邻苯二甲酸二(2-乙基己基)酯暴露在阻塞性睡眠呼吸暂停中的机制性见解：网络毒理学与体外验证
Mechanistic insights into di(2-ethylhexyl) phthalate exposure in obstructive sleep apnea: network toxicology and in vitro validation.
文献信息
| PMID | 42731187 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Yan Li |
| 作者单位 | Second Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi Province, China; Department of Pulmonary and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China. |
| 期刊 | Bioorganic chemistry |
| SCI 分区 | Q1 |
| IF | 4.8 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 鼻科 |
中文摘要
背景： 邻苯二甲酸二(2-乙基己基)酯（DEHP）是一种广泛使用的增塑剂和内分泌干扰化学物，已被认为与多种不良健康结局相关。然而，DEHP暴露是否会导致阻塞性睡眠呼吸暂停（OSA）患者的不良结局，特别是通过与慢性间歇性缺氧（CIH）的相互作用，目前仍不清楚。
方法： 我们使用NHANES数据评估了DEHP暴露与OSA患者全因死亡率之间的关系。通过ChEMBL、SEA和SwissTargetPrediction数据库鉴定了DEHP的环境健康相关靶点。从GeneCards、OMIM和CTD中汇编了OSA相关基因。进行了蛋白质-蛋白质相互作用分析和分子对接，以探索潜在的分子相互作用。在人支气管上皮细胞中使用CCK-8测定、LDH释放测定和RT-qPCR分析进行了体外实验。评估了对DEHP暴露的浓度依赖性反应，并进一步研究了CIH（OSA的标志性特征）的修饰效应。
结果： DEHP暴露增加与OSA患者全因死亡风险升高显著相关，并呈非线性剂量-反应关系。网络毒理学分析揭示了参与炎症、组织重塑和凋亡的关键DEHP相关靶点，如AR、BCL2、CASP3、PRKCA、CTSS和MMP9。分子对接提供了支持DEHP与这些蛋白质之间潜在相互作用的结构证据。体外实验表明，DEHP暴露后核心基因表达发生浓度依赖性改变，其特征为AR、CASP3、PRKCA、CTSS和MMP9表达增加，BCL2表达降低。这些分子反应在DEHP暴露与CIH联合条件下进一步增强。
结论： DEHP暴露与OSA个体死亡风险增加相关。DEHP诱导了OSA相关核心基因表达的浓度依赖性变化，而间歇性缺氧进一步增强了这些变化，为DEHP暴露在OSA中的生物学效应提供了潜在见解。
英文摘要
BACKGROUND: Di(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer and endocrine-disrupting chemical, has been associated with multiple adverse health outcomes. However, whether DEHP exposure contributes to poor outcomes in individuals with obstructive sleep apnea (OSA), particularly through interaction with chronic intermittent hypoxia (CIH), remains unclear.
METHODS: We used NHANES data to assess the relationship between DEHP exposure and all-cause mortality in OSA patients. Environmental health-related targets of DEHP were identified through ChEMBL, SEA, and SwissTargetPrediction databases. OSA-related genes were compiled from GeneCards, OMIM, and CTD. Protein-protein interaction analysis and molecular docking were performed to explore potential molecular interactions. In vitro experiments were conducted in human bronchial epithelial cells using CCK-8 assays, LDH release assays, and RT-qPCR analysis. Concentration-dependent responses to DEHP exposure were evaluated, and the modifying effects of CIH, a hallmark feature of OSA, were further investigated.
RESULTS: Increased DEHP exposure was significantly associated with a higher risk of all-cause mortality in OSA patients, with a non-linear dose-response relationship. Network toxicology analysis revealed key DEHP-related targets involved in inflammation, tissue remodeling, and apoptosis, such as AR, BCL2, CASP3, PRKCA, CTSS, and MMP9. Molecular docking provided structural evidence supporting potential interactions between DEHP and these proteins. In vitro experiments demonstrated concentration-dependent alterations in hub gene expression following DEHP exposure, characterized by increased expression of AR, CASP3, PRKCA, CTSS, and MMP9 and decreased expression of BCL2. These molecular responses were further enhanced under combined DEHP exposure and CIH conditions.
CONCLUSION: DEHP exposure was associated with increased mortality risk among individuals with OSA. DEHP induced concentration-dependent changes in OSA-related hub gene expression, which were further enhanced by intermittent hypoxia, providing potential insights into the biological effects of DEHP exposure in OSA.