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
|Authors||Ali Kermanizadeh, Trine Berthing, Ewa Guzniczak, Melanie Wheeldon, Graeme Whyte, Ulla Vogel, Wolfgang Moritz and Vicki Stone|
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.
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.
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|
|Journal||Particle and Fibre Toxicology|
|Journal citation||Vol 16 (Issue 1), p. Article: 42|
|Publisher||BMC (Springer Nature)|
|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|
|Online||19 Nov 2019|
|Publication process dates|
|Deposited||12 Jun 2023|
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