Life-cycle toxicity testing in Caenorhabditis elegans: comparative effects on traits and their mechanistic basis

A major aim of ecotoxicology is to discover how toxicants impact populations. Often lethality is used as an endpoint in toxicity tests however this in isolation is inadequate to predict consequences for populations. The combination of life cycle toxicity testing and demographic modelling offers an opportunity to provide a solution to this problem, whilst the use of transcriptomic profiling offers the chance to understand how changes in life history are mediated at the molecular level. The nematode Caenorhabditis elegans was utilised to elucidate the effects of environmental toxicants on the life history of individuals, population growth rate, energy utilisation, and gene expression. Toxicity of four common pollutants (cadmium, fluoranthene, atrazine and aldicarb) was assessed in full life-cycle toxicity tests. The impact of each chemical on life history parameters including reproductive output/ period, time to maturity, growth and lifespan, was determined. These experiments revealed complex dose dependent responses indicating the most sensitive trait to be reproductive output. The influence of temperature and strain was investigated on cadmium toxicity indicated an increase in overall sensitivity at higher temperature and strain specific response profiles. Integration of life history data into a demographic model provided a solution to translating effects on individuals into meaningful population responses. Decreases in juvenile survival and reproduction were identified as the traits which caused the largest impacts on population growth rate. Life-cycle toxicity data was also integrated into a process-based model (DEBtox) to assess the effects of the toxicants on energy utilisation by the organisms. Finally, the mechanistic basis of observed life-history responses for the toxicant aldicarb was examined using transcriptomic profiling to identify single genes and biological and energetic pathways responsive to toxicant stress. Analysis of the molecular responses revealed novel mechanisms of toxicity

The Life Science Exchange: a case study of a sectoral and sub-sectoral knowledge exchange programme

Background: Local and national governments have implemented sector-specific policies to support economic development through innovation, entrepreneurship and knowledge exchange. Supported by the Welsh Government through the European Regional Development Fund, The Life Science Exchange® project was created with the aim to increase interaction between stakeholders, to develop more effective knowledge exchange mechanisms, and to stimulate the formation and maintenance of long-term collaborative relationships within the Welsh life sciences ecosystem. The Life Science Exchange allowed participants to interact with other stakeholder communities (clinical, academic, business, governmental), exchange perspectives and discover new opportunities.Methods: Six sub-sector focus groups comprising over 200 senior stakeholders from academia, industry, the Welsh Government and National Health Service were established. Over 18 months, each focus group provided input to inform healthcare innovation policy and knowledge mapping exercises of their respective sub-sectors. Collaborative projects identified during the focus groups and stakeholder engagement were further developed through sandpit events and bespoke support.Results: Each sub-sector focus group produced a report outlining the significant strengths and opportunities in their respective areas of focus, made recommendations to overcome any ‘system failures’, and identified the stakeholder groups which needed to take action. A second outcome was a stakeholder-driven knowledge mapping exercise for each area of focus. Finally, the sandpit events and bespoke support resulted in participants generating more than £1.66 million in grant funding and inward investment. This article outlines four separate outcomes from the Life Science Exchange programme.Conclusions: The Life Science Exchange process has resulted in a multitude of collaborations, projects, inward investment opportunities and special interest group formations, in addition to securing over ten times its own costs in funding for Wales. The Life Science Exchange model is a simple and straightforward mechanism for a regional or national government to adapt and implement in order to improve innovation, skills, networks and knowledge exchange

Linking toxicant physiological mode of action with induced gene expression changes in Caenorhabditis elegans

Background 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). Results 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. Conclusions 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

Transcriptome profiling of developmental and xenobiotic responses in a keystone soil animal, the oligochaete annelid Lumbricus Rubellus

Background Natural contamination and anthropogenic pollution of soils are likely to be major determinants of functioning and survival of keystone invertebrate taxa. Soil animals will have both evolutionary adaptation and genetically programmed responses to these toxic chemicals, but mechanistic understanding of such is sparse. The clitellate annelid Lumbricus rubellus is a model organism for soil health testing, but genetic data have been lacking. Results We generated a 17,000 sequence expressed sequence tag dataset, defining ~8,100 different putative genes, and built an 8,000-element transcriptome microarray for L. rubellus. Strikingly, less than half the putative genes (43%) were assigned annotations from the gene ontology (GO) system; this reflects the phylogenetic uniqueness of earthworms compared to the well-annotated model animals. The microarray was used to identify adult- and juvenile-specific transcript profiles in untreated animals and to determine dose-response transcription profiles following exposure to three xenobiotics from different chemical classes: inorganic (the metal cadmium), organic (the polycyclic aromatic hydrocarbon fluoranthene), and agrochemical (the herbicide atrazine). Analysis of these profiles revealed compound-specific fingerprints which identify the molecular responses of this annelid to each contaminant. The data and analyses are available in an integrated database, LumbriBASE. Conclusion L. rubellus has a complex response to contaminant exposure, but this can be efficiently analysed using molecular methods, revealing unique response profiles for different classes of effector. These profiles may assist in the development of novel monitoring or bioremediation protocols, as well as in understanding the ecosystem effects of exposure

'Systems toxicology' approach identifies coordinated metabolic responses to copper in a terrestrial non-model invertebrate, the earthworm -7

(that is, smallest points represent 0 mg/kg copper, largest points represent 480 mg/kg copper). Colour scale represents weight change (%), data taken from Spurgeon et al [37].<p><b>Copyright information:</b></p><p>Taken from "'Systems toxicology' approach identifies coordinated metabolic responses to copper in a terrestrial non-model invertebrate, the earthworm "</p><p>http://www.biomedcentral.com/1741-7007/6/25</p><p>BMC Biology 2008;6():25-25.</p><p>Published online 3 Jun 2008</p><p>PMCID:PMC2424032.</p><p></p

'Systems toxicology' approach identifies coordinated metabolic responses to copper in a terrestrial non-model invertebrate, the earthworm -6

Lected genes (red). (B) Metallothionein genes. (C) Heat shock protein genes. (D) Genes involved in glutathione metabolism. (E) Genes involved in DNA repair mechanisms. (F) Regulators of apoptosis.<p><b>Copyright information:</b></p><p>Taken from "'Systems toxicology' approach identifies coordinated metabolic responses to copper in a terrestrial non-model invertebrate, the earthworm "</p><p>http://www.biomedcentral.com/1741-7007/6/25</p><p>BMC Biology 2008;6():25-25.</p><p>Published online 3 Jun 2008</p><p>PMCID:PMC2424032.</p><p></p