Banerjee Oly, Paul Tiyesh, Singh Siddhartha, Maji Bithin Kumar, Mukherjee Sandip
Department of Physiology, Serampore College, 9 William Carey Road, Serampore, Hooghly, 712201, West Bengal, India.
Department of Medical Laboratory Technology, School of Allied Health Sciences, Swami Vivekananda University, Bara Kanthalia, West Bengal, 700121, India.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr;398(4):3939-3954. doi: 10.1007/s00210-024-03506-9. Epub 2024 Oct 8.
Bisphenol A (BPA), a pervasive endocrine-disrupting chemical, is known to convey harmful impact on pancreatic islets through estrogen receptors (ERs). Conversely, BPA can activate aryl hydrocarbon receptor (AhR) in certain contexts and has raised concerns about potential toxicological effects. However, BPA-AhR interaction in the context of pancreatic islet toxicity is yet to be reported. We demonstrated the specific role of AhR and its interaction with ERs to mediate BPA toxicity in pancreatic islets. In vitro, isolated islet cells treated with BPA (1 nM), with or without CH22319 (10 mM) and ICI182780 (1 mM) and insulin release, glucose-stimulated insulin secretion (GSIS), cell viability, and pERK1/2 and pAkt expression were measured. In vivo, mice were treated with BPA (10 and 100 µg/kg body weight/day for 21 days) with or without intraperitonial co-treatment of CH22319 (AhR antagonist, 10mg/kg), and ICI182780 (ER antagonist, 500 µg/kg). Glucose homeostasis, insulin resistance, oxidative stress, and inflammatory markers were measured. In vitro data revealed the involvement of AhR in the BPA-mediated alteration in insulin secretion, GSIS, and pERK1/2 and pAkt expression which were counteracted by CH223191 (AhR antagonist) alone or with ICI182780 (ER antagonist). Further, CH223191 alone or with ICI182780 modulated BPA-induced oxidative stress and pro-inflammatory cytokines and alleviated islet cell dysfunction and impaired insulin secretion. In conclusion, therapeutic targeting of AhR and ER combined might be a promising target against diabetogenic action of BPA.
双酚A（BPA）是一种普遍存在的内分泌干扰化学物质，已知其通过雌激素受体（ERs）对胰岛产生有害影响。相反，BPA在某些情况下可激活芳烃受体（AhR），这引发了人们对其潜在毒理学效应的担忧。然而，BPA与AhR在胰岛毒性背景下的相互作用尚未见报道。我们证明了AhR的特定作用及其与ERs的相互作用，以介导BPA在胰岛中的毒性。在体外，用BPA（1 nM）处理分离的胰岛细胞，同时或不同时添加CH22319（10 mM）和ICI182780（1 mM），并测量胰岛素释放、葡萄糖刺激的胰岛素分泌（GSIS）、细胞活力以及pERK1/2和pAkt表达。在体内，给小鼠注射BPA（10和100 μg/kg体重/天，共21天），同时或不同时腹腔内联合注射CH22319（AhR拮抗剂，10 mg/kg）和ICI182780（ER拮抗剂，500 μg/kg）。测量葡萄糖稳态、胰岛素抵抗、氧化应激和炎症标志物。体外数据显示，AhR参与了BPA介导的胰岛素分泌、GSIS以及pERK1/2和pAkt表达的改变，单独使用CH223191（AhR拮抗剂）或与ICI182780（ER拮抗剂）联合使用可抵消这些改变。此外，单独使用CH223191或与ICI182780联合使用可调节BPA诱导的氧化应激和促炎细胞因子，并减轻胰岛细胞功能障碍和胰岛素分泌受损。总之，联合靶向AhR和ER进行治疗可能是对抗BPA致糖尿病作用的一个有前景的靶点。
