuses, and control and prenatal BPA-treated female offspring at 2 years of age (all 3 doses) during synchronized follicular phase of the cycle. Immunohistochemistry was used to determine beta cell number, size, and islet insulin content. In addition, to determine if the pancreas was fibrotic, islet collagen content was determined by Picro Sirius red staining and whole pancreas collagen content was measured with scroll collagen assay. Data were analyzed by ANOVA (Y2) and Students's t-test (D65 and D90), and magnitude of response by Cohen's Effect Size analysis. Findings showed large magnitude reduction of islet insulin content at day 65, significant decrease in islet insulin and beta cell count at D90 along with large magnitude decrease in pancreas/fetal weight. In contrast, in the Y2 sheep prenatal BPA treatment induced a large magnitude decrease in beta cell count (0. 05mg/kg dose group), a large magnitude increase in islet insulin content (5mg/kg dose group) and large magnitude increase in islet collagen content (all 3 BPA doses). The decrease in insulin in the D65 and D90 sheep along with the decrease in beta cells and pancreas/fetal weight at D90 indicates adverse developmental impact of BPA exposure on pancreatic beta cell differentiation. Increase in collagen accumulation in Y2 sheep likely contributes to the beta cell loss reflected as decrease in beta cell number seen in 0. 05 mg/kg dose of BPA. Absence of beta cell loss in 0.5 and 5mg/kg dose in the face of increased collagen is consistent with the nonmonotonic responses these EDCs manifest. Taken together, these results highlight the risks posed by developmental exposure to BPA on beta cell function and the corresponding risk for beta cell loss as animals age. Supported by NIH R01 grants ES016541 and ES030374 Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.