Pyambri Maryam, Pavlidou Athina, Lacorte Sílvia, Jaumot Joaquim, Bedia Carmen
Environmental Chemistry Department. Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona 18-26, Barcelona 08034, Spain; Department of Analytical Chemistry, Faculty of Chemistry, University of Barcelona, Martí i Franquès 1-11, Barcelona 08028, Spain.
Environmental Chemistry Department. Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona 18-26, Barcelona 08034, Spain.
Chem Phys Lipids. 2025 Aug;270:105508. doi: 10.1016/j.chemphyslip.2025.105508. Epub 2025 May 29.
Organophosphate flame retardants (OPFRs) are widely used as additives in plastics, electronics, and construction materials due to their flame-retardant properties. However, previous evidence suggests that OPFRs may pose potential respiratory health risks, including airway hyperresponsiveness, impaired lung function, and potential carcinogenic effects. This study evaluated the effects of seven OPFRs-TBOEP, TPhP, EHDPhP, TDCPP, TEHP, TCP, and TCEP-on the phenotype and lipidomic profile of A549 lung cancer cells, using both 2D and 3D culture models. TDCPP and TPhP significantly reduced cell viability, while TBOEP caused the highest increase in reactive oxygen species (ROS), followed by TPhP, TDCPP, and TCP. Moreover, TPhP, TDCPP, EHDPhP, and TBOEP also elevated the levels of pro-inflammatory cytokine interleukin-8 (IL-8). The lipidomic analysis of 3D cell spheroids exposed to OPFRs for 72 h revealed distinct lipid profiles for each compound at low (25 μM) and high (100 μM) doses. Common features were observed, particularly at high doses, including significant increases in triacylglycerol, diacylglycerol, ceramide, ether-linked phosphatidylethanolamine, and phosphatidylinositol species. These effects were generally more pronounced for TPhP, TDCPP, EHDPhP, TCP, and TBOEP. The accumulation of triglycerides, indicative of augmented energy storage, was confirmed by the visualization of lipid droplets formation. Results suggest disruptions in key toxicological pathways, including oxidative stress, inflammatory signaling (IL-8 upregulation), and apoptosis (ceramide accumulation), all implicated in lung diseases, such as COPD and fibrosis. These results provide a basis for assessing the health risks associated with OPFRs, highlighting the need for further research on chronic low-dose exposure levels.
有机磷酸酯阻燃剂（OPFRs）因其阻燃性能而被广泛用作塑料、电子产品和建筑材料中的添加剂。然而，先前的证据表明，OPFRs可能对呼吸道健康构成潜在风险，包括气道高反应性、肺功能受损和潜在的致癌作用。本研究使用二维和三维培养模型，评估了七种OPFRs（TBOEP、TPhP、EHDPhP、TDCPP、TEHP、TCP和TCEP）对A549肺癌细胞表型和脂质组学特征的影响。TDCPP和TPhP显著降低细胞活力，而TBOEP导致活性氧（ROS）增加最多，其次是TPhP、TDCPP和TCP。此外，TPhP、TDCPP、EHDPhP和TBOEP还提高了促炎细胞因子白细胞介素-8（IL-8）的水平。对暴露于OPFRs 72小时的三维细胞球体进行脂质组学分析，发现在低剂量（25μM）和高剂量（100μM）下，每种化合物都有独特的脂质特征。观察到一些共同特征，特别是在高剂量时，包括三酰甘油、二酰甘油、神经酰胺、醚键连接的磷脂酰乙醇胺和磷脂酰肌醇种类显著增加。这些影响在TPhP、TDCPP、EHDPhP、TCP和TBOEP中通常更为明显。通过脂质滴形成的可视化证实了甘油三酯的积累，这表明能量储存增加。结果表明关键毒理学途径受到干扰，包括氧化应激、炎症信号传导（IL-8上调）和细胞凋亡（神经酰胺积累），所有这些都与慢性阻塞性肺疾病（COPD）和肺纤维化等肺部疾病有关。这些结果为评估与OPFRs相关的健康风险提供了依据，强调了对慢性低剂量暴露水平进行进一步研究的必要性。
