氧化应激
DNA损伤
斑马鱼
芳香烃受体
活性氧
CYP1B1型
细胞凋亡
SOD2
细胞生物学
生物
SOD1
下调和上调
信号转导
化学
内分泌学
超氧化物歧化酶
生物化学
转录因子
DNA
基因
细胞色素P450
新陈代谢
作者
Yan Jiang,Mingxuan Zhang,Jinhao Li,Keqi Hu,Tao Chen
摘要
N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPDQ) has raised significant concerns due to its widespread distribution and high toxicity to aquatic organisms. However, the cardiac developmental toxicity of 6PPDQ and the underlying mechanisms remain unclear. In this study, we observed no notable alterations in heart morphology or embryo survival in zebrafish embryos exposed to 6PPDQ up to 3 days post-fertilization. However, concentrations at 2 μg/L or higher induced cardiac dysfunctions, leading to lethal effects at later stages. We further found that the aryl hydrocarbon receptor (AHR) inhibitor CH22351 attenuated 6PPDQ-induced cardiac dysfunctions, implicating the involvement of AHR signal pathway. Moreover, 6PPDQ exposure led to an overproduction of reactive oxygen species (ROS) and an upregulation of genes associated with oxidative stress (sod1, sod2, and nrf2a). This was accompanied by an increase in oxidative DNA damage and the induction of p53-dependent extrinsic apoptosis. Co-exposure to the ROS scavenger N-acetylcysteine effectively counteracted the DNA damage and apoptosis induced by 6PPDQ. Importantly, inhibition of AHR or its downstream target cyp1b1 attenuated 6PPDQ-induced oxidative stress, DNA damage, and apoptosis. In conclusion, our results provide evidence that 6PPDQ induces oxidative stress through the AHR/cyp1b1 signaling pathway, leading to DNA damage and extrinsic apoptosis, ultimately resulting in cardiac dysfunction.
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