Transcriptional profiling of the rat hypothalamus response to TCDD
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE18257 | GEO | 2009/11/24
SECONDARY ACCESSION(S): PRJNA119601
REPOSITORIES: GEO
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Project description:Rodents exposed to the environmental contaminant, TCDD, suffer from a number of acute and chronic toxicities, including lethality and a wasting syndrome. Hypothesizing that the wasting syndrome may be caused by changes in neural control of energy flux and metabolism, we profiled the transcriptional response of rat hypothalamus to TCDD. We employed two separate rat strains: the Long-Evans strain is sensitive to TCDD toxicities while the Han/Wistar strain is over four orders of magnitude more resistant. Surprisingly, few transcriptional changes were induced by TCDD in either strain. Only four genes were altered in Long-Evans rats, including three classic TCDD-responsive genes: Cyp1a1, Cyp1b1, and Nqo1. These three genes were also altered in Han/Wistar rats, along with 133 additional genes. However, the magnitudes of alteration of these additional genes was very modest, with most changes well below two-fold in magnitude. We therefore concluded that rat hypothalamus is mostly refractory to TCDD exposure, at least at the doses and time-points surveyed here. Two strains, each with drug-treated vs. vehicle-control
2009-11-23 | E-GEOD-18257 | biostudies-arrayexpress
Project description:Rodents exposed to the environmental contaminant, TCDD, suffer from a number of acute and chronic toxicities, including lethality and a wasting syndrome. Hypothesizing that the wasting syndrome may be caused by changes in adipose tissue -- either in its hormonal regulation or in homeostatic effects -- we profiled the transcriptional response of rat white adipose to TCDD. We employed two separate rat strains: the Long-Evans strain is sensitive to TCDD toxicities while the Han/Wistar strain is over four orders of magnitude more resistant. One day after TCDD exposure few genes were altered in either strain, but after four days a modest number of transcriptional alterations were observed. Strikingly, TCDD had far fewer effects than did a feed-restriction protocol intended to mimic the wasting syndrome itself. Notably several classic TCDD-responsive genes were modulated at all time-points, including Cyp1a1, Cyp1b1, and Nqo1. We therefore concluded that rat adipose tissue is unlikely to be the primary driver of the wasting syndrome, and that another tissue is likely involved. Two strains, each with drug-treated vs. vehicle-control
2010-05-19 | E-GEOD-18301 | biostudies-arrayexpress
Project description:Rodents exposed to the environmental contaminant, TCDD, suffer from a number of acute and chronic toxicities, including lethality and a wasting syndrome. Hypothesizing that the wasting syndrome may be caused by changes in adipose tissue -- either in its hormonal regulation or in homeostatic effects -- we profiled the transcriptional response of rat white adipose to TCDD. We employed two separate rat strains: the Long-Evans strain is sensitive to TCDD toxicities while the Han/Wistar strain is over four orders of magnitude more resistant. One day after TCDD exposure few genes were altered in either strain, but after four days a modest number of transcriptional alterations were observed. Strikingly, TCDD had far fewer effects than did a feed-restriction protocol intended to mimic the wasting syndrome itself. Notably several classic TCDD-responsive genes were modulated at all time-points, including Cyp1a1, Cyp1b1, and Nqo1. We therefore concluded that rat adipose tissue is unlikely to be the primary driver of the wasting syndrome, and that another tissue is likely involved.
2009-11-24 | GSE18301 | GEO
Project description:In many mammals, halogenated aromatic hydrocarbon (HAH) exposure causes wasting syndrome, defined as lethal weight loss as a result of severe and persistent hypophagia. The most potent HAH in causing wasting is 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD), which exerts its toxic effects through the aryl hydrocarbon receptor (AHR) – a transcription factor. Because TCDD toxicity is thought to predominantly arise from dysregulation of AHR-transcribed genes, we hypothesized that wasting syndrome is due to TCDD-induced dysregulation of genes involved in regulation of food-intake. We therefore focused on the hypothalamus, as it is the regulatory center of food-intake and energy balance in the central nervous system. We profiled mRNA abundance in hypothalamic tissue from two rat strains with widely differing sensitivities to wasting syndrome: TCDD-sensitive Long-Evans rats and TCDD-resistant Han/Wistar rats, 23 hours after exposure to TCDD (100 μg/kg) or corn oil vehicle. We found that TCDD exposure caused minimal transcriptional dysregulation effects in the hypothalamus, with only 6 genes changed in Long-Evans rats and 15 genes in Han/Wistar rats. Two of the most dysregulated genes were Cyp1a1 and Nqo1, which are induced by TCDD across a wide range of tissues and are considered sensitive markers of TCDD exposure. The minimal response of the hypothalamic transcriptome to a lethal dose of TCDD at an early time-point suggests that the hypothalamus is not the predominant site of initial events leading to hypophagia and associated wasting. TCDD may affect feeding behaviour via events upstream or downstream of the hypothalamus, and further work is required to evaluate this at the level of individual hypothalamic nuclei and subregions. Two strains, each with drug-treated vs vehicle-control
2014-12-23 | E-GEOD-61039 | biostudies-arrayexpress
Project description:In many mammals, halogenated aromatic hydrocarbon (HAH) exposure causes wasting syndrome, defined as lethal weight loss as a result of severe and persistent hypophagia. The most potent HAH in causing wasting is 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD), which exerts its toxic effects through the aryl hydrocarbon receptor (AHR) – a transcription factor. Because TCDD toxicity is thought to predominantly arise from dysregulation of AHR-transcribed genes, we hypothesized that wasting syndrome is due to TCDD-induced dysregulation of genes involved in regulation of food-intake. We therefore focused on the hypothalamus, as it is the regulatory center of food-intake and energy balance in the central nervous system. We profiled mRNA abundance in hypothalamic tissue from two rat strains with widely differing sensitivities to wasting syndrome: TCDD-sensitive Long-Evans rats and TCDD-resistant Han/Wistar rats, 23 hours after exposure to TCDD (100 μg/kg) or corn oil vehicle. We found that TCDD exposure caused minimal transcriptional dysregulation effects in the hypothalamus, with only 6 genes changed in Long-Evans rats and 15 genes in Han/Wistar rats. Two of the most dysregulated genes were Cyp1a1 and Nqo1, which are induced by TCDD across a wide range of tissues and are considered sensitive markers of TCDD exposure. The minimal response of the hypothalamic transcriptome to a lethal dose of TCDD at an early time-point suggests that the hypothalamus is not the predominant site of initial events leading to hypophagia and associated wasting. TCDD may affect feeding behaviour via events upstream or downstream of the hypothalamus, and further work is required to evaluate this at the level of individual hypothalamic nuclei and subregions.
