Ferrous Oxide Nanoparticles Induced Abnormal Cardiac Development in Zebrafish Through Hypoxia and Ferroptosis

Abstract

Ferrous oxide nanoparticles(nFeO) have potential applications in biomedicine, industrial processes, and waste water treatment. However, the biocompatibility of nFeO remains uncertain. In this study, we synthesized rhombus-shaped nFeO and exposed them to zebrafish embryos to investigate the bio-safety of nFeO. Our results showed that exposure to nFeO led to pericardial edema, heart bleeding, and enlarged ventricles. Furthermore, the content of dissolved oxygen decreased. Fe²+ ions, which were released from the core of nFeO, were oxidized into Fe³⁺. This caused the overexpression of tfa and fpn genes, which carried Fe³⁺ into and out of the cell membrane, respectively. The overload of Fe³⁺ caused ferroptosis in zebrafish larvae, which was evidenced by the overexpression of the marker gene ptgs2 and the marker production malondialdehyde(MDA) of ferroptosis. However, neither the ferrostatin-1(Fer-1) inhibitor nor deferoxiamine(DFO) could completely rescue the toxicity caused by nFeO. We found that co-treatment of nFeO with CaO₂, a dissolved oxygen donor, and Fer-1 or DFO could totally rescue pericardial edema and heart bleeding. Our results provide new knowledge that both hypoxia and ferroptosis play important roles in nFeO-induced zebrafish cardiac developmental toxicity, which is beneficial for the development and safe application of iron-based nanomaterials in the future.

Keywords

Nanoparticle / Biocompatibility / Heart / Zebrafish / Iron

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