Transcriptomic analyses of TCDD treated zebrafish liver
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE49915 | GEO | 2013/11/12
SECONDARY ACCESSION(S): PRJNA215326
REPOSITORIES: GEO
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Project description:To fully understand molecular toxicity of TCDD in an in vivo animal model, adult zebrafish were exposed to TCDD at 10 nM for 96 h and the livers were sampled for RNA-sequencing based transcriptomic profiling. A total of 1,058 differently expressed genes were identified based on fold-change>2 and TPM (transcripts per million) >10. Among the top 20 up-regulated genes, 10 novel responsive genes were identified and verified by qRT-PCR analysis on independent samples. Transcriptomic analysis indicated several deregulated pathways associated with cell cycle, endocrine disruptors, signal transduction and immune systems. Comparative analyses of TCDD-induced transcriptomic changes between fish and mammalian models revealed that proteomic pathway is consistently up-regulated while calcium signaling pathway and several immune-related pathways are generally down-regulated. Transcriptome profiling of treated sample (TCDD) and control sample (DMSO) were generated by deep sequencing using 3' RNA-SAGE with SOLiD system
2013-11-12 | E-GEOD-49915 | biostudies-arrayexpress
Project description:2,3,7,8M-bM-^@M-^Stetrachlorodibenzo-p-dixion (TCDD) is a dioxin congener that causes a wide range of toxic effects in rodent species. Previous studies discovered that males and females of the same species display different sensitivities to TCDD exposure. Although it is now clear that most TCDD-induced toxic outcomes are mediated by the Aryl Hydrocarbon Receptor (AHR), a transcription factor, the mechanism of sex-specific responses to TCDD remains largely unknown. To understand the differential sensitivity in male and female animals, we profiled the hepatic transcriptomic responses to single doses of TCDD (125, 250, 500, or 1000 M-BM-5g/kg) in male and female C57BL6 mice. Several key findings were revealed by our study: 1) transcriptomic profiles varied largely between sexes at all doses; 2) the mRNA abundance profiles of female mice were less altered from basal level; 3) the alteration of M-bM-^@M-^XAHR-coreM-bM-^@M-^Y genes were consistent regardless of sex; 4) a list of sex-specific TCDD-responsive genes were identified, including Fmo3 and Nr1i3 upregulated in male mice and Sult3a1 downregulated in female mice; 5) functional analysis of these candidate genes showed various biological pathway enrichments in a sex-dependent manner. Our study shows that the sex-dependent sensitivities to TCDD exposure are associated with a set of sex-specific TCDD-responsive genes that are indirectly regulated by AHR activity. The exact roles of these genes in response to TCDD exposure are not clear and require further investigation. Adult male and female C57BL/6 mice were treated by gavage with one single-dose TCDD (125, 250, 500, or 1000 M-NM-<g/kg) in corn oil or corn oil vehicle alone. Animals were euthanized at 96 hours after treatment and tissues were harvested. RNA was isolated from hepatic tissue and the transcriptome for each animal assayed on an individual microarray.
2015-03-01 | E-GEOD-61038 | biostudies-arrayexpress
Project description:We determined global gene changes in immature ovaries and testes in response to an in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure. Microarray analysis was performed using testes and ovaries of the dioxin-exposed dams’ offspring. One hundred and thirteen genes were differentially expressed in ovaries and 56 genes in testes of 14 and 5 days-old, respectively. Real-time PCR was used to validate and extend data using RNA extracted from 5 to 145-day old rat testes and 3 to 25-day old rat ovaries. A single gene of the classic dioxin battery, i.e., the repressor of the aryl hydrocarbon receptor (Ahrr) was found altered in testes. In contrast, several of them including Cyp1a1, Cyp1b1, Nqo1, and Ahrr were found up-regulated in ovary, pituitary (a different endocrine organ) and liver. In addition to Ahrr, we identified 6 genes targeted by dioxin in both gonads, including the chemokines Cxcl4, Ccl5. Ccl5 gene expression levels were also regulated in pituitary and liver, so as pituitary Cxcl4. Four genes targeted by TCDD in testis and meeting stringent criteria were further surveyed. It included 2 genes with no previous reported function in testis, Art2b, Gzmf, Hpgds and Fgf13. Fgf13 was down-regulated in testis, and pituitary but not in ovary or liver. Interestingly, Art2b and Gzmf were up-regulated in testis, liver and pituitary but not ovary. Finally, Hpgds was unique in that expressed in various tissues it was regulated by TCDD in the gonads but not in the other tissues studied. Transcriptomic analysis on testes at 5 days and in ovaries at 14 days. In both cases, 3 rats treated in utero by TCDD were compared to 3 rats treated with sesame-oil vehicle
2011-10-11 | E-GEOD-32890 | biostudies-arrayexpress
Project description:Environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are known to cause a wide range of toxicities. The consequences of acute exposure to TCDD in rodents, and to a lesser degree in humans, can range from mild chloracne to terminal illness, such as cancer. The aryl hydrocarbon receptor (AHR) plays a critical role in mediating the toxic effects of TCDD. However, the underlying mechanism of differential sensitivities to TCDD across organisms remain poorly understood, however differences in the AHR are known to play a role. To further investigate this, we profiled the transcriptomic responses in liver from TCDD sensitive or resistant mice, 19 hours following exposure to either 5 or 500 μg/kg TCDD. Analysis of transcriptomic profiles revealed several key findings: 1) TCDD sensitive C57BL/6 mice demonstrated an increased number of changes within the hepatic transcriptome than the TCDD resistant DBA/2 mice following exposure to low dose (5 μg/kg) TCDD, but this balanced out at the high dose (500 μg/kg), and the transcriptome from ratonized mice showed more changes than either C57BL/6 or DBA/2, regardless of dose; 2) mRNA abundance of the ‘AHR-core’ battery of genes was consistently perturbed in dioxin sensitive mice (C57BL/6 and rWT) in comparison to dioxin resistant mice (DBA/2), with Inmt showing significant changes in transcription only in the ratonized mouse liver and Cyp1a2 more response in non-transgenic mice (C57BL/6 and DBA/2); 3) a small subset of genes had significantly altered transcription in either the TCDD-resistant DBA/2 mouse liver (including Rpl18a, Mbd6, Onecut2 and Lipg) or the TCDD-sensitive cohorts (C57BL/6 and rWT; including Smcp, Acpp, Acot2 and Acot3). Overall, our results demonstrate considerable TCDD-induced transcriptomic differences between DBA/2 and C57BL/6 mouse lines.
