title: Hepatic toxicology following single and multiple exposure of engineered nanomaterials utilising a novel primary human 3D liver microtissue model.
abstract: 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.
authors.affiliation: Department of Public Health, University of Copenhagen, Section of Environmental Health, Copenhagen, 1014, Denmark. alke@sund.ku.dk.|Heriot Watt University, School of Life Sciences, Nanosafety research group, Edinburgh, EH14 4AS, UK. alke@sund.ku.dk.
authors.forename: Ali
authors.initials: A
authors.lastname: Kermanizadeh
authors.affiliation: Department of Public Health, University of Copenhagen, Section of Environmental Health, Copenhagen, 1014, Denmark. millo@sund.ku.dk.
authors.forename: Mille
authors.initials: M
authors.lastname: Løhr
authors.affiliation: Department of Public Health, University of Copenhagen, Section of Environmental Health, Copenhagen, 1014, Denmark. mwro@sund.ku.dk.
authors.forename: Martin
authors.initials: M
authors.lastname: Roursgaard
authors.affiliation: InSphero AG, Wagistrasse 27, Schlieren, 8952, Switzerland. simon.messner@insphero.com.
authors.forename: Simon
authors.initials: S
authors.lastname: Messner
authors.affiliation: InSphero AG, Wagistrasse 27, Schlieren, 8952, Switzerland. patrina.gunness@insphero.com.
authors.forename: Patrina
authors.initials: P
authors.lastname: Gunness
authors.affiliation: InSphero AG, Wagistrasse 27, Schlieren, 8952, Switzerland. jens.kelm@insphero.com.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Kelm
authors.affiliation: Department of Public Health, University of Copenhagen, Section of Environmental Health, Copenhagen, 1014, Denmark. pemo@sund.ku.dk.
authors.forename: Peter
authors.initials: P
authors.lastname: Møller
authors.affiliation: Heriot Watt University, School of Life Sciences, Nanosafety research group, Edinburgh, EH14 4AS, UK. v.stone@hw.ac.uk.
authors.forename: Vicki
authors.initials: V
authors.lastname: Stone
authors.affiliation: Department of Public Health, University of Copenhagen, Section of Environmental Health, Copenhagen, 1014, Denmark. stl@hw.ac.uk.
authors.forename: Steffen
authors.initials: S
authors.lastname: Loft
mesh_terms: D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000819:agonists / Q000378:metabolism; D004249:DNA Damage; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053768:Metal Nanoparticles / Q000737:chemistry / Q000633:toxicity / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D049329:Nanostructures / Q000737:chemistry / Q000633:toxicity* / Q000648:ultrastructure; D037742:Nanotubes, Carbon / Q000737:chemistry / Q000633:toxicity / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects*; D012709:Serum Albumin / Q000096:biosynthesis*; D000075462:Serum Albumin, Human; D012834:Silver / Q000737:chemistry / Q000633:toxicity; D017154:Stromal Cells / Q000166:cytology; D014025:Titanium / Q000737:chemistry / Q000633:toxicity; D023382:Toxicity Tests, Acute / Q000379:methods*; D015034:Zinc Oxide / Q000737:chemistry / Q000633:toxicity
chemical_list: C422455:ALB protein, human; D016207:Cytokines; D037742:Nanotubes, Carbon; D012709:Serum Albumin; C009495:titanium dioxide; D012834:Silver; D014025:Titanium; D015034:Zinc Oxide; D000075462:Serum Albumin, Human