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

Iron oxides nanoparticles (FeOX NPs), including alpha-Fe2O3, gamma-Fe2O3, and Fe3O4, are employed in many technological applications. However, very few studies have investigated the embryonic developmental toxicity of FeOX NPs. In this study, metabolomics analysis were used to uncover the potential mechanisms of FeOX NPs developmental toxicity on embryo-larval zebrafish and mice. Our results indicated that gamma-Fe2O3 NP treatment could cause increased mortality, dropped hatching rate, etc., while alpha-Fe2O3 and Fe3O4 NPs showed no obvious effect. Through metabolomics analysis, a total of 42 metabolites were found to be significantly changed between the gamma-Fe2O3 NP-treated group and the control group (p < 0.05). Pathway enrichment analysis indicated the impairment of mitochondria function. gamma-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 gamma-Fe2O3 NP-treated group. Additionally, gamma-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 gamma-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.