Endocrine-disrupting chemical exposure during differentiation alters the proliferation–maturation balance in stem-cell islets

Exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a risk factor for diabetes, primarily through disruption of pancreatic beta-cell function and insulin signaling. These effects can arise not only from adult exposure but also during development, as many EDCs can cross the placental barrier. However, models that accurately mimic human pancreatic islet development are limited. In this study, we reported the first toxicological application of stem cell islets (SC-islets) to investigate the developmental effect of EDCs. Using human-induced pluripotent stem cells (iPSCs), we generated SC-islets and exposed them to a mixture of bisphenol A, bisphenol S, and trans-nonachlor during differentiation. EDC exposure resulted in SC-islets with an altered transcriptional profile, characterized by reduced expression of beta-cell maturity markers, increased proliferation markers, and elevated KI67-positive cell counts. These features resembled earlier developmental stages and deviated from mature human islet profiles, suggesting a delay in differentiation. Our findings establish SC-islet differentiation as a novel and relevant in vitro model for assessing the developmental toxicity of EDCs, with outcomes consistent with in vivo studies. This model opens new avenues for mechanistic studies and chemical safety assessment in endocrine development.