Development of a mechanistically informative genome-wide, in vitro chemicals screening technology

Modern industrial society generates large amounts of novel chemicals to which humans are exposed both directly and indirectly through environmental release. Governments specify test procedures with which to regulate the release of these chemicals, though ensuring that the chosen test method relates to the safety and environmental consequences of release is a major scientific issue. In principle the most informative tests involve experiments on whole, living animals, but there is powerful societal pressure to reduce the numbers of animals used this way.
Scientists have sought to identify alternatives to the use of living animals, and two systems are now being developed, namely the use of cell cultures and the use of early stage, developing embryos. This project seeks to greatly refine these alternative test methods to generate far more information on how the cells or embryos respond to chemicals treatment by using a new technology for simultaneously interrogating the performance of all of the genes in the cells or embryo. This technique holds much promise for identifying the properties of the entire system and this gives a much more profound view of how chemicals have their effects. This information will be use with computer modeling to generate an ability to predict the responses of animals to chemicals with unknown properties.

The testing of chemicals remains an important regulatory activity that in many cases requires the use of animals. This requirement is likely to increase in the near future as EC legislation on more widespread chemicals testing come into force. Reducing the numbers of animals used depends on the development of alternative test procedures that do not use living animals, but yield information that is relevant to the health and environmental impacts of the chemicals in questions. Two methods coming into use are permanent cell lines and early stage fish embryos. However, these methods provide little information on the underpinning mechanisms of chemical effects. This project seeks substantially to increase the information content of these alternative test methods by applying contemporary post-genomic techniques of assessment. We wish to apply refined microarray technologies, alongside powerful statistical technique, and utilising the experimental power of well-controlled experimental designs to define a large number of responding genes responding to toxic exposure. This procedure will describe the distributed nature of gene responses which can be modelled as affected processes and pathways, and as a network of regulatory effects. Thus we propose a system-wide view of toxic effect which relates to the full complexity of the system. We will compare and contrast the performance of cells and embryos as the test method of the future and demonstrate how this system-wide view of toxicological effects generates more understanding and predictive power than a candidate gene-centered view.