Different cellular mechanisms from low- and high-dose zinc oxide nanoparticles-induced heart tube malformation during embryogenesis

Abstract

With the wide application of nanometer materials in daily life, people pay more attention to the potential toxicity of nanoparticles to human fetal development once the nanoparticles are absorbed into the human body during pregnancy. However, there was no directly solid evidence for ZnO NPs-caused congenital heart defects. Hence, we investigated the effect of ZnO NPs exposure on early cardiogenesis using the chicken/mouse embryo models. First, we showed ZnO NPs reduced H9c2 cell viability in a dose- and time-dependent manner, while cell autophagy was significantly activated too on the same pattern. During early cardiogenesis, ZnO NPs exposure increased the chance of heart tube malformation, while precardiac cell apoptosis rises in the phenotype of closure defect and Bifida. The hypertrophy was also observed in late-stage chicken/mouse survival embryos exposed to ZnO NPs. Apart from cell apoptosis, high-dose ZnO NPs exposure led to massive programmed necrosis, and further experiments verified that ferroptosis remained primarily in ZnO NPs-induced programmed necrosis. We also revealed that the toxicology of low-dose ZnO NPs was mainly featured in the changes of expressions of key genes instead of causing precardiac cell death. MYL2 and CSRP3 could work as the downstream molecules of the above key genes in the context of ZnO NPs exposure to early cardiogenesis based on RNA sequencing. Taken together, this study for the first time revealed the potential risk of heart tube malformation induced by ZnO NPs exposure through different cellular mechanisms, which depended on low- or high-dose ZnO NPs.

Keywords:

• Zinc oxide nanoparticles
• chicken/mouse embryo
• heart tube formation
• ferroptosis

Acknowledgements

The authors sincerely acknowledge the assistance received from Medical experimental center, School of medicine.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This work was supported by NSFC grant [32170825, 31771331], Research Funds for the Central Universities [21621106] and Research Grant of Key Laboratory of Regenerative Medicine, Ministry of Education, Jinan University [ZSYXM202217].