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

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.

Turner C, Sawle A, Fenske M, Cossins A (2012) Implications of the solvent vehicles dimethylformamide and dimethylsulfoxide for establishing transcriptomic endpoints in the zebrafish embryo toxicity test. Environmental Toxicology and Chemistry 31(3): 593-604 doi:10.1002/etc.1718

Bittner D, Cossins AR, Segner H, Excoffier L, Largiadèr CR (2011). Identification of candidate genes and physiological pathways involved in gonad deformation in whitefish (Coregonus spp.) from Lake Thun, Switzerland. Int J Environ Res Public Health 8(7): 2706-33 doi:10.3390/ijerph8072706

Sawle AD, Wit E, Whale G, Cossins AR (2010) An information-rich alternative, chemicals testing strategy using a high definition toxicogenomics and zebrafish (Danio rerio) embryos. Toxicological Sciences 118(1): 128-139 doi:10.1093/toxsci/kfq237

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Project grant

Status:

Closed

Principal investigator

Professor Andrew Cossins

Institution

University of Liverpool

Co-Investigator

Professor Ernst Wit

Grant reference number

G0800702/1

Award date:

Sep 2008 - Nov 2011

Grant amount

£532,559