*3.2.3 Genetically engineered models*

The above-mentioned models have been in use for more than 30 years and allow for a deeper understanding of the pathogenic mechanisms involved in chronic liver

#### *Models of Hepatotoxicity for the Study of Chronic Liver Disease DOI: http://dx.doi.org/10.5772/intechopen.106219*

disease and malignant transformation. The better known genetically engineered models include HBV-transgenic, HCV-transgenic, *c-myc*-transgenic, *c-myc*-/ TGF-α transgenic, E2F-1 transgenic, *c-myc*-/E2F-1 transgenic, *Apc* knockout mice, β-catenin/H-ras mutant, and cMyc+shp53 mice. Transgenic technology was initiated by inserting exogenous viral DNA into mice to induce the expression of different components of the viral particle [57]. Afterward, several important protein-coding genes and transcriptional enhancers associated with cancer were micro-injected into single-cell embryos of specific mice strains. Most transgenic mice show micro- and macro-fat vacuoles (at 6 and 11 months of age). Although inflammation is not commonly observed between 6 and 15 months of age, most mice develop preneoplastic hepatic lesions and adenomas at 6 and 11 months [100]. Those changes are accompanied by alterations in glycolysis and lipogenesis, which play a key role in the early (preneoplastic) stages of hepatocarcinogenesis. A high incidence of adenomas and carcinomas appears between 40 and 136 weeks. The advantage of these models is that they are highly reproducible and resemble human disease.

### *3.2.4 Humanized mouse model*

Humanized mouse models are widely used to mimic the human immune system in mice [101]. This mouse model is based on transplanted human cells and tissues that have been uniquely engineered to produce combinations of human cytokines in immunocompromised mice and avoid rejection of implanted cells. This kind of model results in a more physiologically relevant model system for evaluating new cancer therapies, immuno-oncology, and effective treatments targeting the tumor microenvironment. Proteomics studies of humanized models have shown that there is an increase in proteins related to apoptosis at 12 months, the defense of fatty acid metabolism against oxidative stress [102]. Other studies have shown that, in combination with DEN, there can be an increase in the size of neoplastic nodules [103]. The mouse is the most widely used animal model in biomedical research because it is versatile, inexpensive, and genetically very similar to humans. However, success depends on animal age, sex, and strain.
