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Article

Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals

1
Entity of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium
2
KaLy-Cell, 67115 Plobsheim, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Current affiliation: International Iberian Nanotechnology Laboratory, 4715-330 Braga, Portugal.
Academic Editor: Rolf Teschke
Int. J. Mol. Sci. 2021, 22(20), 11005; https://doi.org/10.3390/ijms222011005
Received: 3 September 2021 / Revised: 7 October 2021 / Accepted: 7 October 2021 / Published: 12 October 2021
(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges)
Drug-induced liver injury, including cholestasis, is an important clinical issue and economic burden for pharmaceutical industry and healthcare systems. However, human-relevant in vitro information on the ability of other types of chemicals to induce cholestatic hepatotoxicity is lacking. This work aimed at investigating the cholestatic potential of non-pharmaceutical chemicals using primary human hepatocytes cultured in 3D spheroids. Spheroid cultures were repeatedly (co-) exposed to drugs (cyclosporine-A, bosentan, macitentan) or non-pharmaceutical chemicals (paraquat, tartrazine, triclosan) and a concentrated mixture of bile acids for 4 weeks. Cell viability (adenosine triphosphate content) was checked every week and used to calculate the cholestatic index, an indicator of cholestatic liability. Microarray analysis was performed at specific time-points to verify the deregulation of genes related to cholestasis, steatosis and fibrosis. Despite the evident inter-donor variability, shorter exposures to cyclosporine-A consistently produced cholestatic index values below 0.80 with transcriptomic data partially supporting its cholestatic burden. Bosentan confirmed to be hepatotoxic, while macitentan was not toxic in the tested concentrations. Prolonged exposure to paraquat suggested fibrotic potential, while triclosan markedly deregulated genes involved in different types of hepatotoxicity. These results support the applicability of primary human hepatocyte spheroids to study hepatotoxicity of non-pharmaceutical chemicals in vitro. View Full-Text
Keywords: primary human hepatocytes; spheroids; cholestasis; hepatotoxicity; cyclosporine-A; bosentan; macitentan; paraquat; tartrazine; triclosan primary human hepatocytes; spheroids; cholestasis; hepatotoxicity; cyclosporine-A; bosentan; macitentan; paraquat; tartrazine; triclosan
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MDPI and ACS Style

Vilas-Boas, V.; Gijbels, E.; Leroy, K.; Pieters, A.; Baze, A.; Parmentier, C.; Vinken, M. Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals. Int. J. Mol. Sci. 2021, 22, 11005. https://doi.org/10.3390/ijms222011005

AMA Style

Vilas-Boas V, Gijbels E, Leroy K, Pieters A, Baze A, Parmentier C, Vinken M. Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals. International Journal of Molecular Sciences. 2021; 22(20):11005. https://doi.org/10.3390/ijms222011005

Chicago/Turabian Style

Vilas-Boas, Vânia, Eva Gijbels, Kaat Leroy, Alanah Pieters, Audrey Baze, Céline Parmentier, and Mathieu Vinken. 2021. "Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals" International Journal of Molecular Sciences 22, no. 20: 11005. https://doi.org/10.3390/ijms222011005

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