Project description:Although non-coplanar PCBs are ubiquitous organic chemicals known to induce numerous biological responses and thus are toxic to man and wildlife, little is known about the toxic mode of action. Using PCB52, an ortho-substituted, 2,2’,5,5’-tetrachlorobiphenyl, it was possible to pinpoint the relationship between induced gene expression and observed toxicity in the model nematode Caenorhabditis elegans. Keywords: stress response
Project description: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 atrazine (AZ). 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.
Project description: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 cadmium. 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. 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.
Project description:Toxic chemical contaminants have variety of detrimental effects on various species and the impact of pollutants on ecosystems has become an urgent issue. However, very limited species have been examined to date and those studies are mainly limited to vertebrates. In this study, we aimed to establish an ecotoxicogenomic bases for Daphnia magna. Based on a daphnia EST database, we made oligonucleotide-based DNA microarray that has high reproducibility. The DNA microarray was applied to evaluate gene expression profiles of daphnid exposed to chemicals. Characteristic gene expression patterns depending on chemicals indicate that the Daphnia microarray can be used for mechanistic understanding of chemical toxicity. Although acute toxicity test or reproductive toxicity test can provide hazardous concentrations of chemicals, they give no information about mode of action. Our study can be a breakthrough for the evaluation of chemical toxicity on environmental organisms. Keywords: Chemical response
Project description: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 atrazine (AZ). 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. Adults of C. elegans strain GE-31 exposed as biological replicate groups (approx 10,000) to a control and 4 concentrations of atrazine from L1 stage. Replicate populations were sampled 12 hours after the on-set of egg laying and hybridised against a common reference for purposes of normalisation. All experiments were conducted following a reference design with the reference sample compiled from a mixture of RNA extracted from control and cadmium-, fluoranthene-, atrazine- and copper-exposed worms from L1, L4 and adult life-stages. Use of this reference was intended to provide optimal coverage of the spotted genes.
Project description:This SuperSeries is composed of the SubSeries listed below. Purpose: Historically, the Syrian Hamster Embryo - cell transformation assay (SHE-CTA) has provided a method to predict the carcinogenicity of test chemicals. Note that the cells harvested for the SHE-CTA are from fetuses at gestation day 13.5 and not from embryos as historically recorded. This method has been criticized for insufficient mechanistic understanding and subjective assessment of colonies morphological transformation. A more objective method is needed that additionally provides mode of action information. A possible mode of action of carcinogens includes disruption of DNA methylation in gene regulatory regions and consequent changes in gene expression. Such genetic loci could provide biomarkers to assist in predicting the carcinogenicity of both genotoxic and non-genotoxic chemicals acting through DNA methylation disruption.
Project description:Here, we examined the liver microRNA profile of male Fischer rats exposed through their diet to genotoxic (2-acetylaminofluorene) and epigenetic (phenobarbital, diethylhexylphthalate, methapyrilene HCL, monuron, and chlorendic acid) chemical hepatocarcinogens, as well as to non-hepatocarcinogenic treatments (benzophenone, and diethylthiourea) for three months. The aim of the study was to investigate how liver miRNA profiles relate to mode of action and carcinogenic potential of chemicals.
Project description: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 cadmium. 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. 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. Adults of C. elegans strain GE-31 exposed as biological replicate groups (approx 10,000) to a control and 4 concentrations of cadmium from L1 stage. Replicate populations were sampled 12 hours after the on-set of egg laying and hybridised against a common oligonucleotide reference for purposes of normalisation. All experiments were conducted following a reference design with the reference sample compiled from a mixture of RNA extracted from control and cadmium-, fluoranthene-, atrazine- and copper-exposed worms from L1, L4 and adult life-stages. Use of this reference was intended to provide optimal coverage of the spotted genes.
Project description:We are presenting the application of toxicogenomics in the evaluation of the toxic effects of retinoic acid and one of its isoforms the 9-cis retinoic acid. The main goal is to distinguish the pattern of action of the both chemical compounds and their action in an extended exposure. The results suggest a different pattern within the days and the chemicals. Representatives of each GO functional groups were selected and quantified by real-time PCR to validate the microarray data and to differentiate the action of retinoic acid compounds studied.