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
Authors | Ali Kermanizadeh, Trine Berthing, Ewa Guzniczak, Melanie Wheeldon, Graeme Whyte, Ulla Vogel, Wolfgang Moritz and Vicki Stone |
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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. |
Keywords | 3D primary human multi-cellular liver microtissue; In vitro hepatotoxicology; n vitro vs. in vivo comparisons; Kupffer cells |
Year | 2019 |
Journal | Particle and Fibre Toxicology |
Journal citation | Vol 16 (Issue 1), p. Article: 42 |
Publisher | BMC (Springer Nature) |
ISSN | 1743-8977 |
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 status | Published |
Publication dates | |
Online | 19 Nov 2019 |
Publication process dates | |
Deposited | 12 Jun 2023 |
https://repository.derby.ac.uk/item/9z35q/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
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