TY - JOUR

T1 - Hepatic toxicology following single and multiple exposure of engineered nanomaterials utilising a novel primary human 3D liver microtissue model

AU - Kermanizadeh, Ali

AU - Løhr, Mille

AU - Roursgaard, Martin

AU - Messner, Simon

AU - Gunness, Patrina

AU - Kelm, Jens M

AU - Møller, Peter

AU - Stone, Vicki

AU - Loft, Steffen

PY - 2014/10/20

Y1 - 2014/10/20

N2 - BACKGROUND: The liver has a crucial role in metabolic homeostasis as well as being the principal detoxification centre of the body, removing xenobiotics and waste products which could potentially include some nanomaterials (NM). With the ever increasing public and occupational exposure associated with accumulative production of nanomaterials, there is an urgent need to consider the possibility of detrimental health consequences of engineered NM exposure. It has been shown that exposure via inhalation, intratracheal instillation or ingestion can result in NM translocation to the liver. Traditional in vitro or ex vivo hepatic nanotoxicology models are often limiting and/or troublesome (i.e. reduced metabolism enzymes, lacking important cell populations, unstable with very high variability, etc.).METHODS: In order to rectify these issues and for the very first time we have utilised a 3D human liver microtissue model to investigate the toxicological effects associated with a single or multiple exposure of a panel of engineered NMs (Ag, ZnO, MWCNT and a positively charged TiO₂).RESULTS: Here we demonstrate that the repeated exposure of the NMs is more damaging to the liver tissue as in comparison to a single exposure with the adverse effects more significant following treatment with the Ag and ZnO as compared with the TiO₂ and MWCNT NMs (in terms of cytotoxicity, cytokine secretion, lipid peroxidation and genotoxicity).CONCLUSIONS: Overall, this study demonstrates that the human microtissue model utilised herein is an excellent candidate for replacement of traditional in vitro single cell hepatic models and further progression of liver nanotoxicology.

AB - BACKGROUND: The liver has a crucial role in metabolic homeostasis as well as being the principal detoxification centre of the body, removing xenobiotics and waste products which could potentially include some nanomaterials (NM). With the ever increasing public and occupational exposure associated with accumulative production of nanomaterials, there is an urgent need to consider the possibility of detrimental health consequences of engineered NM exposure. It has been shown that exposure via inhalation, intratracheal instillation or ingestion can result in NM translocation to the liver. Traditional in vitro or ex vivo hepatic nanotoxicology models are often limiting and/or troublesome (i.e. reduced metabolism enzymes, lacking important cell populations, unstable with very high variability, etc.).METHODS: In order to rectify these issues and for the very first time we have utilised a 3D human liver microtissue model to investigate the toxicological effects associated with a single or multiple exposure of a panel of engineered NMs (Ag, ZnO, MWCNT and a positively charged TiO₂).RESULTS: Here we demonstrate that the repeated exposure of the NMs is more damaging to the liver tissue as in comparison to a single exposure with the adverse effects more significant following treatment with the Ag and ZnO as compared with the TiO₂ and MWCNT NMs (in terms of cytotoxicity, cytokine secretion, lipid peroxidation and genotoxicity).CONCLUSIONS: Overall, this study demonstrates that the human microtissue model utilised herein is an excellent candidate for replacement of traditional in vitro single cell hepatic models and further progression of liver nanotoxicology.

KW - Cells, Cultured

KW - Chemical and Drug Induced Liver Injury/immunology

KW - Coculture Techniques

KW - Cytokines/agonists

KW - DNA Damage

KW - Hepatocytes/cytology

KW - Humans

KW - Lipid Peroxidation/drug effects

KW - Liver/drug effects

KW - Metal Nanoparticles/chemistry

KW - Microscopy, Electron, Transmission

KW - Nanostructures/chemistry

KW - Nanotubes, Carbon/chemistry

KW - Oxidative Stress/drug effects

KW - Serum Albumin/biosynthesis

KW - Serum Albumin, Human

KW - Silver/chemistry

KW - Stromal Cells/cytology

KW - Titanium/chemistry

KW - Toxicity Tests, Acute/methods

KW - Zinc Oxide/chemistry

U2 - 10.1186/s12989-014-0056-2

DO - 10.1186/s12989-014-0056-2

M3 - Article

C2 - 25326698

VL - 11

SP - 56

JO - Particle and fibre toxicology

JF - Particle and fibre toxicology

SN - 1743-8977

ER -