Abstract

This study was conducted to determine the endocrine-disrupting effects of phthalate esters (PAEs) on the glucocorticoid receptor (GR) signaling. Potential (anti)glucocorticoid activities of six typical PAEs including di (2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), diethyl phthalate (DEP) and dimethyl phthalate (DMP) were evaluated on human GR using cell viability assessment, reporter gene expression analysis, mRNA analysis, and molecular docking and simulation. For all tested chemicals, co-treatment of DEHP and DINP with dexamethasone (DEX) exhibited a synergistic effect on GR transactivity in the reporter assays. Such co-treatment also synergistically enhanced DEX-induced upregulation of GR mediated gene (PEPCK, FAS and MKP-1) mRNA expression in HepG2 cells and A549 cells. Molecular docking and dynamics simulations showed that hydrophobic interactions may stabilize the binding between molecules and GR. In summary, DEHP and DINP may be involved in synergistic effects via human GR, which highlight the potential endocrine-disrupting activities of PAEs as contaminants.

摘要

进行这项研究来确定邻苯二甲酸酯（PAE）对糖皮质激素受体（GR）信号传导的内分泌干扰作用。六种典型PAE的潜在（抗）糖皮质激素活性，包括邻苯二甲酸二（2-乙基己基）酯，邻苯二甲酸二异壬酯（DINP），邻苯二甲酸二丁酯（DBP），邻苯二甲酸二异丁酯（DIBP），邻苯二甲酸二乙酯（DEP）和邻苯二甲酸二甲酯（DMP）使用细胞生存力评估，报告基因表达分析，mRNA分析以及分子对接和模拟对人类GR进行评估。对于所有测试的化学药品，在报告基因检测中，DEHP和DINP与地塞米松（DEX）的共处理对GR交易性具有协同作用。这种共同治疗还协同增强了DEX诱导的GR介导的基因（PEPCK，FAS和MKP-1）mRNA在HepG2细胞和A549细胞中的表达。分子对接和动力学模拟表明疏水相互作用可以稳定分子与GR之间的结合。总之，DEHP和DINP可能通过人类GR参与协同作用，这突出了PAE作为污染物的潜在内分泌干扰活性。