Linking toxicant physiological mode of action with induced gene expression changes in Caenorhabditis elegans
- Equal contributors
1 King's College London, Department of Biochemistry, Pharmaceutical Sciences Research Division, 150 Stamford Street, London SE1 9NH, UK
2 Centre for Ecology and Hydrology, Maclean Building, Benson Lane, Crowmarsh Gifford, Wallingford, Oxon, OX10 8BB, UK
3 Cardiff School of Biosciences, BIOSI 1, University of Cardiff, PO Box 915, Cardiff, CF10 3TL, UK
4 Department of Theoretical Biology, Vrije Universiteit Amsterdam, De Boelelaan 1085, NL-1081 HV Amsterdam, The Netherlands
5 Microarray Department and Integrative Bioinformatics Unit, Faculty of Science, University of Amsterdam, Kruislaan 318, Building I, Room 105C, 1098 SM Amsterdam, The Netherlands
6 Integrated Centre for Applied Population Biology, University of Edinburgh, Kings Buildings, Edinburgh, EH9 3JT, UK
BMC Systems Biology 2010, 4:32 doi:10.1186/1752-0509-4-32Published: 23 March 2010
Physiologically based modelling using DEBtox (dynamic energy budget in toxicology) and transcriptional profiling were used in Caenorhabditis elegans to identify how physiological modes of action, as indicated by effects on system level resource allocation were associated with changes in gene expression following exposure to three toxic chemicals: cadmium, fluoranthene (FA) and atrazine (AZ).
For Cd, the physiological mode of action as indicated by DEBtox model fitting was an effect on energy assimilation from food, suggesting that the transcriptional response to exposure should be dominated by changes in the expression of transcripts associated with energy metabolism and the mitochondria. While evidence for effect on genes associated with energy production were seen, an ontological analysis also indicated an effect of Cd exposure on DNA integrity and transcriptional activity. DEBtox modelling showed an effect of FA on costs for growth and reproduction (i.e. for production of new and differentiated biomass). The microarray analysis supported this effect, showing an effect of FA on protein integrity and turnover that would be expected to have consequences for rates of somatic growth. For AZ, the physiological mode of action predicted by DEBtox was increased cost for maintenance. The transcriptional analysis demonstrated that this increase resulted from effects on DNA integrity as indicated by changes in the expression of genes chromosomal repair.
Our results have established that outputs from process based models and transcriptomics analyses can help to link mechanisms of action of toxic chemicals with resulting demographic effects. Such complimentary analyses can assist in the categorisation of chemicals for risk assessment purposes.