Abstract:Increasing evidence indicates that numerous genetic pathways responding to environmental stress in animals are regulated co-ordinately as well as independently. These stress-response systems should therefore be viewed in holistic terms as a network. As such, their behaviour is susceptible to mathematical modelling using a systems biology approach. This review outlines relevant evidence and describes a newly launched project to develop just such a model using stressresponse data from multiple transgenic strains of C. elegans and D. melanogaster. We hope that our eventual model will be capable of predicting the effects of simple stressor mixtures with reasonable accuracy. To maximise the effectiveness and scope of this model, we appeal for help from colleagues to share reagents and data relevant to this project. We also present preliminary data where RNA interference has implicated the key transcription factor DAF-16 in an unexpected upregulation of cyp-34A9 reporter expression by high cadmium.
STRESS RESPONSES AND MIXTURE TOXICITYIn multicellular organisms, the defensive cellular responses evoked by environmental stresses do not result from simple linear pathways, but rather from a network of interlinked pathways with multiple outputs. This makes it difficult to predict the biological effects of multiple stressors acting together, even though this is the normal situation for industrial pollution of soil or water, where several different contaminants are usually present together. There are few studies and no useful predictive models describing the molecular responses of multicellular organisms to several toxicants acting in concert. This is essentially a systems biology problem, requiring integration of complex molecular and toxicological information. Under the auspices of a Major Award from the UK-India Education and Research Initiative (UK-IERI), we intend to develop an in silico model describing the principal elements of a consensus stress response network (SRN) and its in vivo responses to single stressors, using data from two invertebrate model systems, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster. This model will be used to predict the likely SRN responses to stressor mixtures, and such predictions will then be tested experimentally in both species so that the model can be refined accordingly. Since the SRN core pathways are highly conserved among animal taxa, general features of this model should find wider application in ecotoxi-*Address correspondence to this author at the School of Biology, Nottingham University, Nottingham NG7 2RD, UK; Tel: (0044) 115 951 3250; Fax: (0044) 115 951 3251; E-mail: david.depomerai@nottingham.ac.uk cology. The dynamic aspects of this model, and in particular its ability to integrate multiple toxicant inputs for predicting likely SRN outputs, distinguish this from a simple map of the regulatory gene-circuits comprising the SRN.
THE C. ELEGANS STRESS-RESPONSE NETWORKThe free-living soil nematode, C. elegans, is particularly suitable fo...