Transcription profiling of rat liver display strain-specific, hereditary and AHR-Dependent Components
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
SUBMITTER: Paul Boutros
PROVIDER: E-GEOD-10448 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Background The rat is a major model organism in toxicogenomics and pharmacogenomics, and the use of steady-state hepatic mRNA levels to predict and understand drug toxicity and mechanism is well-established. Surprisingly, the inter- and intra-strain variability of rat mRNA expression has not been evaluated, nor has the extent of its hereditability been established. We address these issues by studying three rat strains (Long-Evans, Hans/Wistar, and Sprague-Dawley) and two F2 lines derived from Long-Evans x Hans/Wistar crosses. Results Using three independent techniques – variance analysis, linear modelling, and unsupervised pattern recognition – we characterize large amounts of both intra- and inter-strain variability in mRNA levels. Importantly, both sources of variability are highly non-random, and are enriched for specific functional groups. Specific transcription-factor binding-sites are enriched in their promoter regions, and these genes occur in “islands” throughout the rat genome. Using the two F2 crosses we study the hereditability of hepatic mRNA levels and show that the majority of rat genes appear to exhibit directional genetics, with only a small fraction having evidence for interacting loci. Finally, a comparison of inter-strain heterogeneity between mouse and rat orthologs shows more heterogeneity in rats than mice, and find that rat and mouse heterogeneity are uncorrelated. Conclusions Our results establish that hepatic mRNA levels are relatively homogeneous within rat strains, but highly variable between them. This variability may be related to increased activity specific transcription-factors, and has clear functional consequences. Future toxicogenomic and pharmacogenomic studies may take advantage of this phenomenon by surveying panels of rat strains. Keywords: Inter-Strain Comparison
2009-11-24 | GSE10448 | GEO
Project description:Background; Mouse and rat models are mainstays in pharmacology, toxicology and drug development â but differences between strains and between species complicate data interpretation and application to human health. Dioxin-like polyhalogenated aromatic hydrocarbons represent a major class of environmentally and economically relevant toxicants. In mammals dioxin exposure leads to a broad spectrum of adverse affects, including hepatotoxicity of varying severity. Several studies have shown that dioxins extensively alter hepatic mRNA levels. Surprisingly, though, analysis of a limited portion of the transcriptome revealed that rat and mouse responses diverge greatly (Boverhof et al. Toxicol Sci 94:398â416, 2006). Results; We employed oligonucleotide arrays to compare the response of 8,125 rat and mouse orthologs. We confirmed that there is limited inter-species overlap in dioxin-responsive genes. Rat-specific and mouse-specific genes are enriched for specific functional groups which differ between species, conceivably accounting for species-specificities in liver histopathology. While no evidence for the involvement of copy-number variation was found, extensive inter-species variation in the transcriptional-regulatory network was identified; Nr2f1 and Fos emerged as candidates to explain species-specific and species-independent responses, respectively. Conclusion; Our results suggest that a small core of genes is responsible for mediating the similar features of dioxin hepatotoxicity in rats and mice but non-overlapping pathways are simultaneously at play to result in distinctive histopathological outcomes. The extreme divergence between mouse and rat transcriptomic responses appears to reflect divergent transcriptional-regulatory networks. Taken together, these data suggest that both rat and mouse models should be used to screen the acute hepatotoxic effects of drugs and toxic compounds. Experiment Overall Design: Wild-type Long-Evans(Kuopio) rats were treated with 100 ug/kg TCDD (n=4) or with cornoil vehicle as control (n=4) for 19 hours. Their livers were then excised, RNA extracted, and the resulting samples hybridized to Affymetrix RAE230A arrays to survey changes in the transcriptome profile.
