Background
Humans are exposed to many chemicals in the form of drugs, and through the environment. Collectively these are called xenobiotics. Many cause no toxicity at the normal dose or exposure level that is much less that the level at which they will have been extensively tested. For a few individuals, or environmental species, though undesirable reactions can occur and these are often related to individual genetic characteristics. These reactions are difficult to predict and for drugs are called adverse reactions. They are a specialised form of toxicity because they are particular to an individual or group of individuals. The opposite of sensitivity is resistance, also a toxicological phenomenon. For drugs this is often manifest where very toxic drugs are used in the treatment of a disease such as cancer. The aim of cancer chemotherapy is to kill cancer cells. Sadly though sometimes after several rounds of chemotherapy cancer cells can become resistant to the drugs, and they are no longer effective. Like sensitivity this reflects changed genetic characteristics. Both resistance and sensitivity to drugs and chemicals are research interests of the Systems Toxicology Group.
In order to understand the consequence of sensitivity and resistance of humans to drugs and chemicals it is necessary to understand how individual, and combinations, of xenobiotics may affect normal cellular biochemical processes.
In the Systems Toxicology Group we apply these genomic methods to understand the effects of xenobiotics at the level of the gene code sequence and downstream regulation in the processes used to make proteins from the genome known as transcription and translation. Our key research programmes in which these technologies are applied are; 1) understanding drug resistance in cancer, 2) understanding mechanisms of toxicity for certain drug types that have caused adverse reactions, 3) refining toxicity testing by developing novel biomarkers for the recognition of toxicity in humans and, 4) understanding the mechanism by which some common environmental chemicals may affect the development of sperm though an effect on the sperm progenitor cells. This latter project is a type of toxicity that affects the germline and so may have an effect in the offspring of an affected individual. In this case the sensitive individual is not the one exposed but rather the offspring.
Lastly the output of these genomic assays can be used as a signature of xenobiotic exposure, and thus as a test procedure for the recognition of toxicological hazard and assessment of risk. Genomic assays may be utilised to reduce the number of animals used in toxicological testing.
Our main aims are to:
