Simulating Nanomaterial Transformation in Cascaded Biological Compartments to Enhance the Physiological Relevance of In Vitro Dosing Regimes: Optional or Required?

Llewellyn, S.; Kämpfer, Angela A. M.; Keller, Johannes G.; Vilsmeier, K.; Büttner, Veronika; Şeleci, Didem Ağ; Schins, Roel P. F.; Doak, Shareen H.; Wohlleben, Wendel

doi:10.1002/smll.202004630

Cited by 12 publications

(12 citation statements)

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“…It is widely acknowledged that it is unsustainable and ethically divisive to rely primarily on in vivo based test systems for comprehensive ENM hazard assessment, as such, research into suitable, physiologically relevant in vitro alternatives has been at the forefront of nanotoxicology in recent years. Not only have scientists strived to alleviate the limitations of current in vitro models to enhance the longevity and predictivity of the models, but, as in the present study, there have been recent efforts to start addressing the manner in which humans are exposed to ENMs in natural life [ 38 , 39 ]. This study aimed to determine, firstly, if a more realistic, low-dose prolonged ENM exposure would provoke a significantly different (geno)toxicological effect compared to an acute exposure in 3D HepG2 spheroids.…”

Section: Discussionmentioning

confidence: 99%

“…Not only is it important to fully characterize an ENM prior to exposure, it is equally as important to characterize these materials under biological exposure conditions as these materials may undergo transformation (e.g. dissolution, aggregation and reprecipitation) when they come into contact with different biological fluids [ 39 ]. As a result, these novel size-specific characteristics often heavily influence the toxicological potential for such materials.…”

Section: Discussionmentioning

confidence: 99%

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Understanding the impact of more realistic low-dose, prolonged engineered nanomaterial exposure on genotoxicity using 3D models of the human liver

et al. 2021

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Background With the continued integration of engineered nanomaterials (ENMs) into everyday applications, it is important to understand their potential for inducing adverse human health effects. However, standard in vitro hazard characterisation approaches suffer limitations for evaluating ENM and so it is imperative to determine these potential hazards under more physiologically relevant and realistic exposure scenarios in target organ systems, to minimise the necessity for in vivo testing. The aim of this study was to determine if acute (24 h) and prolonged (120 h) exposures to five ENMs (TiO2, ZnO, Ag, BaSO4 and CeO2) would have a significantly different toxicological outcome (cytotoxicity, (pro-)inflammatory and genotoxic response) upon 3D human HepG2 liver spheroids. In addition, this study evaluated whether a more realistic, prolonged fractionated and repeated ENM dosing regime induces a significantly different toxicity outcome in liver spheroids as compared to a single, bolus prolonged exposure. Results Whilst it was found that the five ENMs did not impede liver functionality (e.g. albumin and urea production), induce cytotoxicity or an IL-8 (pro-)inflammatory response, all were found to cause significant genotoxicity following acute exposure. Most statistically significant genotoxic responses were not dose-dependent, with the exception of TiO2. Interestingly, the DNA damage effects observed following acute exposures, were not mirrored in the prolonged exposures, where only 0.2–5.0 µg/mL of ZnO ENMs were found to elicit significant (p ≤ 0.05) genotoxicity. When fractionated, repeated exposure regimes were performed with the test ENMs, no significant (p ≥ 0.05) difference was observed when compared to the single, bolus exposure regime. There was < 5.0% cytotoxicity observed across all exposures, and the mean difference in IL-8 cytokine release and genotoxicity between exposure regimes was 3.425 pg/mL and 0.181%, respectively. Conclusion In conclusion, whilst there was no difference between a single, bolus or fractionated, repeated ENM prolonged exposure regimes upon the toxicological output of 3D HepG2 liver spheroids, there was a difference between acute and prolonged exposures. This study highlights the importance of evaluating more realistic ENM exposures, thereby providing a future in vitro approach to better support ENM hazard assessment in a routine and easily accessible manner.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Understanding the impact of more realistic low-dose, prolonged engineered nanomaterial exposure on genotoxicity using 3D models of the human liver

et al. 2021

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“…The amorphous fumed SiO 2 NM sample was obtained from Sigma-Aldrich, Munich, Germany (#S5130). This sample has been previously characterised in detail [ 83 ]. To check the particle size for the material batches applied in this study, the primary particle size distributions of the pristine NMs were determined using scanning electron microscopy (SEM) by measuring 425 primary particles (CeO 2 ) and 500 particles (SiO 2 ), respectively.…”