2008-10-25 | E-GEOD-10770 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE8467: Micro-RNAs in Adult Rat Liver are Refractory to 19 Hours Dioxin Exposure GSE8468: Micro-RNAs levels in wildtype vs. Ahr-null adult mouse liver constitutively and in response to doxin treatment. GSE8469: Micro-RNAs in Adult Long-Evans (Turku/AB) Rat Liver are Refractory to 96 Hours Dioxin Treatment GSE8470: Micro-RNAs in Adult Rat Liver are Refractory to Dioxin Treatment Keywords: SuperSeries Refer to individual Series
2007-08-14 | E-GEOD-8474 | biostudies-arrayexpress
Project description:Dioxin-like chemicals are well-known for their ability to upregulate expression of numerous genes via the AH receptor (AHR). However, recent transcriptomic analyses in several laboratories indicate that dioxin-like chemicals or AHR genotype itself also can downregulate levels of mRNAs encoded by numerous genes. The mechanism responsible for such downregulation is unknown. We hypothesized that microRNAs (miRNAs), which have emerged as powerful negative regulators of mRNA levels in several systems, might be responsible for mRNA downregulation in dioxin/AHR pathways. We used the Ambion miRNA array platform as well as quantitative RT-PCR to measure miRNA levels in dioxin-sensitive Long-Evans (Turku/AB; L-E) rats vs. dioxin-resistant Han/Wistar(Kuopio; H/W) rats. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vivo caused no significant changes in miRNA levels in rat livers. AHR genotype had no effect on hepatic miRNA levels in response to TCDD – no miRNAs differed in expression between between L-E rats (that have wildtype AHR) compared to H/W rats (whose AHR has a large deletion in the transactivation domain). It is unlikely that mRNA downregulation by dioxins is mediated by miRNAs, nor are miRNAs likely to play a significant role in dioxin toxicity in adult rodent liver. Manuscript Submitted: Moffat ID, Boutros PC, Celius T, Pohjanvirta R & Okey AB. Micro-RNAs in rodent liver are refractory to dioxin treatment. Toxicological Sciences May, 2007. Keywords: miRNA expression, response to xenobiotics, genetic modification, comparative genome hybridization In the dioxin-sensitive L-E rats we compared miRNA expression levels 19 h post-TCDD treatment vs. corn oil vehicle treatment. In the dioxin-resistant H/W rats we compared miRNA levels 19 h post-TCDD treatment vs.corn oil vehicle treatment.
2007-08-15 | E-GEOD-8467 | biostudies-arrayexpress
Project description:Dioxin-like chemicals are well-known for their ability to upregulate expression of numerous genes via the AH receptor (AHR). However, recent transcriptomic analyses in several laboratories indicate that dioxin-like chemicals or AHR genotype itself also can downregulate levels of mRNAs encoded by numerous genes. The mechanism responsible for such downregulation is unknown. We hypothesized that microRNAs (miRNAs), which have emerged as powerful negative regulators of mRNA levels in several systems, might be responsible for mRNA downregulation in dioxin/AHR pathways. We used the Exiqon miRNA array platform as well as quantitative RT-PCR to measure miRNA levels in dioxin-sensitive Long-Evans (Turku/AB; L-E) rats vs. dioxin-resistant Han/Wistar(Kuopio; H/W) rats. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vivo caused few changes in miRNA levels in rat livers and those changes that were statistically significant were of modest magnitude. AHR genotype had little effect on hepatic miRNA levels, either in constitutive expression or in response to TCDD – only a few miRNAs differed in expression between between L-E rats (that have wildtype AHR) compared to H/W rats (whose AHR has a large deletion in the transactivation domain). It is unlikely that mRNA downregulation by dioxins is mediated by miRNAs, nor are miRNAs likely to play a significant role in dioxin toxicity in adult rodent liver. We conducted a thorough investigation to address the following questions: (1) does AHR genotype itself affect constitutive expression of microRNAs? (2) does TCDD affect microRNA levels and, if so, is this response dependent on the AHR? (3) does TCDD affect microRNA levels differently in animals that are sensitive to dioxin toxicity versus those that are dioxin-resistant? We assessed the in vivo effect of TCDD on microRNA levels in liver at multiple time points after TCDD treatment using microRNA arrays along with quantitative RT-PCR. The cumulative results of our experiments indicate that downregulation of mRNA levels by dioxins in adult rodent livers is very unlikely to involve microRNAs. Manuscript Submitted: Moffat ID, Boutros PC, Celius T, Pohjanvirta R & Okey AB. Micro-RNAs in rodent liver are refractory to dioxin treatment. Toxicological Sciences May, 2007. Keywords: miRNA expression, Time course, response to xenobiotics, genetic modification, comparative genome hybridization We examined strain differences in miRNA expression independent of TCDD: 19-h vehicle-treated dioxin-resistant H/W AHRH/W/H/W rats (HC19) vs. vehicle- control dioxin-sensitive L-E AHRWT/WT rats (LC19). In the dioxin-sensitive rats we compared miRNA expression levels 3 h (LT3) or 19 h (LT19) post-TCDD treatment vs. LC19. In the dioxin-resistant rats we compared miRNA levels 3 h (HT3), 19 h (HT19), or 96 h (HT96) post-TCDD treatment vs. HC19.
