Su Xincong, Kai Li, Han Xiaowen, Wang Rongzhi, Yang Xiao, Wang Xuedong, Yan Jin, Qian Qiuhui, Wang Zejun, Wang Huili
School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, China; School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Yangtze Delta Region Institute of Tsinghua University, Zhejiang, Jiaxing 314000, China.
Sci Total Environ. 2025 May 15;977:179405. doi: 10.1016/j.scitotenv.2025.179405. Epub 2025 Apr 15.
Bisphenol S (BPS) and Bisphenol F (BPF), as alternatives to bisphenol A (BPA), are recognized for their endocrine-disrupting properties, but their combined immune toxicity mechanisms remain poorly understood. This study systematically evaluates the individual and joint immune toxicity effects of BPS and BPF through ADMET predictions, transgenic zebrafish models, and molecular docking analyses. The results indicate that equal effect concentration BPS and BPF act through distinct immune pathways: BPS primarily targets macrophages to mediate immune responses, while BPF significantly stimulates neutrophil proliferation and induces a stronger inflammatory response through chemokine signaling. Molecular docking studies show that BPF binds more stably to pro-apoptotic protein Mapk8 and oxidative stress-related protein Hsp90aa1, leading to significantly higher levels of apoptosis and reactive oxygen species (ROS) compared to BPS. The similarity of modes of action (MOA)between BPS and BPF based on relevant immune indicators calculated and experimentally is about 0.3; this quantitative result also proves that modes of action differ widely. Nonetheless, most of the indicators showed superimposed effects in the combined experiments, and it is noteworthy that the oxidative stress indicators (SOD, MDA) showed synergistic effects, suggesting that BPS and BPF, which have very different modes of action, are able to be risk assessed using an additive model with respect to immunity, but may exhibit synergistic risks with respect to oxidative stress. This research demonstrates that BPS and BPF induce immune toxicity via different molecular targets and pathways and highlights the need to account for their synergistic effects in risk assessments. These findings provide important insights into the immune toxicity mechanisms of BPA substitutes and the potential risks of combined exposures.
双酚S（BPS）和双酚F（BPF）作为双酚A（BPA）的替代品，因其内分泌干扰特性而受到关注，但其联合免疫毒性机制仍知之甚少。本研究通过ADMET预测、转基因斑马鱼模型和分子对接分析，系统评估了BPS和BPF的单独及联合免疫毒性效应。结果表明，等效效应浓度的BPS和BPF通过不同的免疫途径起作用：BPS主要靶向巨噬细胞来介导免疫反应，而BPF则显著刺激中性粒细胞增殖，并通过趋化因子信号诱导更强的炎症反应。分子对接研究表明，BPF与促凋亡蛋白Mapk8和氧化应激相关蛋白Hsp90aa1结合更稳定，导致与BPS相比，凋亡水平和活性氧（ROS）显著更高。基于计算和实验得出的相关免疫指标，BPS和BPF之间的作用模式（MOA）相似性约为0.3；这一量化结果也证明了作用模式差异很大。尽管如此，大多数指标在联合实验中显示出叠加效应，值得注意的是，氧化应激指标（SOD、MDA）显示出协同效应，这表明作用模式差异很大的BPS和BPF在免疫方面能够使用相加模型进行风险评估，但在氧化应激方面可能表现出协同风险。本研究表明，BPS和BPF通过不同的分子靶点和途径诱导免疫毒性，并强调在风险评估中需要考虑它们的协同效应。这些发现为BPA替代品的免疫毒性机制和联合暴露的潜在风险提供了重要见解。
