Chronic Bisphenol‐A Exposure Enhances ROS and AGEs Production via the RAGE/PI3K/AKT/mTOR Signaling Pathway, Inducing Apoptosis in Human Pancreatic β‐Cells

ABSTRACT Type 2 diabetes mellitus (T2D) is characterized by insulin resistance and a progressive decline in pancreatic β‐cell function. Bisphenol‐A (BPA), an industrial chemical widely used in manufacturing plastics and resins, is known to disrupt endocrine function and impair pancreatic β‐cell activity. This study aims to investigate the effects of chronic exposure to low concentrations of BPA on pancreatic β‐cells and to elucidate the underlying molecular mechanisms involved. 1.2B4 cells (RRID: CVCL_2258) were cultured in medium containing BPA at concentrations of 0.0002, 0.002, 0.01, and 0.02 μM for 7 days. Cellular outcomes measured included viability, apoptosis, ATP levels, and proliferation. Insulin secretion and content were also assessed as indicators of β‐cell function. Additionally, levels of intracellular reactive oxygen species (ROS), advanced glycation end‐products (AGEs), and soluble receptor for AGEs (sRAGE) were quantified. Apoptosis markers and gene expression related to apoptotic pathways were analyzed using quantitative real‐time PCR (qRT‐PCR). The involvement of specific signaling pathways, such as RAGE/PI3K/AKT/mTOR, was investigated. BPA exposure markedly inhibited proliferation and growth of 1.2B4 cells, with a reduction of up to 50% compared to controls, indicating potent antiproliferative effects. BPA also increased ROS and AGEs production through activation of the RAGE/PI3K/AKT/mTOR pathway, leading to enhanced apoptosis. The data suggest that low‐dose BPA induces mitochondrial apoptosis in pancreatic β‐cells in a dose‐dependent manner, mediated by oxidative stress and AGE accumulation. Chronic exposure to low concentrations of BPA impairs pancreatic β‐cell viability and function by promoting oxidative stress and apoptosis via RAGE‐dependent signaling cascades. These findings highlight the potential health risks associated with BPA exposure and underscore its possible role in β‐cell dysfunction related to T2D development.