Hou Tingting, Wang Fei, Wang Lei, Zhang Huiqiang, Fan Xiaoteng
School of Public Health, Xi'an Medical University, Xi'an 710021, China.
Shaanxi Key Laboratory of Environmental Monitoring and Forewarning of Trace Pollutants, Shaanxi Environmental Monitoring Centre, Xi'an 710054, China.
Comp Biochem Physiol C Toxicol Pharmacol. 2025 Oct;296:110258. doi: 10.1016/j.cbpc.2025.110258. Epub 2025 Jun 23.
Dibutyl phthalate (DBP) is extensively contaminated in aquatic environment with severe threats to fishes, its toxic mechanisms and the susceptibility across different tissues require further investigations. In this study, zebrafish (Danio rerio) were used to investigate the histopathology with ferroptosis responses to DBP exposure through physiological and biochemical detection, histological examination, and transcript analyses. Following the chronic DBP exposure at environmental-relevant concentrations (0, 5, and 50 μg/L), the body weight, body length, condition factor, and gonadosomatic index of female zebrafish were decreased, along with a slightly increased hepatosomatic index and retarded development. Notably, the total iron content and distribution were elevated in the liver and brain, accompanied by increased lipid peroxidation and decreased glutathione peroxidase 4 (GPX4) and glutathione (GSH) levels, ultimately leading to histological impairments. Transcript analyses showed that DBP induced ferroptosis by down-regulating genes expression of system Xc and gpx4b, while up-regulating genes expression related to iron metabolism and lipid peroxidation in the liver. In the brain, similarly ferroptosis responses were observed, characterized by the downregulation of gpx4b and upregulation of iron metabolism-related genes and acsl4a expression. In contrast, the gill and ovary exhibited oxidative stress, lipid peroxidation, structural disruption or follicular retardation without pronounced ferroptosis response. Taken together, this study demonstrates that DBP exposure could induce ferroptosis in zebrafish in a tissue-specific manner, that contributes to an in-depth understanding of the biotoxicity and tolerance to chemical contamination.
邻苯二甲酸二丁酯（DBP）在水生环境中广泛污染，对鱼类构成严重威胁，其毒性机制以及不同组织的易感性需要进一步研究。在本研究中，通过生理生化检测、组织学检查和转录分析，利用斑马鱼（Danio rerio）研究了DBP暴露下的组织病理学和铁死亡反应。在环境相关浓度（0、5和50μg/L）下长期暴露于DBP后，雌性斑马鱼的体重、体长、肥满度和性腺指数下降，同时肝体指数略有增加且发育迟缓。值得注意的是，肝脏和大脑中的总铁含量和分布升高，同时脂质过氧化增加，谷胱甘肽过氧化物酶4（GPX4）和谷胱甘肽（GSH）水平降低，最终导致组织学损伤。转录分析表明，DBP通过下调系统Xc和gpx4b的基因表达诱导铁死亡，同时上调肝脏中与铁代谢和脂质过氧化相关的基因表达。在大脑中，观察到类似的铁死亡反应，其特征是gpx4b下调，铁代谢相关基因和acsl4a表达上调。相比之下，鳃和卵巢表现出氧化应激、脂质过氧化、结构破坏或卵泡发育迟缓，没有明显的铁死亡反应。综上所述，本研究表明DBP暴露可在斑马鱼中以组织特异性方式诱导铁死亡，这有助于深入了解生物毒性和对化学污染的耐受性。
