AHR/cyp1b1 signaling-mediated extrinsic apoptosis contributes to 6PPDQ-induced cardiac dysfunction in zebrafish embryos

• Published in: Environmental pollution (1987) 2024-03, Vol.345, p.123467-123467, Article 123467
• Main Authors: Jiang, Yan, Zhang, Mingxuan, Li, Jinhao, Hu, Keqi, Chen, Tao
• Format: Article
• Language: English
• Subjects: 6PPDQ; AHR; Apoptosis; Cardiac dysfunction; Zebrafish embryo
• ISSN: 0269-7491; 1873-6424
• DOI: 10.1016/j.envpol.2024.123467

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 (0.2–2000 μg/L) up to 3 days post-fertilization (dpf). However, concentrations at 2 μg/L or higher induced cardiac dysfunctions, leading to lethal effects at later stages (6–8 dpf). 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. [Display omitted] •6PPDQ at an environmental relevant concentration induces cardiac dysfunction in zebrafish embryos.•Aryl hydrocarbon receptor signaling mediates 6PPDQ-induced cardiac dysfunction.•Aryl hydrocarbon receptor activated by 6PPDQ induces oxidative stress and DNA damage.•6PPDQ triggers p53-dependent exogenous apoptosis in zebrafish embryonic hearts.