Assessment of nanomaterial-induced hepatotoxicity using a 3D human primary multi-cellular microtissue exposed repeatedly over 21 days - the suitability of the in vitro system as an in vivo surrogate

Journal article

Ali Kermanizadeh, Trine Berthing, Ewa Guzniczak, Melanie Wheeldon, Graeme Whyte, Ulla Vogel, Wolfgang Moritz and Vicki Stone 2019. Assessment of nanomaterial-induced hepatotoxicity using a 3D human primary multi-cellular microtissue exposed repeatedly over 21 days - the suitability of the in vitro system as an in vivo surrogate. Particle and Fibre Toxicology. Vol 16 (Issue 1), p. Article: 42. https://doi.org/10.1186/s12989-019-0326-0
AuthorsAli Kermanizadeh, Trine Berthing, Ewa Guzniczak, Melanie Wheeldon, Graeme Whyte, Ulla Vogel, Wolfgang Moritz and Vicki Stone
Abstract

Background

With ever-increasing exposure to engineered nanomaterials (NMs), there is an urgent need to evaluate the probability of consequential adverse effects. The potential for NM translocation to distal organs is a realistic prospect, with the liver being one of the most important target organs. Traditional in vitro or ex vivo hepatic toxicology models are often limiting (i.e. short life-span, reduced metabolic activity, lacking important cell populations, etc.). In this study, we scrutinize a 3D human liver microtissue (MT) model (composed of primary hepatocytes and non-parenchymal cells). This unique experiment benefits from long-term (3 weeks) repeated very low exposure concentrations, as well as incorporation of recovery periods (up to 2 weeks), in an attempt to account for the liver’s recovery capacity in vivo. As a means of assessing the toxicological potential of NMs, cell cytotoxicity (cell membrane integrity and aspartate aminotransferase (AST) activity), pro/anti-inflammatory response and hepatic function were investigated.

Results

The data showed that 2 weeks of cell culture might be close to limits before subtle ageing effects start to overshadow low sub-lethal NM-induced cellular responses in this test system (adenylate kinase (AK) cytotoxicity assay). We showed that in vitro AST measurement are not suitable in a nanotoxicological context. Moreover, the cytokine analysis (IL6, IL8, IL10 and TNF-α) proved useful in highlighting recovery periods as being sufficient for allowing a reduction in the pro-inflammatory response. Next, low soluble NM-treated MT showed a concentration-dependent penetration of materials deep into the tissue.

Conclusion

In this study the advantages and pitfalls of the multi-cellular primary liver MT are discussed. Furthermore, we explore a number of important considerations for allowing more meaningful in vitro vs. in vivo comparisons in the field of hepatic nanotoxicology.

Keywords3D primary human multi-cellular liver microtissue; In vitro hepatotoxicology; n vitro vs. in vivo comparisons; Kupffer cells
Year2019
JournalParticle and Fibre Toxicology
Journal citationVol 16 (Issue 1), p. Article: 42
PublisherBMC (Springer Nature)
ISSN1743-8977
Digital Object Identifier (DOI)https://doi.org/10.1186/s12989-019-0326-0
Web address (URL)https://doi.org/10.1186/s12989-019-0326-0
Output statusPublished
Publication dates
Online19 Nov 2019
Publication process dates
Deposited12 Jun 2023
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