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

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.