Citarella Anna, Besharat Zein Mersini, Coppola Lucia, Sabato Claudia, Autilio Tanja Milena, Vicentini Elena, Bimonte Viviana Maria, Catanzaro Giuseppina, Pediconi Natalia, Fabi Alessandra, Migliaccio Silvia, Milella Michele, Bei Roberto, Ferretti Elisabetta, Po Agnese
Department of Experimental Medicine, Sapienza University, Rome, Italy; Department of Life, Health and Health Professions Sciences, Link Campus University, Rome, Italy.
Department of Experimental Medicine, Sapienza University, Rome, Italy.
Environ Pollut. 2025 Jul 1;376:126422. doi: 10.1016/j.envpol.2025.126422. Epub 2025 May 11.
Bisphenol A (BPA) is a chemical compound found in a wide range of everyday consumer products, resulting in human exposure. BPA has been described as an endocrine disruptor, affecting different systems of the human body. Notably, nanomolar levels of BPA have been detected in human matrices, including plasma and milk. BPA exposure has been associated with the development of breast cancer, and the increase in breast cancer incidence prompted us to investigate the effects of BPA in MCF10A, a model of non-transformed mammary epithelium. Cells were treated with 10 nM BPA for 24 h to capture early molecular alterations preceding phenotypic transitions. Comprehensive transcriptomic analyses were conducted to identify differentially expressed genes and enriched signaling pathways. Subsequent validations included assessment of cytokine release, protein expression, immunofluorescence for subcellular localization of Nuclear Factor-Kappa B (NF-κB), and evaluation of actin cytoskeletal organization. Transcriptome analysis revealed enrichment in interleukin signaling and activation of the NF-κB pathway following BPA exposure. Functional assays demonstrated that BPA treatment enhanced cell motility, accompanied by increased phosphorylation of NF-κB. Inhibition of NF-κB effectively mitigated BPA-induced effects, including augmented cell motility, nuclear translocation of NF-κB, and cytoskeletal rearrangements. Notably, inhibition of the Mitogen-Activated Protein Kinase (MAPK) pathway, and to a lesser extent of the AKT pathway, counteracted BPA-induced NF-κB activation and the associated increase in cell motility. In conclusion, we show that nanomolar concentration of BPA induces significant changes in the molecular setting and behaviour of non-tranformed breast cells, activating NF-κB signalling that in turn controls inflammation, cell cycle, proliferation and cell motility. Our findings indicate that nanomolar concentrations of BPA can induce significant molecular and behavioral changes in non-transformed breast epithelial cells. These results contribute to a deeper understanding of how environmental pollutants like BPA may perturb breast epithelial cell function and potentially contribute to carcinogenesis.
双酚A（BPA）是一种存在于多种日常消费品中的化合物，会导致人体接触。BPA被描述为一种内分泌干扰物，会影响人体的不同系统。值得注意的是，在包括血浆和乳汁在内的人体样本中已检测到纳摩尔水平的BPA。BPA暴露与乳腺癌的发生有关，乳腺癌发病率的上升促使我们研究BPA对MCF10A（一种未转化的乳腺上皮模型）的影响。用10 nM BPA处理细胞24小时，以捕捉表型转变之前的早期分子变化。进行了全面的转录组分析，以鉴定差异表达基因和富集的信号通路。后续验证包括评估细胞因子释放、蛋白质表达、核因子-κB（NF-κB）亚细胞定位的免疫荧光以及肌动蛋白细胞骨架组织的评估。转录组分析显示，BPA暴露后白细胞介素信号通路富集且NF-κB通路激活。功能测定表明，BPA处理增强了细胞运动性，同时NF-κB的磷酸化增加。抑制NF-κB有效地减轻了BPA诱导的效应，包括增强的细胞运动性、NF-κB的核转位和细胞骨架重排。值得注意的是，抑制丝裂原活化蛋白激酶（MAPK）通路以及在较小程度上抑制AKT通路，可抵消BPA诱导的NF-κB激活以及相关的细胞运动性增加。总之，我们表明纳摩尔浓度的BPA会在未转化的乳腺细胞的分子环境和行为中引起显著变化，激活NF-κB信号通路，进而控制炎症、细胞周期、增殖和细胞运动性。我们的研究结果表明，纳摩尔浓度的BPA可在未转化的乳腺上皮细胞中诱导显著的分子和行为变化。这些结果有助于更深入地了解像BPA这样的环境污染物如何扰乱乳腺上皮细胞功能并可能导致致癌作用。
