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Int. J. Mol. Sci. 2018, 19(7), 1993; https://doi.org/10.3390/ijms19071993

Human 3D Cultures as Models for Evaluating Magnetic Nanoparticle CNS Cytotoxicity after Short- and Repeated Long-Term Exposure

1
Laboratory of Clinical and Experimental Toxicology, Toxicology Unit, ICS Maugeri SpA-BC, IRCCS Pavia, 27100 Pavia, Italy
2
Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo and University of Pavia, 27100 Pavia, Italy
3
European Commission, Directorate General Joint Research Centre, Directorate F-Health, Consumers and Reference Materials, Chemicals Safety and Alternative Methods Unit, 21027 Ispra, Italy
4
Università degli Studi di Milano, Dipartimento di Medicina Veterinaria (DIMEVET), 20133 Milano, Italy
*
Author to whom correspondence should be addressed.
Received: 6 June 2018 / Revised: 2 July 2018 / Accepted: 4 July 2018 / Published: 8 July 2018
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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Abstract

Since nanoparticles (NPs) can translocate to the brain and impact the highly vulnerable central nervous system (CNS), novel in vitro tools for the assessment of NP-induced neurotoxicity are advocated. In this study, two types of CNS spheroids have been developed from human D384 astrocyte- and SH-SY5Y neuronal-like cells, and optimized in combination with standard assays (viability readout and cell morphology) to test neurotoxic effects caused by Fe3O4NPs, as NP-model, after short- (24–48 h; 1–100µg/ml) and long-term repeated exposure (30days; 0.1–25µg/ml). Short-term exposure of 3D-spheroids to Fe3O4NP induced cytotoxicity at 10 µg/mL in astrocytes and 25 µg/mL neurons. After long-term repeated dose regimen, spheroids showed concentration- and time-dependent cell mortality at 10 µg/mL for D384 and 0.5 µg/mL for SH-SY5Y, indicating a higher susceptibility of neurons than astrocytes. Both spheroid types displayed cell disaggregation after the first week of treatment at ≥0.1 µg/mL and becoming considerably evident at higher concentrations and over time. Recreating the 3D-spatial environment of the CNS allows cells to behave in vitro more closely to the in vivo situations, therefore providing a model that can be used as a stand-alone test or as a part of integrated testing strategies. These models could drive an improvement in the species-relevant predictivity of toxicity testing. View Full-Text
Keywords: Fe3O4NPs; in vitro screening; D384 cells; SH-SY5Y cells; neurotoxicity; nanotoxicology Fe3O4NPs; in vitro screening; D384 cells; SH-SY5Y cells; neurotoxicity; nanotoxicology
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De Simone, U.; Roccio, M.; Gribaldo, L.; Spinillo, A.; Caloni, F.; Coccini, T. Human 3D Cultures as Models for Evaluating Magnetic Nanoparticle CNS Cytotoxicity after Short- and Repeated Long-Term Exposure. Int. J. Mol. Sci. 2018, 19, 1993.

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