Lin Xuan, Lin Kun, Lai Yue, Peng Qingping, Xu Miao, Xu Yiting, Yang Jialin, Liu Huan, Shen Jianlin
Central Laboratory, Affiliated Hospital of Putian University, Putian, Fujian Province 351100, China; Department of Environmental and Biological Engineering, Putian University, Putian, Fujian Province 351100, China.
Department of Laboratory Medicine, the Affiliated Hospital of Putian University, Putian University, Putian 351100, China.
Ecotoxicol Environ Saf. 2025 Jan 1;289:117434. doi: 10.1016/j.ecoenv.2024.117434. Epub 2024 Nov 29.
This study aims to elucidate the intricate effects of Acetyl tributyl citrate (ATBC) on bone metabolism, disentangling the underlying molecular mechanisms that govern the impact of environmental contaminants on disease processes. Leveraging the exhaustive exploration of databases such as ChEMBL, STITCH, GeneCards, and OMIM, we have identified a comprehensive list of 164 potential targets intimately associated with both ATBC and bone metabolism. Following rigorous refinement using the STRING platform and Cytoscape software, we pinpointed ten core targets, encompassing KDM1A, EP300, HDAC2, EHMT2, DNMT1, and several others. In-depth Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, conducted within the Metascape database, revealed that the core targets of ATBC's influence on bone metabolism are predominantly concentrated within vital signaling cascades, including thyroid hormone signaling, FOXO signaling, glucagon signaling, AMPK signaling, insulin signaling, adipocytokine signaling, and Notch signaling pathways. Additionally, molecular docking simulations performed with AutoDock software confirmed the robust binding interactions between ATBC and these core targets, reinforcing our understanding of their interactions. To explore the cellular impact of ATBC, we performed in vitro experiments using osteoblasts (MC3T3-E1) exposed to relevant concentrations. Our findings revealed that low-dose ATBC (100 μM) significantly impaired cell proliferation and migration. Concurrently, we observed a downregulation in the transcriptional expression of key epigenetic regulators (KDM1A, EP300, HDAC2), suggesting that ATBC can disrupt bone metabolism at the cellular level. Collectively, our findings provide a theoretical scaffold for comprehending the intricate molecular mechanisms mediating ATBC's effects on bone metabolism, and paves the way for the development of preventive and therapeutic strategies against orthopedic disorders that may arise from exposure to plastic products containing ATBC or excessive ATBC environments.
本研究旨在阐明柠檬酸乙酰三丁酯（ATBC）对骨代谢的复杂影响，厘清环境污染物对疾病进程产生影响的潜在分子机制。通过对ChEMBL、STITCH、GeneCards和OMIM等数据库进行详尽探索，我们确定了与ATBC和骨代谢密切相关的164个潜在靶点的综合列表。使用STRING平台和Cytoscape软件进行严格筛选后，我们确定了十个核心靶点，包括KDM1A、EP300、HDAC2、EHMT2、DNMT1等。在Metascape数据库中进行的深入基因本体（GO）和京都基因与基因组百科全书（KEGG）通路分析表明，ATBC对骨代谢影响的核心靶点主要集中在重要的信号级联反应中，包括甲状腺激素信号通路、FOXO信号通路、胰高血糖素信号通路、AMPK信号通路、胰岛素信号通路、脂肪细胞因子信号通路和Notch信号通路。此外，使用AutoDock软件进行的分子对接模拟证实了ATBC与这些核心靶点之间存在强大的结合相互作用，加深了我们对它们相互作用的理解。为了探究ATBC对细胞的影响，我们使用暴露于相关浓度的成骨细胞（MC3T3-E1）进行了体外实验。我们的研究结果表明，低剂量ATBC（100μM）显著损害细胞增殖和迁移。同时，我们观察到关键表观遗传调节因子（KDM1A、EP300、HDAC2）的转录表达下调，这表明ATBC可在细胞水平上破坏骨代谢。总体而言，我们的研究结果为理解介导ATBC对骨代谢影响的复杂分子机制提供了理论框架，并为开发针对因接触含ATBC的塑料制品或ATBC过量环境而可能引发的骨科疾病的预防和治疗策略铺平了道路。
