Toxicity and biodegradation of zinc ferrite nanoparticles in Xenopus laevis
Zn-doped Fe3O4 magnetic nanoparticles have been proposed as the ideal ferrite for some biomedical applications like magnetic hyperthermia or photothermal therapy because of the possibility to adjust their size and chemical composition in order to design tailored treatments. However, reliable approaches are needed to risk assess Zn ferrite nanoparticles before clinical development. In this work, the in vitro toxicity of the nanoparticles was evaluated in five cellular models (Caco-2, HepG2, MDCK, Calu-3 and Raw 264.7) representing different target organs/systems (gastrointestinal system, liver, kidney, respiratory system and immune system). For the first time, these nanoparticles were evaluated in an in vivo Xenopus laevis model to study whole organism toxicity and their impact on iron and zinc metabolic pathways. Short- and long-term in vivo exposure studies provided insights into the contrasting adverse effects between acute and chronic exposure. Quantitative PCR combined with elemental analysis and AC magnetic susceptibility measurements revealed that at short-term exposure (72 h), the nanoparticles’ absorption process is predominant, with the consequent over-expression of metal transporters and metal response proteins. At long-term exposure (120 h), there is an upregulation of metal accumulation involved genes and the return to basal levels of both iron and zinc transporters, involved in the uptake of metals. This suggests that at this stage, the nanoparticles’ absorption process is residual compared with the following steps in metabolism, distribution and/or excretion processes, indicated by the increase of iron accumulation proteins at both transcriptional and translational level. This testing approach based on a battery of cellular systems and the use of the Xenopus laevis model could be a viable strategy for studying the toxicity, degradability and ultimately the long-term fate of zinc ferrites in the organism.
KeywordsZinc ferrite nanoparticles Xenopus laevis Toxicity Biodegradation Metabolism Environmental and health effects
Servicio General de Apoyo a la Investigación-SAI, Universidad de Zaragoza is acknowledged. The authors also acknowledge the facilities and the scientific and technical assistance, especially that of Bertrand Leze from the SEM service of the University of East Anglia.
M. Marín-Barba has been supported by the People Program (Marie Curie Actions) of the European Union’s Seventh Framework Program FP7 under REA grant agreement number 607142 (DevCom). A. Ruiz was supported by FP7-People Framework – Marie Curie Industry and Academia Partnerships & Pathways scheme (DNA-TRAP project, grant agreement no. 612338). L. Gutiérrez recognizes financial support from the Ramón y Cajal subprogram (RYC-2014-15512). E. Lozano-Velasco acknowledges support from Marie Curie fellowship (705089-MIR-CHROM-C).
Compliance with ethical standards
All experiments were performed in compliance with the relevant laws and institutional guidelines at the University of East Anglia. The research has been approved by the local ethical review committee according to UK Home Office regulations.
Conflict of interest
The authors declare that there are no conflicts of interest.
- Al-Yousuf K et al (2017) Combining Cytotoxicity Assessment and Xenopus laevis Phenotypic Abnormality assay as a predictor of nanomaterial safety. Curr Protoc Toxicol 73:20(13.1–20):13–33Google Scholar
- Bacchetta R, Moschini E, Santo N, Fascio U, del Giacco L, Freddi S, Camatini M, Mantecca P (2014) Evidence and uptake routes for zinc oxide nanoparticles through the gastrointestinal barrier in Xenopus laevis. Nanotoxicology 8(7):728–744. https://doi.org/10.3109/17435390.2013.824128 CrossRefGoogle Scholar
- Bonfanti P, Moschini E, Saibene M, Bacchetta R, Rettighieri L, Calabri L, Colombo A, Mantecca P (2015) Do nanoparticle physico-chemical properties and developmental exposure window influence nano ZnO embryotoxicity in Xenopus laevis? Int J Environ Res Public HealthISSN 123390:8828–8848. https://doi.org/10.3390/ijerph120808828 CrossRefGoogle Scholar
