Multimodal mechanisms of di (2-ethylhexyl) phthalate-induced cardiovascular-kidney-metabolic syndrome: Integrating epidemiology, network toxicology and experimental validation

作者：Weixing Wen, Zhi‐Jie Liu, Lingxiao Li, Feipeng Qiu, Hao Zhang, Yue Cao, Jun Li, Xiaohui Huang, Yuli Huang · 发表于：Ecotoxicology and Environmental Safety · 年份：2025 · DOI：10.1016/j.ecoenv.2025.119515 · 被引用次数：6 · 研究领域：Effects and risks of endocrine disrupting chemicals、Biochemical Acid Research Studies、Polymer Science and PVC

BACKGROUND: Di (2-ethylhexyl) phthalate (DEHP), a pervasive environmental plasticizer, is associated with diabetes, cardiovascular disease (CVD), and chronic kidney disease (CKD); however, its role in driving Cardiovascular-Kidney-Metabolic (CKM) syndrome remains unconfirmed. METHODS: We employed an integrated approach combining NHANES epidemiological data, network toxicology, computational simulations, and experimental validation. Cytotoxicity was assessed via Lactate Dehydrogenase (LDH) release assays in cardiomyocytes and renal tubular epithelial cells following DEHP exposure (0-150 μM) over 24-48 h. RESULTS: Urinary DEHP metabolites showed dose-dependent associations with CKM (stages 2-4). Each unit increase in Ln (DEHP) was associated with a 35 % elevated risk of CKM (OR=1.35, 95 % CI: 1.03-1.78). Compared to the lowest exposure tertile, individuals in the highest tertile had a 132 % increased risk (OR=2.32, 95 % CI: 1.18-4.58). Body mass index (BMI) synergistically amplified this association, with obese individuals exhibiting a 2.89-fold higher risk per unit exposure. Network toxicology identified eight core targets, and pathway analysis revealed interconnected metabolic, inflammatory, and fibrotic processes. Molecular docking and dynamics simulations confirmed stable binding with three core targets: PPARG, PTGS2, and MMP2. Furthermore, in vitro experiments showed that DEHP induced concentration- and time-dependent cytotoxicity in both cardiomyocytes and renal tubular e...