{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:05:59Z","timestamp":1792033559008,"version":"4.4.0"},"reference-count":41,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Type 2 diabetes mellitus (T2D) is characterized by insulin resistance and a progressive decline in pancreatic \u03b2\u2010cell function. Bisphenol\u2010A (BPA), an industrial chemical widely used in manufacturing plastics and resins, is known to disrupt endocrine function and impair pancreatic \u03b2\u2010cell activity. This study aims to investigate the effects of chronic exposure to low concentrations of BPA on pancreatic \u03b2\u2010cells 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\u2009\u03bcM for 7 days. Cellular outcomes measured included viability, apoptosis, ATP levels, and proliferation. Insulin secretion and content were also assessed as indicators of \u03b2\u2010cell function. Additionally, levels of intracellular reactive oxygen species (ROS), advanced glycation end\u2010products (AGEs), and soluble receptor for AGEs (sRAGE) were quantified. Apoptosis markers and gene expression related to apoptotic pathways were analyzed using quantitative real\u2010time PCR (qRT\u2010PCR). 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\u2010dose BPA induces mitochondrial apoptosis in pancreatic \u03b2\u2010cells in a dose\u2010dependent manner, mediated by oxidative stress and AGE accumulation. Chronic exposure to low concentrations of BPA impairs pancreatic \u03b2\u2010cell viability and function by promoting oxidative stress and apoptosis via RAGE\u2010dependent signaling cascades. These findings highlight the potential health risks associated with BPA exposure and underscore its possible role in \u03b2\u2010cell dysfunction related to T2D development.<\/jats:p>","DOI":"10.1002\/jbt.70569","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T05:30:24Z","timestamp":1762407024000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Chronic Bisphenol\u2010A Exposure Enhances ROS and AGEs Production via the RAGE\/PI3K\/AKT\/mTOR Signaling Pathway, Inducing Apoptosis in Human Pancreatic \u03b2\u2010Cells"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7560-0575","authenticated-orcid":false,"given":"Ioanna A.","family":"Anastasiou","sequence":"first","affiliation":[{"name":"Diabetes Center, First Department of Propaedeutic Internal Medicine Medical School, National and Kapodistrian University of Athens, Laiko General Hospital Athens Greece"},{"name":"Department of Pharmacology Medical School, National and Kapodistrian University of Athens  Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasios","family":"Tentolouris","sequence":"additional","affiliation":[{"name":"Diabetes Center, First Department of Propaedeutic Internal Medicine Medical School, National and Kapodistrian University of Athens, Laiko General Hospital Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis","family":"Sarantis","sequence":"additional","affiliation":[{"name":"Molecular Oncology Unit, Department of Biological Chemistry Medical School, National and Kapodistrian University of Athens  Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Rebelos","sequence":"additional","affiliation":[{"name":"Diabetes Center, First Department of Propaedeutic Internal Medicine Medical School, National and Kapodistrian University of Athens, Laiko General Hospital Athens Greece"},{"name":"Department of Clinical and Experimental Medicine University of Pisa Pisa Italy"},{"name":"Turku PET centre, University of Turku Turku Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna","family":"Eleftheriadou","sequence":"additional","affiliation":[{"name":"Diabetes Center, First Department of Propaedeutic Internal Medicine Medical School, National and Kapodistrian University of Athens, Laiko General Hospital Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0615-2534","authenticated-orcid":false,"given":"Nikolaos","family":"Tentolouris","sequence":"additional","affiliation":[{"name":"Diabetes Center, First Department of Propaedeutic Internal Medicine Medical School, National and Kapodistrian University of Athens, Laiko General Hospital Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"183","article-title":"IDF Diabetes Atlas: Global, Regional and Country\u2010Level Diabetes Prevalence Estimates for 2021 and Projections for 2045","author":"Sun H.","year":"2022","journal-title":"Diabetes Research and Clinical Practice"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12403-022-00486-0"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-019-4940-z"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2022.115068"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2022.1047827"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph14090959"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21165761"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.12.013"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-14-0714"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.8451"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2019.03.002"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/07482337211054372"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.23099"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.319"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2014.04.019"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1289\/EHP1674"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2003-1099"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.70036"},{"key":"e_1_2_11_20_1","unstructured":"I. 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