2014-12-23 | GSE61039 | GEO
Project description:The dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic effects in rodent species, all of which are mediated by a ligand-dependent transcription-factor, the aryl hydrocarbon receptor (AHR). The Han/Wistar (Kuopio) (H/W) strain shows exceptional resistance to many TCDD-induced toxicities; the LD50 of >9600 µg/kg for H/W rats is higher than for any other wild-type mammal known. We have previously shown that this resistance primarily results from H/W rats expressing a variant AHR isoform that has a substantial portion of the AHR transactivation domain deleted. Despite this large deletion, H/W rats are not entirely refractory to the effects of TCDD; the variant AHR in these animals remains fully competent to up-regulate well-known dioxin-inducible genes. TCDD-sensitive (Long-Evans, L-E) and resistant (H/W) rats were treated with either corn-oil (with or without feed-restriction) or 100 µg/kg TCDD for either four or ten days. Hepatic transcriptional profiling was done using microarrays, and was validated by RT-PCR analysis of 41 genes. . A core set of genes was altered in both strains at all time points tested, including CYP1A1, CYP1A2, CYP1B1, Nqo1, Aldh3a1, Tiparp, Exoc3, and Inmt. Outside this core, the strains differed significantly in the breadth of response: three-fold more genes were altered in L-E than H/W rats. At ten days almost all expressed genes were dysregulated in L-E rats, likely reflecting emerging toxic responses. Far fewer genes were affected by feed-restriction, suggesting that only a minority of the TCDD-induced changes are secondary to the wasting syndrome. Rats from sensitive (Long-Evans, LE) and resistant (Han/Wistar, HW) strains were treated with 100 ug/kg TCDD or corn oil vehicle and sacrificed either 4 or 10 days after treatment. LE control rats were either fed normally or feed-restricted to control for the wasting effects of TCDD treatment. Each treatment group contains four or five animals (biological replicates), each of which was assayed on an individual microarray.
2011-11-14 | E-GEOD-13513 | biostudies-arrayexpress
Project description:The dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic effects in rodent species, all of which are mediated by a ligand-dependent transcription-factor, the aryl hydrocarbon receptor (AHR). The Han/Wistar (Kuopio) (H/W) strain shows exceptional resistance to many TCDD-induced toxicities; the LD50 of >9600 µg/kg for H/W rats is higher than for any other wild-type mammal known. We have previously shown that this resistance primarily results from H/W rats expressing a variant AHR isoform that has a substantial portion of the AHR transactivation domain deleted. Despite this large deletion, H/W rats are not entirely refractory to the effects of TCDD; the variant AHR in these animals remains fully competent to up-regulate well-known dioxin-inducible genes. TCDD-sensitive (Long-Evans, L-E) and resistant (H/W) rats were treated with either corn-oil (with or without feed-restriction) or 100 µg/kg TCDD for either four or ten days. Hepatic transcriptional profiling was done using microarrays, and was validated by RT-PCR analysis of 41 genes. . A core set of genes was altered in both strains at all time points tested, including CYP1A1, CYP1A2, CYP1B1, Nqo1, Aldh3a1, Tiparp, Exoc3, and Inmt. Outside this core, the strains differed significantly in the breadth of response: three-fold more genes were altered in L-E than H/W rats. At ten days almost all expressed genes were dysregulated in L-E rats, likely reflecting emerging toxic responses. Far fewer genes were affected by feed-restriction, suggesting that only a minority of the TCDD-induced changes are secondary to the wasting syndrome.
2011-11-14 | GSE13513 | GEO
Project description:We profiled hepatic transcriptional responses of 6 strains of rats with varying sensitivity to a dioxin, TCDD, at 19 hours following exposure. The resistant rats exhibited significantly reduced transcriptional responses in comparison to the sensitive strains. We hypothesize that genes which show differential changes between the resistant and sensitive rats may potentially explain sensitivity. Rats with varying sensitivities (Long-Evans, L-E; Han/Wistar, H/W; Fischer 344, F344; Wistar, Wis; Line-A, Ln-A; and Line-C, Ln-C) were treated with 100 ug/kg TCDD or corn oil vehicle and euthanized 19 hours post-treatment. Each treatment group contains four or six animals (biological replicates), each of which was assayed on an individual microarray.
2011-08-16 | E-GEOD-31411 | biostudies-arrayexpress
Project description:We have used Affymetrix microarray-driven gene profiling to comprehensively describe the expression of mRNAs in the brainstem and hypothalamus in the adult male spontaneously hypertensive rat (SHR) as compared to its normotensive parental Wistar-Kyoto (WKY) strain.
2018-10-01 | GSE41552 | GEO
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