Section: Methodsmentioning

confidence: 99%

Effects of subchronic dietary exposure to the engineered nanomaterials SiO2 and CeO2 in C57BL/6J and 5xFAD Alzheimer model mice

et al. 2022

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Background There is an increasing concern about the neurotoxicity of engineered nanomaterials (NMs). To investigate the effects of subchronic oral exposures to SiO2 and CeO2 NMs on Alzheimer’s disease (AD)-like pathology, 5xFAD transgenic mice and their C57BL/6J littermates were fed ad libitum for 3 or 14 weeks with control food pellets, or pellets dosed with these respective NMs at 0.1% or 1% (w/w). Behaviour effects were evaluated by X-maze, string suspension, balance beam and open field tests. Brains were analysed for plaque load, beta-amyloid peptide levels, markers of oxidative stress and neuroinflammation. Results No marked behavioural impairments were observed in the mice exposed to SiO2 or CeO2 and neither treatment resulted in accelerated plaque formation, increased oxidative stress or inflammation. In contrast, the 5xFAD mice exposed to 1% CeO2 for 14 weeks showed significantly lower hippocampal Aβ plaque load and improved locomotor activity compared to the corresponding controls. Conclusions The findings from the present study suggest that long-term oral exposure to SiO2 or CeO2 NMs has no neurotoxic and AD-promoting effects. The reduced plaque burden observed in the mice following dietary CeO2 exposure warrants further investigation to establish the underlying mechanism, given the easy applicability of this administration method.

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“…[21] The human intestinal model also includes an optional artificial digestion protocol to mimic the influence of stomach passage, whereby ingested NM subsequently interact with the strongly acidic gastric juice and the alkaline intestinal fluid. [18,22] Furthermore, a second intestinal triple culture model has been developed that incorporates M-cells (specialized epithelial cells in close association with Peyers patches), also with the capacity for mucous formation. [23] Although models discussed above are representative of healthy human tissues (equivalent to testing substances in healthy animals), it is important to note that the toxicological response in vulnerable populations with a pre-existing disease may be different.…”

Section: Complex Human Lung Liver and Intestinal Culture Models For L...mentioning

confidence: 99%

The Road to Achieving the European Commission's Chemicals Strategy for Nanomaterial Sustainability—A PATROLS Perspective on New Approach Methodologies

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et al. 2022

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The European Green Deal outlines ambitions to build a more sustainable, climate neutral, and circular economy by 2050. To achieve this, the European Commission has published the Chemicals Strategy for Sustainability: Towards a Toxic‐Free Environment, which provides targets for innovation to better protect human and environmental health, including challenges posed by hazardous chemicals and animal testing. The European project PATROLS (Physiologically Anchored Tools for Realistic nanOmateriaL hazard aSsessment) has addressed multiple aspects of the Chemicals Strategy for Sustainability by establishing a battery of new approach methodologies, including physiologically anchored human and environmental hazard assessment tools to evaluate the safety of engineered nanomaterials. PATROLS has delivered and improved innovative tools to support regulatory decision‐making processes. These tools also support the need for reducing regulated vertebrate animal testing; when used at an early stage of the innovation pipeline, the PATROLS tools facilitate the safe and sustainable development of new nano‐enabled products before they reach the market.

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Simulating Nanomaterial Transformation in Cascaded Biological Compartments to Enhance the Physiological Relevance of In Vitro Dosing Regimes: Optional or Required?

Cited by 12 publications

References 44 publications

Understanding the impact of more realistic low-dose, prolonged engineered nanomaterial exposure on genotoxicity using 3D models of the human liver

Understanding the impact of more realistic low-dose, prolonged engineered nanomaterial exposure on genotoxicity using 3D models of the human liver

Effects of subchronic dietary exposure to the engineered nanomaterials SiO2 and CeO2 in C57BL/6J and 5xFAD Alzheimer model mice

The Road to Achieving the European Commission's Chemicals Strategy for Nanomaterial Sustainability—A PATROLS Perspective on New Approach Methodologies

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