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

Part Fibre Toxicol. 2014 Oct 20:11:56. doi: 10.1186/s12989-014-0056-2.


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.

Publication types

  • Comparative Study
  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury* / immunology
  • Chemical and Drug Induced Liver Injury* / metabolism
  • Coculture Techniques
  • Cytokines / agonists
  • Cytokines / metabolism
  • DNA Damage*
  • Hepatocytes / cytology
  • Humans
  • Lipid Peroxidation / drug effects
  • Liver / drug effects*
  • Liver / immunology
  • Liver / metabolism
  • Liver / pathology
  • Metal Nanoparticles / chemistry
  • Metal Nanoparticles / toxicity
  • Metal Nanoparticles / ultrastructure
  • Microscopy, Electron, Transmission
  • Nanostructures / chemistry
  • Nanostructures / toxicity*
  • Nanostructures / ultrastructure
  • Nanotubes, Carbon / chemistry
  • Nanotubes, Carbon / toxicity
  • Nanotubes, Carbon / ultrastructure
  • Oxidative Stress / drug effects*
  • Serum Albumin / biosynthesis*
  • Serum Albumin, Human
  • Silver / chemistry
  • Silver / toxicity
  • Stromal Cells / cytology
  • Titanium / chemistry
  • Titanium / toxicity
  • Toxicity Tests, Acute / methods*
  • Zinc Oxide / chemistry
  • Zinc Oxide / toxicity


  • ALB protein, human
  • Cytokines
  • Nanotubes, Carbon
  • Serum Albumin
  • titanium dioxide
  • Silver
  • Titanium
  • Zinc Oxide
  • Serum Albumin, Human