Hao Miao, Shi Naixu, Zhao Yuan, Chen Jiajun
Scientific Research Center, China-Japan Union Hospital of Jilin University, 130033, Changchun, Jilin, China.
Department of Stomatology, China-Japan Union Hospital of Jilin University, 130033, Changchun, Jilin, China.
Environ Pollut. 2025 Sep 15;381:126642. doi: 10.1016/j.envpol.2025.126642. Epub 2025 Jun 9.
Dibutyltin dilaurate (DBTDL) is an organotin compound widely used in industrial chemical generation, recognized for its toxicity upon exposure. However, its association with brain injury remains unexplored. This study aims to identify and validate the molecular targets of DBTDL-induced brain toxicity using network toxicology approach and molecular docking analysis, and to elucidate its mechanisms. We used comprehensive databases including ChEMBL, STITCH, GeneCards and OMIM to screen potential targets related to DBTDL exposure and brain injury. STRING database and Cytoscape software were further analyzed to identify the core targets. Functional and pathway enrichment analyses were conducted to infer biological relevance. Molecular docking was utilized to predict the interactions between DBTDL and its targets. Expression validation and mechanism exploration were performed in vitro using human microglial cell (HMC3) and human brain microvascular endothelial cells (HBMEC). We identified 143 potential target and 24 core targets related to DBTDL exposure and brain injury. The core targets were mainly enriched in signal transduction, synaptic, hormonal and inflammatory pathways. Molecular docking revealed high-affinity interactions between DBTDL and five core targets, demonstrating binding energies of -7.8 (AGT), -9.9 (AGTR1), -11.2 (GNB1), -6.7 (GNG2) and -3.7 (POMC). In vitro validation was conducted using HMC3 and HBMEC cells. These cells were exposed to concentrations ranging from 0.1 to 20 μM, which are reported to be biologically effective. The results revealed that DBTDL exhibits significant cytotoxicity on two types of cells. Additionally, DBTDL activates oxidative stress pathways by inducing intracellular ROS production. After DBTDL treatment, the expressions of all five core targets were significantly upregulated, and expressions of neurotrophic factors were also increased. Our results identified a set of core targets for DBTDL-induced brain injury and indicate that DBTDL may affect neuroinflammatory and neurotoxicity in the brain through these targets. Our results not only advance our knowledge of DBTDL-induced brain injury and potential therapeutic interventions, but also emphasize the need for regulatory measures to limit DBTDL exposure and protect public health.
二月桂酸二丁基锡（DBTDL）是一种广泛应用于工业化学品生产的有机锡化合物，因其暴露时具有毒性而闻名。然而，其与脑损伤的关联仍未得到探索。本研究旨在使用网络毒理学方法和分子对接分析来识别和验证DBTDL诱导脑毒性的分子靶点，并阐明其机制。我们使用了包括ChEMBL、STITCH、GeneCards和OMIM在内的综合数据库来筛选与DBTDL暴露和脑损伤相关的潜在靶点。进一步分析STRING数据库和Cytoscape软件以识别核心靶点。进行功能和通路富集分析以推断生物学相关性。利用分子对接预测DBTDL与其靶点之间的相互作用。使用人小胶质细胞（HMC3）和人脑微血管内皮细胞（HBMEC）在体外进行表达验证和机制探索。我们确定了143个与DBTDL暴露和脑损伤相关的潜在靶点和24个核心靶点。核心靶点主要富集于信号转导、突触、激素和炎症通路。分子对接揭示了DBTDL与五个核心靶点之间的高亲和力相互作用，显示出-7.8（AGT）、-9.9（AGTR1）、-11.2（GNB1）、-6.7（GNG2）和-3.7（POMC）的结合能。使用HMC3和HBMEC细胞进行体外验证。这些细胞暴露于0.1至20μM的浓度范围，据报道这些浓度具有生物学效应。结果显示DBTDL对两种类型的细胞均表现出显著的细胞毒性。此外，DBTDL通过诱导细胞内活性氧产生来激活氧化应激通路。DBTDL处理后，所有五个核心靶点的表达均显著上调，神经营养因子的表达也增加。我们的结果确定了一组DBTDL诱导脑损伤的核心靶点，并表明DBTDL可能通过这些靶点影响脑中的神经炎症和神经毒性。我们的结果不仅推进了我们对DBTDL诱导脑损伤及潜在治疗干预的认识，还强调了采取监管措施限制DBTDL暴露和保护公众健康的必要性。
