Abstract
Whilst the liver possesses the ability to repair and restore sections of damaged tissue following acute injury, prolonged exposure to engineered nanomaterials (ENM) may induce repetitive injury leading to chronic liver disease. Screening ENM cytotoxicity using 3D liver models has recently been performed, but a significant challenge has been the application of such in vitro models for evaluating ENM associated genotoxicity; a vital component of regulatory human health risk assessment. This review considers the benefits, limitations, and adaptations of specific in vitro approaches to assess DNA damage in the liver, whilst identifying critical advancements required to support a multitude of biochemical endpoints, focusing on nano(geno)toxicology (e.g., secondary genotoxicity, DNA damage, and repair following prolonged or repeated exposures).
Highlights
Whilst the liver possesses the ability to repair and restore sections of dammanufacturing, electronics, energy, and the biomedical field
In response to double stranded breaks in the DNA induced by a genotoxic agent, the DNA damage response will be activated through the recruitment of ataxia telangiectasia mutated and ataxia telangiectasia, and Rad3-related protein at the DNA damage loci
It is important to consider the suitability of the 3D in vitro hepatic models currently available for genotoxicity evaluation, given that DNA damage is an important key event in hepatocellular carcinoma etiology
Summary
Prolonged incidence of hepatic apoptosis and/or necrosis often leads to the formation of hard scar tissue in place of healthy soft liver tissue; a process more commonly known as liver fibrosis. Liver fibrosis is mediated by a plethora of growth factors and cytokines released by damaged or dying hepatocytes This leads to the activation of integrated signaling cascades, which are responsible for the phenotypic transformation of quiescent vitamin-A storing hepatic stellate cells into contractile, proliferative, and fibrogenic myofibroblast-like cells.[32,36] the majority of in vitro liver fibrosis models are found to comprise of hepatic epithelial cells cocultured independently with hepatic stellate cells or with the addition of other non-parenchymal cell types (e.g., human Kupffer cells and LSECs). Multiple models have been developed in an attempt to recreate a pro-fibrotic environment using the introduction of hepatic stellate cells, which have been acknowledged as the leading scar forming cell type in most liver injuries.[32,37] It has been frequently found that the greater presence of hepatic stellate cells is commonly linked to the proliferation of hepatoma cells and enhanced tumor metastasis.[38,39]
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