2019-10-29 | GSE127217 | GEO
Project description:The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor in the PAS superfamily of environmental sensors that is linked to several metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). Much remains unknown regarding the impact of genetic variation in AHR-driven disease, as past studies have focused on a small number of inbred strains. Recently, the presence of a wide-range of interindividual variability amongst humans was reported in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the prototypical ligand of the AHR. In this study, a panel of 14 diverse mouse strains were exposed to TCDD for 10 days to characterize the AHR-mediated response across genetic backgrounds. In this study, responses to TCDD are heavily-dependent on genetic background. While mice carry one of four Ahr alleles that impact the AHR-mediated responses, we observed significant intra-allelic variability suggesting the presence of novel genetic modifiers of AHR signaling. A regression-based approach was used to scan for genes regulated by the AHR and/or associated with TCDD-induced phenotypes. The approach identified seven genes, 2 of which are novel, that are likely regulated by the AHR based on association with hepatic TCDD burden (p≤0.05). Finally, we identified a gene, Dio1, which was associated with change in percent body fat across the diverse set of strains (p≤0.05). Overall, the results in this study exemplify the power of genetics-based approaches in identifying novel genes that are putatively regulated by the AHR.
2021-05-01 | GSE167328 | GEO
Project description:A global RNA-Seq analysis was conducted using RNA isolated from the axial region of DMSO- and 0.3 nM TCDD-exposed medaka to identify targets within the osteochondral pathway potentially impacted by TCDD exposure. In total, 597 genes were significantly up- or down-regulated (q<0.05) and were associated with select pathological states including inflammatory disease, connective tissue disorders, and skeletal and muscular disorders.
2017-03-07 | GSE87168 | GEO
Project description:2,3,7,8–tetrachlorodibenzo-p-dixion (TCDD) is the most potent of the dioxin congeners, capable of causing a wide range of toxic effects across numerous animal models. Previous studies have demonstrated that males and females of the same species can display divergent sensitivity phenotypes to TCDD toxicities. Although it is now clear that most TCDD-induced toxic outcomes are mediated by the aryl hydrocarbon receptor (AHR), the mechanism of differential responses to TCDD exposure between sexes remains largely unknown. To investigate the differential sensitivities in male and female mice, we profiled the hepatic transcriptomic responses 4 days following exposure to various amounts of TCDD (125, 250, 500 or 1000 µg/kg) in adult male and female C57BL/6Kuo mice. Several key findings were revealed by our study. 1) Hepatic transcriptomes varied significantly between the sexes at all doses examined. 2) The liver transcriptome of males was more dysregulated by TCDD than that of females. 3) The alteration of ‘AHR-core’ genes was consistent in magnitude, regardless of sex. 4) A subset of genes demonstrated sex-dependent TCDD-induced transcriptional changes, including Fmo3 and Nr1i3, which were significantly induced in livers of male mice only. In addition, a meta-analysis was performed to contrast transcriptomic profiles of various organisms and tissues following exposure to equitoxic doses of TCDD. Minimal overlap was observed in the differences between TCDD-sensitive or TCDD-resistant models. Sex-dependent sensitivities to TCDD exposure are associated with a set of sex-specific TCDD-responsive genes. In addition, complex interactions between the aryl hydrocarbon and sex hormone receptors may affect the observable differences in sensitivity phenotypes between the sexes. Further work is necessary to better understand the roles of those genes altered by TCDD in a sex-dependent manner, and their association with changes to sex hormones and receptors.
