电压依赖性阴离子通道
细胞生物学
线粒体
化学
线粒体通透性转换孔
下调和上调
邻苯二甲酸二丁酯
脂质过氧化
磷脂过氧化氢谷胱甘肽过氧化物酶
程序性细胞死亡
生物
细胞凋亡
氧化应激
生物化学
超氧化物歧化酶
谷胱甘肽过氧化物酶
细菌外膜
基因
有机化学
大肠杆菌
作者
Tingting Hou,Xiaoteng Fan,Qian‐qing Zhang,Haowei Zhang,Dingfu Zhang,Tao Lü,Zaizhao Wang
标识
DOI:10.1016/j.envpol.2024.123846
摘要
Dibutyl phthalate (DBP) contamination has raised global concern for decades, while its health risk with toxic mechanisms requires further elaboration. This study used zebrafish ZF4 cells to investigate the toxicity of ferroptosis with underlying mechanisms in response to DBP exposure. Results showed that DBP induced ferroptosis, characterized by accumulation of ferrous iron, lipid peroxidation, and decrease of glutathione peroxidase 4 levels in a time-dependent manner, subsequently reduced cell viability. Transcriptome analysis revealed that voltage-dependent anion-selective channel (VDAC) in mitochondrial outer membrane was upregulated in ferroptosis signaling pathways. Protecting mitochondria with a VDAC2 inhibitor or siRNAs attenuated the accumulation of mitochondrial superoxide and lipid peroxides, the opening of mitochondrial permeability transition pore (mPTP), and the overload of iron levels, suggesting VDAC2 oligomerization mediated the influx of iron into mitochondria that is predominant and responsible for mitochondria-dependent ferroptosis under DBP exposure. Furthermore, the pivotal role of activating transcription factor 4 (ATF4) was identified in the transcriptional regulation of vdac2 by ChIP assay. And the intervention of atf4b inhibited DBP-induced VDAC2 upregulation and oligomerization. Taken together, this study reveals that ATF4-VDAC2 signaling pathway is involved in the DBP-induced ferroptosis in zebrafish ZF4 cells, contributing to the in-depth understanding of biotoxicity and the ecological risk assessment of phthalates.
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