- Chaurasia N (2017) Nanotechnology and nanomaterials in everyday life. Int J Sci Res 6(4):1560–1562Google Scholar
- Cohen LA, Gutierrez L, Weiss A, Leichtmann-Bardoogo Y, Zhang DL, Crooks DR, Sougrat R, Morgenstern A, Galy B, Hentze MW, Lazaro FJ, Rouault TA, Meyron-Holtz EG (2010) Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 116(9):1574–1584. https://doi.org/10.1182/blood-2009-11-253815 CrossRefGoogle Scholar
- Estelrich J, Sánchez-Martín M, Busquets M (2015) Nanoparticles in magnetic resonance imaging: from simple to dual contrast agents. Int J Nanomedicine 10:1727–1741Google Scholar
- Galdiero E, Falanga A, Siciliano A, Maselli V, Guida M, Carotenuto R, Tussellino M, Lombardi L, Benvenuto G, Galdiero S (2017) Daphnia magna and Xenopus laevis as in vivo models to probe toxicity and uptake of quantum dots functionalized with gH625. Int J Nanomed Dove Press 12:2717–2731. https://doi.org/10.2147/IJN.S127226 CrossRefGoogle Scholar
- Garrick MD, Dolan KG, Horbinski C, Ghio AJ, Higgins D, Porubcin M, Moore EG, Hainsworth LN, Umbreit JN, Conrad ME, Feng L, Lis A, Roth JA, Singleton S, Garrick LM (2003) DMT1: a mammalian transporter for multiple metals. BioMetals 16(1):41–54. https://doi.org/10.1023/A:1020702213099 CrossRefGoogle Scholar
- Kruszewski M, Iwaneńko T (2003) Labile iron pool correlates with iron content in the nucleus and the formation of oxidative DNA damage in mouse lymphoma L5178Y cell lines. Acta Biochim Pol 50(1):211–215Google Scholar
- Marín-Barba M, Gavilán H, Gutiérrez L, Lozano-Velasco E, Rodríguez-Ramiro I, Wheeler GN, Morris CJ, Morales MP, Ruiz A (2018) Unravelling the mechanisms that determine the uptake and metabolism of magnetic single and multicore nanoparticles in a Xenopus laevis model. Nanoscale 10(690–704):690–704. https://doi.org/10.1039/C7NR06020C CrossRefGoogle Scholar
- Mazuel F, Espinosa A, Luciani N, Reffay M, le Borgne R, Motte L, Desboeufs K, Michel A, Pellegrino T, Lalatonne Y, Wilhelm C (2016) Massive intracellular biodegradation of iron oxide nanoparticles evidenced magnetically at single-endosome and tissue levels. ACS Nano 10(8):7627–7638. https://doi.org/10.1021/acsnano.6b02876 CrossRefGoogle Scholar
- Mazur M, Barras A, Kuncser V, Galatanu A, Zaitzev V, Turcheniuk KV, Woisel P, Lyskawa J, Laure W, Siriwardena A, Boukherroub R, Szunerits S (2013) Iron oxide magnetic nanoparticles with versatile surface functions based on dopamine anchors. Nanoscale 5(7):2692–2702. https://doi.org/10.1039/c3nr33506b CrossRefGoogle Scholar
- Naqvi et al (2010) Concentration-dependent toxicity of iron oxide nanoparticles mediated by increased oxidative stress. Int J Nanomed:983. https://doi.org/10.2147/ijn.s13244
- Nieuwkoop PD, Faber J (1994) Normal table of Xenopus laevis (Daudin): a systematical and chronological survey of the development from the fertilized egg till the end of metamorphosis. Garland Pub, New YorkGoogle Scholar
- Palmiter RD, Findley SD (1995) Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. EMBO J 14(4):639–649. https://doi.org/10.1002/j.1460-2075.1995.tb07042.x CrossRefGoogle Scholar
- Saide K, Sherwood V, Wheeler G (2018) Paracetamol-induced liver injury modelled in Xenopus laevis embryos. Toxicol LettGoogle Scholar
- Saquib Q, al-Khedhairy AA, Ahmad J, Siddiqui MA, Dwivedi S, Khan ST, Musarrat J (2013) Zinc ferrite nanoparticles activate IL-1b, NFKB1, CCL21 and NOS2 signaling to induce mitochondrial dependent intrinsic apoptotic pathway in WISH cells. Toxicol Appl Pharmacol Elsevier Inc 273(2):289–297. https://doi.org/10.1016/j.taap.2013.09.001 CrossRefGoogle Scholar
- Tefft B et al (2015) Cell labeling and targeting with superparamagnetic iron oxide nanoparticles. J Vis Exp 19(1105):e53099Google Scholar
- Tussellino M, Ronca R, Formiggini F, Marco ND, Fusco S, Netti PA, Carotenuto R (2015) Polystyrene nanoparticles affect Xenopus laevis development. J Nanopart Res 17(2). https://doi.org/10.1007/s11051-015-2876-x