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

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalInternational Journal of Molecular Sciences
Volume19
Issue number7
DOIs
Publication statusPublished - Jul 8 2018

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central nervous system
Neurology
Cytotoxicity
Cell culture
Nanoparticles
spheroids
Central Nervous System
Astrocytes
nanoparticles
Neurons
cells
neurons
Testing
Toxicity
Assays
Brain
mortality
test stands
Cell Survival
viability

Keywords

  • Cell Culture Techniques/methods
  • Cells, Cultured
  • Central Nervous System/cytology
  • Dose-Response Relationship, Drug
  • Humans
  • Magnetite Nanoparticles/toxicity
  • Models, Biological
  • Spheroids, Cellular/cytology
  • Time Factors

Cite this

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title = "Human 3D Cultures as Models for Evaluating Magnetic Nanoparticle CNS Cytotoxicity after Short- and Repeated Long-Term Exposure",
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.",
keywords = "Cell Culture Techniques/methods, Cells, Cultured, Central Nervous System/cytology, Dose-Response Relationship, Drug, Humans, Magnetite Nanoparticles/toxicity, Models, Biological, Spheroids, Cellular/cytology, Time Factors",
author = "{De Simone}, Uliana and Marianna Roccio and Laura Gribaldo and Arsenio Spinillo and Francesca Caloni and Teresa Coccini",
year = "2018",
month = "7",
day = "8",
doi = "10.3390/ijms19071993",
language = "English",
volume = "19",
journal = "International Journal of Molecular Sciences",
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TY - JOUR

T1 - Human 3D Cultures as Models for Evaluating Magnetic Nanoparticle CNS Cytotoxicity after Short- and Repeated Long-Term Exposure

AU - De Simone, Uliana

AU - Roccio, Marianna

AU - Gribaldo, Laura

AU - Spinillo, Arsenio

AU - Caloni, Francesca

AU - Coccini, Teresa

PY - 2018/7/8

Y1 - 2018/7/8

N2 - 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.

AB - 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.

KW - Cell Culture Techniques/methods

KW - Cells, Cultured

KW - Central Nervous System/cytology

KW - Dose-Response Relationship, Drug

KW - Humans

KW - Magnetite Nanoparticles/toxicity

KW - Models, Biological

KW - Spheroids, Cellular/cytology

KW - Time Factors

U2 - 10.3390/ijms19071993

DO - 10.3390/ijms19071993

M3 - Article

VL - 19

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

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ER -