Baralić Katarina, Pavić Aleksandar, Javorac Dragana, Živančević Katarina, Božić Dragica, Radaković Nataša, Antonijević Miljaković Evica, Buha Djordjevic Aleksandra, Ćurčić Marijana, Bulat Zorica, Antonijević Biljana, Đukić-Ćosić Danijela
Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia.
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Serbia.
J Hazard Mater. 2023 Mar 5;445:130404. doi: 10.1016/j.jhazmat.2022.130404. Epub 2022 Nov 15.
Connections between the mixture containing bis(2- ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and bisphenol A (BPA) and liver injury were explored through in silico investigation and 2 in vivo models. Comparative Toxicogenomics Database (CTD), ShinyGO, ToppCluster and Cytoscape were used for bioinformatic analysis. In vivo subacute study was performed on rats - five groups (n = 6): (1) Control: corn oil, (2) DEHP: 50 mg/kg b.w./day, (3) DBP: 50 mg/kg b.w./day, (4) BPA: 25 mg/kg b.w./day, (5) MIX: DEHP + DBP + BPA. Zebrafish embryos were exposed to the investigated substances in different doses, singularly and combined (binary and ternary mixtures). Liver injury was linked to 75 DEHP, DBP, and BPA genes, mostly connected to inflammation/oxidative stress. In rats, significant alterations in redox status/bioelements and pathohistology were most notable or exclusively present in MIX (probable additive effects). BPA decreased liver area (LA) index in dose-dependent manner. DEHP (< 2 µg/mL) and DBP (≤ 5 µg/mL) reduced LA values, while their higher doses increased LA index. The effect of DBP in binary mixtures led to a lethal outcome at the two highest concentrations, while the hepatotoxicity of DEHP/DBP/BPA mixture was dictated by BPA (confirmed by the benchmark dose analysis).
通过计算机模拟研究和两种体内模型，探讨了含有邻苯二甲酸二（2-乙基己基）酯（DEHP）、邻苯二甲酸二丁酯（DBP）和双酚A（BPA）的混合物与肝损伤之间的联系。使用比较毒理基因组学数据库（CTD）、ShinyGO、ToppCluster和Cytoscape进行生物信息学分析。对大鼠进行了体内亚急性研究——五组（n = 6）：（1）对照组：玉米油，（2）DEHP组：50 mg/kg体重/天，（3）DBP组：50 mg/kg体重/天，（4）BPA组：25 mg/kg体重/天，（5）混合组：DEHP + DBP + BPA。将斑马鱼胚胎暴露于不同剂量的受试物质中，单独暴露以及联合暴露（二元和三元混合物）。肝损伤与75个DEHP、DBP和BPA基因有关，这些基因大多与炎症/氧化应激相关。在大鼠中，氧化还原状态/生物元素和病理组织学的显著改变在混合组中最为明显或仅在混合组中出现（可能存在相加效应）。BPA以剂量依赖的方式降低肝脏面积（LA）指数。DEHP（<2 μg/mL）和DBP（≤5 μg/mL）降低了LA值，而它们的高剂量则增加了LA指数。DBP在二元混合物中的作用在两个最高浓度下导致了致死结果，而DEHP/DBP/BPA混合物的肝毒性由BPA决定（经基准剂量分析证实）。