2007-08-15 | E-GEOD-8470 | biostudies-arrayexpress
Project description:Background; Mouse and rat models are mainstays in pharmacology, toxicology and drug development â?? but differences between strains and between species complicate data interpretation and application to human health. Dioxin-like polyhalogenated aromatic hydrocarbons represent a major class of environmentally and economically relevant toxicants. In mammals dioxin exposure leads to a broad spectrum of adverse affects, including hepatotoxicity of varying severity. Several studies have shown that dioxins extensively alter hepatic mRNA levels. Surprisingly, though, analysis of a limited portion of the transcriptome revealed that rat and mouse responses diverge greatly (Boverhof et al. Toxicol Sci 94:398â??416, 2006). Results; We employed oligonucleotide arrays to compare the response of 8,125 rat and mouse orthologs. We confirmed that there is limited inter-species overlap in dioxin-responsive genes. Rat-specific and mouse-specific genes are enriched for specific functional groups which differ between species, conceivably accounting for species-specificities in liver histopathology. While no evidence for the involvement of copy-number variation was found, extensive inter-species variation in the transcriptional-regulatory network was identified; Nr2f1 and Fos emerged as candidates to explain species-specific and species-independent responses, respectively. Conclusion; Our results suggest that a small core of genes is responsible for mediating the similar features of dioxin hepatotoxicity in rats and mice but non-overlapping pathways are simultaneously at play to result in distinctive histopathological outcomes. The extreme divergence between mouse and rat transcriptomic responses appears to reflect divergent transcriptional-regulatory networks. Taken together, these data suggest that both rat and mouse models should be used to screen the acute hepatotoxic effects of drugs and toxic compounds. Experiment Overall Design: Wild-type C57BL/6 mice were treated with 1000 ug/kg TCDD (n=6) or with cornoil vehicle as control (n=5) for 19 hours. Their livers were then excised, RNA extracted, and the resulting samples hybridized to Affymetrix MOE430-2 arrays to survey changes in the transcriptome profile.
2008-10-26 | E-GEOD-10769 | biostudies-arrayexpress
Project description:The aryl hydrocarbon receptor (AHR) is a widely-expressed ligand-dependent transcription-factor that mediates cellular responses to dioxins and other planar aromatic hydrocarbons. Indeed, AHR-null mice are refractory to the physiological effects of dioxin-exposure. Although some mechanistic aspects of AHR activity are well understood, the tissue-specificity of AHR effects remains unclear, both during development and following administration of exogenous ligands. Previously we employed studied the transcriptional responses of wild-type and AHR-null C57BL/6J mice to dioxin-exposure. We found that essentially all hepatic effects of dioxin were mediated by the AHR, and that large numbers of genes were affected by dioxin exposure. Surprisingly, we also identified a large effect of AHR genotype, even in the absence of dioxin-exposure. To help assess the tissue-specificity of AHR activity we replicated that prior study in the kidney from the same animals previously studied, and extensively compared the hepatic and renal transcriptional profiles. We find that dioxin-exposure causes essentially no transcriptional effects in the absence of a functional AHR in either liver or kidney. Surprisingly, aside from a number of well-established AHR target genes, dioxin-exposure has few effects in animals harbouring a wild-type AHR. By contrast, AHR genotype profoundly remodels the renal transcriptome, and is associated with perturbation of specific functional pathways and with specific DNA motifs. Our results demonstrate the importance of inter-tissue comparisons and highlight the basal role of AHR activity in renal and hepatic development or normal physiology. Two-Factor, Two-Level. AHRnull and wildtype mice were treated with dioxin (TCDD) or corn oil vehicle. 3 replicates per treatment for AHRnull mice, 6 replicates of dioxin treatment for wildtype mice, and 5 replicates of corn oil treatment for wildtype mice.
2009-09-21 | E-GEOD-15858 | biostudies-arrayexpress
Project description:The aryl hydrocarbon receptor (AHR) is a widely-expressed ligand-dependent transcription-factor that mediates cellular responses to dioxins and other planar aromatic hydrocarbons. Indeed, AHR-null mice are refractory to the physiological effects of dioxin-exposure. Although some mechanistic aspects of AHR activity are well understood, the tissue-specificity of AHR effects remains unclear, both during development and following administration of exogenous ligands. Previously we employed studied the transcriptional responses of wild-type and AHR-null C57BL/6J mice to dioxin-exposure. We found that essentially all hepatic effects of dioxin were mediated by the AHR, and that large numbers of genes were affected by dioxin exposure. Surprisingly, we also identified a large effect of AHR genotype, even in the absence of dioxin-exposure. To help assess the tissue-specificity of AHR activity we replicated that prior study in the kidney from the same animals previously studied, and extensively compared the hepatic and renal transcriptional profiles. We find that dioxin-exposure causes essentially no transcriptional effects in the absence of a functional AHR in either liver or kidney. Surprisingly, aside from a number of well-established AHR target genes, dioxin-exposure has few effects in animals harbouring a wild-type AHR. By contrast, AHR genotype profoundly remodels the renal transcriptome, and is associated with perturbation of specific functional pathways and with specific DNA motifs. Our results demonstrate the importance of inter-tissue comparisons and highlight the basal role of AHR activity in renal and hepatic development or normal physiology. Two-Factor, Two-Level. AHRnull and wildtype mice were treated with dioxin (TCDD) or corn oil vehicle. 3 replicates per treatment for AHRnull mice, and 6 replicates per treatment for wildtype mice.