2015-03-01 | GSE61038 | GEO
Project description:The aryl hydrocarbon receptor (AHR) mediates most of the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, TCDD toxicity phenotypes vary widely between species, strains and even between sexes within a strain. While the exact reasons for this variation remain unclear, it is thought to be related to differences in the structure of the AHR. Previous studies comparing the downstream effects of TCDD exposure between animals with different AHR isoforms have been confounded by the genetic differences between these model systems. To address this issue conclusively, we evaluated three transgenic mouse lines, each of which express a different rat AHR isoform (rWT, DEL, and INS) from two strains of rat with highly divergent TCDD-susceptibilities, within identical genetic backgrounds. Here we profile hepatic transcriptomic responses following exposure to TCDD, and use these to identify transcripts associated with toxicity. We have confirmed that the variation in toxicity is inherent to the AHR isoform. Additionally, we note the enhanced activity of the modified transactivation domain of the DEL isoform, relative to the INS isoform, and provide further evidence that the INS isoform is responsible for the high resistance to TCDD observed in H/W rats. We also uncover several candidate genes that were consistently differentially expressed in TCDD-sensitive mice and rats.
2016-01-01 | GSE72270 | GEO
Project description:2,3,7,8-TCDD (TCDD) is a reproductive toxicant and endocrine disruptor in nearly all vertebrates, yet the mechanisms by which TCDD induces these reproductive alterations have not been fully characterized. Fish are among the most sensitive vertebrates to the toxic effects of TCDD, and even subtle physiologic changes induced by TCDD can impair reproduction. Previously, we have shown that chronic, sub-lethal exposure to TCDD decreased reproductive capacity, reduced serum estradiol and vitellogenin concentrations, and altered follicular development. Here we investigate the transcriptional changes in zebrafish ovary as they relate to observed attenuated estradiol concentrations and ovarian development. We used quantitative RT-PCR to assess TCDDâs effects on the expression of several candidate genes important in the regulation of follicular development and steroidogenesis. Additionally, global changes in gene expression in the ovary caused by TCDD exposure were identified using Affymetrix Gene Chip Analysis. Our data suggest that TCDD may inhibit follicle maturation via attenuated gonadotropin responsiveness and/or depressed estradiol biosynthesis. Additionally, genes involved in glucose and lipid metabolism, regulation of transcription, and immune function were dysregulated by at least 2-fold suggesting that TCDD alters various integrated networks of signaling pathways. Approximately 89% of dysregulated transcripts contain putative AHR response elements (AHRE) within 5kb upstream of the predicted transcriptional start site suggesting ovarian toxicity is AHRE driven. Furthermore, approximately 49% of dysregulated transcripts contain putative estrogen response elements (ERE) suggesting that dysregulation of estrogen-responsive genes may also contribute to TCDD-induced attenuated follicular development. Patterns in gene expression were correlated with putative EREs and AHREs, and suggest that impacts on the regulation of transcription may play a large role in TCDDâs ovarian toxicity. Taken together, these data illustrate the complexity of TCDDâs ovarian toxicity. Experiment Overall Design: A total of eight samples were analyzed including three TCDD doses (10, 40, 100 ppb, dietary exposure) and vehicle control samples. cRNA targets were synthesized from pooled total RNA isolated from five ovaries from different individuals in each treatment group. Each individual contributed equally to a given pool. Two technical replicates were run for each treatment group. Several genes of interest arising from this microarray study were validated by Quantitative RT-PCR with individual ovary samples to assess biological variability.
2009-04-30 | E-GEOD-4859 | biostudies-arrayexpress
Project description:Juvenile zebrafish were fed Biodiet starter (4% body weight per day) for 42 d with TCDD added at 0 ppb, 0.1 ppb, 1 ppb, 10 ppb or 100 ppb. Fish were collected, sexed, weighed and length measured at 0, 7, 14, 28 or 42 d for TCDD assessment, histopathologic and microarray analysis. Microarray experiments were conducted in TCDD-treated (at 0, 0.1, 1, 10 and 100 ppb) for male and female sexed zebrafish at 28 d. NimbleGen Gene Expression 12X135K zebrafish microarrays and One-Color DNA labeling Kit (NimbleGen, WI) were used for genome-wide expression analysis of TCDD-treated zebrafish. TCDD accumulated in a dose- and time-dependent manner and 100 ppb TCDD caused TCDD accumulation in female (15.49 ppb) and male (18.04 ppb) fish at 28 d post exposure. TCDD caused multiple lesions in liver, kidney, intestine and ovary of zebrafish and functional dysregulation such as depletion of glycogen in liver, retrobulbar edema, degeneration of neurosensory epithelium, underdevelopment of intestine, and diminution in the fraction of ovarian follicles containing vitellogenic oocytes. Microarray gene expression analysis comparing control to post TCDD diet revealed dysregulated genes located in pathways associated with cardiac necrosis/cell death, cardiac fibrosis, renal necrosis/cell death and liver necrosis/cell death. These baseline toxicological effects provide evidence for the potential biomarkers, mechanisms and pathology of TCDD induced dysregulation.
2014-12-01 | GSE47434 | GEO