Development and uses of in vitro hepatic models in toxicology studies

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Coltman, Nicholas James ORCID: https://orcid.org/0000-0002-8210-9178 (2022). Development and uses of in vitro hepatic models in toxicology studies. University of Birmingham. Ph.D.

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Abstract

The central role of the human liver in normal physiology gives rise to organ susceptibility in terms of the on and off-target effects of xenobiotics. The most widely used models for the study of liver biology are one of either in vivo murine origin or in vitro cell culture models; however, as is often the case, these models do not translate adequately enough to humans and thus chemical exposure risk is missed, underpredicted or underreported. Accordingly, in Chapters 2 – 3 we implemented a HepG2/C3A spheroid model generated using an optimised forced-aggregate approach, into a series of in vitro (geno)- toxicology and hepatotoxicity studies. Uniform spheroids, formed over 7 days, were produced with enhanced basal mRNA expression of key ADME (Nuclear receptors, CYP450s, UGTs, SULTs) and liver related gene sets (ALB, CPS1, HNF4A), when compared to monolayers of cells. Exposure to pro- genotoxicants benzo[a]pyrene, 2-aminoanthracene and 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine revealed increased ADME and DNA damage response In spheroids versus monolayers at both the transcriptional (qRT-PCR) and phenotypical level (comet assay, quantification of

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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