Metabolomics reveals the role of acetyl-l-carnitine metabolism in γ-Fe₂O₃ NP-induced embryonic development toxicity via mitochondria damage

Abstract

Iron oxides nanoparticles (FeO_X NPs), including α-Fe₂O₃, γ-Fe₂O₃, and Fe₃O₄, are employed in many technological applications. However, very few studies have investigated the embryonic developmental toxicity of FeO_X NPs. In this study, metabolomics analysis were used to uncover the potential mechanisms of FeO_X NPs developmental toxicity on embryo–larval zebrafish and mice. Our results indicated that γ-Fe₂O₃ NP treatment could cause increased mortality, dropped hatching rate, etc., while α-Fe₂O₃ and Fe₃O₄ NPs showed no obvious effect. Through metabolomics analysis, a total of 42 metabolites were found to be significantly changed between the γ-Fe₂O₃ NP-treated group and the control group (p < 0.05). Pathway enrichment analysis indicated the impairment of mitochondria function. γ-Fe₂O₃ NP treatment caused abnormal mitochondrion structure and a decrease in mitochondrial membrane potential in zebrafish embryos. Meanwhile, ATP synthesis was decreased while oxidative stress levels were affected. It is noteworthy that acetyl-l-carnitine (ALCAR) (p = 6.79E − 04) and l-carnitine (p = 1.43E − 03) were identified with minimal p values, the relationship between the two counter-balance was regulated by acetyltransferase (crata). Subsequently, we performed rescue experiments with ALCAR on zebrafish embryos, and found that the mortality rates reduced and hatching rates raised significantly in the γ-Fe₂O₃ NP-treated group. Additionally, γ-Fe₂O₃ exposure could lead to increased absorbed fetus rate, decreased placental weight, lower expression of acetyltransferase (Crat), reduced ATP synthesis as well as increased oxidative stress (p < 0.05). Our findings demonstrated that γ-Fe₂O₃ NP might affect the mitochondrial membrane potential and ATP synthesis by affecting the metabolism of ALCAR, thereby stimulating oxidative stress, cell apoptosis, and causing embryonic development toxicity.

Keywords:

• Iron oxide nanoparticles
• mitochondria
• acetyl-l-carnitine
• zebrafish embryo
• metabolomics

Acknowledgements

We thank all the research staff and students who took part in this work.

Ethics approval

The mice study was passed through the laboratory animal welfare ethics review of Nanjing Medical University (IACUC-1703004).

Disclosure statement

The authors declare that they have no conflicts of interest.

Additional information

Funding

This work was supported by the National Key Research and Development Program of China [2017YFC0211605 and 2017YFC0211606], National Natural Science Foundation of China [81671461, 81602884, 81502832, and 81872650], and the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).