The aim of the research described in this thesis entitled ‘The use of transcriptomics data in detecting non-genotoxic carcinogens’ was to develop in vitro tests to improve testing strategies for... Show moreThe aim of the research described in this thesis entitled ‘The use of transcriptomics data in detecting non-genotoxic carcinogens’ was to develop in vitro tests to improve testing strategies for cancer hazard assessment of chemicals, to reduce the use of in vivo experiments. The scope of this thesis was twofold. First, an improved in vitro approach to assess genotoxicity was developed, with the intention to reduce the number of misleading positive test results. The emphasis was on characterization of the cell system, primary hepatocytes derived from transgenic mice. Results showed that this cell system will be of added value in genotoxicity testing. In the second part of this thesis, the focus was on the development of a ‘trancriptomics’-based approach to detect modes of action of non-genotoxic carcinogens. It has been demonstrated that the described comparison approach is promising in recognizing gene expression patterns, which can be related to modes of action. In addition, the approach is also suitable to detect toxicity of chemicals in general. In conclusion, through the development of in vitro approaches, as described within this thesis, an important contribution in the improvement of testing strategies for cancer hazard assessment of chemicals has been delivered. Show less
DNA damage, mutations and genomic instability are established driving forces of cancer and other age-related diseases. Mutations in tumor suppressor genes and oncogenes are very frequently found in... Show moreDNA damage, mutations and genomic instability are established driving forces of cancer and other age-related diseases. Mutations in tumor suppressor genes and oncogenes are very frequently found in tumors and genomic instability is the most common enabling characteristic of cancer. Aging is also believed to be enabled, amongst others, by genomic instability. DNA repair pathways, like the nucleotide excision repair (NER) pathway and cell cycle control (e.g. p53-dependent) processes are therefore vital to organisms, since these processes counteract or prevent genomic instability, and are thought to underlie, when affected, aging and age-related diseases like cancer. To unravel the functions, mechanisms and pathways involved in the onset of aging and age-related diseases we have investigated several mouse models deficient in either DNA repair (NER) capacity (Chapter 3, 4), cell cycle control (p53) (Chapter 6) or both (Chapter 5), and compared this to a wild type situation (Chapter 2). The use of mouse models enabled us to investigate cancer and aging in a controlled environment, minimizing possible confounding factors. Additionally, the mouse models can be useful as an alternative tool to identify genotoxic and non-genotoxic carcinogens that can be harmful to the society and the environment (Chapter 5). Show less