2009-09-21 | E-GEOD-15857 | biostudies-arrayexpress
Project description:Dioxin-like chemicals are well-known for their ability to upregulate expression of numerous genes via the AH receptor (AHR). However, recent transcriptomic analyses in several laboratories indicate that dioxin-like chemicals or AHR genotype itself also can downregulate levels of mRNAs encoded by numerous genes. The mechanism responsible for such downregulation is unknown. We hypothesized that microRNAs (miRNAs), which have emerged as powerful negative regulators of mRNA levels in several systems, might be responsible for mRNA downregulation in dioxin/AHR pathways. We used the Exiqon miRNA array platform as well as quantitative RT-PCR to measure miRNA levels in dioxin-sensitive Long-Evans (Turku/AB; L-E) rats. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 96 hr in vivo caused few changes in miRNA levels in rat livers and those changes that were statistically significant were of modest magnitude. Feed-restricted-control L-E rats were included to ensure that changes in miRNA levels were due to TCDD-treatment per se and not the result of the decreased feed intake which occurs in dioxin-sensitive strains within 96 h after TCDD exposure. Manuscript Submitted: Moffat ID, Boutros PC, Celius T, Pohjanvirta R & Okey AB. Micro-RNAs in rodent liver are refractory to dioxin treatment. Toxicological Sciences May, 2007. Keywords: miRNA expression, response to xenobiotics, feed restriction response A loop design used to profile miRNA levels from dioxin-sensitive L-E AHRWT/WT vehicle-control rats (LC96), those exposed to TCDD for 96 h (LT96), and feed-restricted (LF96) rats.
2007-08-14 | E-GEOD-8469 | biostudies-arrayexpress
Project description:Major toxicities of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) result from dysregulation of gene expression mediated by the aryl hydrocarbon receptor (AHR). Dioxin-like chemicals alter expression of numerous genes in liver but the specific genes whose dysregulation leads to toxicities such as wasting, hepatotoxicity and lethality have not been identified. We searched for genes that are most likely to be key to dioxin toxicity by using gene expression arrays to contrast hepatic gene expression after TCDD treatment in dioxin-sensitive rats (that carry wildtype AHR) with gene expression in H/W(Kuopio) rats which are highly resistant to dioxin toxicity due to a major deletion in the AHR's transactivation domain (TAD). The total number of TCDD-responsive genes was smaller in rats with the AHRH/W genotype than in rats with wildtype AHR. However, genes in the classic AH gene battery such as CYP1A1, CYP1A2 and CYP1B1 remained fully responsive to TCDD in AHRH/W rats; thus the TAD deletion selectively interferes with expression of a subset of hepatic genes rather than abolishing global AHR-mediated responses. Genes in the following functional categories differ in response to TCDD between dioxin-sensitive rats and dioxin-resistant rats: fatty acid oxidation, metabolism (xenobiotic, alcohol, amino acid, and fatty acid), phosphate transport, regulation of steroid biosynthesis, nitrogen compound catabolism, and generation of precursor metabolites and energy. Many of these differentially-responsive genes are integral parts of pathways such as: protein degradation and synthesis, fatty acid metabolism and synthesis, cytokinesis, cell growth, and apoptosis which may be part of mechanisms which lead to TCDD-induced wasting, hepatotoxicity, tumors, and death. These differentially-responsive genes are worthy candidates for further mechanistic studies to test their role in mediating or protecting from major dioxin toxicities. Experiment Overall Design: Four strains of rats were either treated with 100 ug/kg TCDD or cornoil vehicle and profiled at 19 hours, each with four replicates. Two strains were also analyzed at 3 hours, each with four replicates.
2009-12-02 | E-GEOD-10083 | biostudies-arrayexpress