Mus musculus
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ABSTRACT:
PROVIDER: PRJNA260127 | ENA |
REPOSITORIES: ENA
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Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that produces myriad toxicities in most mammals. In rodents alone, there is a huge divergence in the toxicological response across species, as well as among different strains within a species. But there are also significant differences between males and females animals of a single strain. These differences are inconsistent across model systems: the severity of toxicity is greater in female rats than males, while male mice and guinea pigs are more sensitive than females. Because the specific events that underlie this difference remain unclear, we characterized the hepatic transcriptional response of adult male and female C57BL/6 mice to 500μg/kg TCDD at multiple time-points. The transcriptional profile diverged significantly between the sexes. Female mice demonstrated a large number of altered transcripts as early as 6h following treatment, suggesting a large primary response. Conversely, male animals showed the greatest TCDD-mediated response 144h following exposure, potentially implicating significant secondary responses. Nr1i3 was statistically significantly induced at all time-points in the sensitive male animals. This mRNA encodes the constitutive androstane receptor (CAR), a transcription factor involved in the regulation of xenobiotic metabolism, lipid metabolism, cell cycle and apoptosis. Surprisingly though, changes at the protein level (aside from the positive control, CYP1A1) were modest, with only FMO3 showing clear induction, and no genes with sex-differences. Thus, while male and female mice show transcriptional differences in their response to TCDD, their association with TCDD-induced toxicities remains unclear.
2015-03-01 | GSE61037 | GEO
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: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:In rats, direct exposure to TCDD causes myriad toxicities. Exposed rats experience hepatotoxicity, wasting syndrome and immune suppression, amongst others. “Inherited exposure”, as occurs in the F3 generation of directly exposed F0 animals, has also been shown to cause toxicity: both male and female F3 rats demonstrate an increased incidence of adult onset disease, females also display reproductive abnormalities and increased incidence of ovarian diseases while males show increased incidence of kidney disease and an altered sperm epigenome. Here, we explore the hepatic transcriptomic profile of male and female F3 Sprague-Dawley rats bred through the paternal germ line from F0 dams exposed to a single dose of TCDD (0, 30, 100, 300 or 1000 ng/kg body weight) by oral gavage. We hypothesize that RNA transcripts with altered abundance in livers of unexposed F3 progeny of treated F0 Sprague-Dawley rats may result from epigenetic modifications to the genome. Female F3 rats demonstrated more TCDD-mediated hepatic transcriptomic changes than males, with differences primarily in the lowest dose group.
2020-12-31 | GSE143368 | GEO
Project description:2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that produces myriad toxicities across various experimental models. In rodents alone, there is huge divergence in the toxicological response across species, between strains within a species and even between sexes within a strain. This difference in sensitivities between sexes has been characterized in multiple rodent models, however with contrasting results: the severity of toxicity is greater in female rats than in males while male mice and guinea pigs are more sensitive to the effects of TCDD than females. While the presence of estrogens or androgens has a known impact on response, the specific transcriptional events that cause this difference remain unclear. We sought to characterize the transcriptional environment of male and female C57BL/6 mice treated with 500 M-NM-<g/kg TCDD and followed across a time-course. This dose was chosen as it is greater than the LD50 for male mice yet produces minimal effects in females. Additionally, evaluation along a time-course allows for the detection of specific changes that occur throughout the development of phenotypic toxicities. The transcriptional profile across the time-course was highly divergent between the sexes. Female TCDD-treated mice demonstrated a large number of altered transcripts as early as 6 hours following treatment, suggesting a large primary response, possibly indicative of the activation of numerous defense mechanisms. Conversely, male animals showed the greatest TCDD-mediated response 144 hours following exposure, potentially implicating significant secondary responses for the increased appearance of TCDD toxicities. Nr1i3 is statistically significantly altered at all time-points in the sensitive male animals. This mRNA encodes a transcription factor (constitutive androstane receptor; CAR) involved in the regulation of xenobiotic metabolism, as well as lipid metabolism, cell cycle and apoptosis. In particular, increased levels of CAR may result in induction of the anti-apoptotic gene Gadd45b and carboxylesterase Ces1d, both of which we identify as transcriptionally altered and may be responsible for phenotypic hepatic abnormalities, such as steatohepatitis and tumor formation. Further evaluation across studies of mice and rats into the role of Nr1i3 and associated genes are crucial to enhance our understanding of various TCDD-induced toxicities. Adult male and female C57BL/6 mice were treated by gavage with either 500 ug/kg TCDD in corn oil or corn oil vehicle alone. Animals were euthanized at either 6, 24, 72 or 144 hours after treatment and tissues were harvested. RNA was isolated from hepatic tissue and the transcriptome for each animal assayed on an individual microarray. Please note that 7 samples (out of total 65 samples) were identified as outliers and therefore the data were processed without the outliers as well. The normalized data without outliers were provided in the 'normalized_data_without_outliers.txt' file.
2015-03-01 | E-GEOD-61037 | 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:Purpose: Observing the response of the heart to dietary interventation at the metabolomic and transcriptomic level may have relevance for cardiovascular diseases Methods: RNA Seq of 12 week old WT male mice on chow or HFD and WT female mice on Chow or HFD; RNA was extracted and reverse-transcribed after polyA selection to complementary DNA for sequencing on an Illumina NovaSeq platform Results: RNAseq from heart tissue revealed significant differences in expression of 292 mRNA, with an FDR <0.05. PCA showed that there were significant sex differences in chow-fed mice. It also separated HFD-fed vs. Chow-fed samples for both male and female mice. Conclusions: This work reveals the response of a vital organ to dietary intervention at both metabolomic and transcriptomic levels, which is a fundamental question in physiology that may have relevance for cardiovascular diseases. This work also reveals significant sex differences in cardiac metabolites and gene expression.
2022-04-11 | GSE198546 | GEO
Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent aryl hydrocarbon receptor (AhR) agonist that elicits a broad spectrum of dose-dependent effects in the liver, including hepatic lipid accumulation coupled with inflammation. To determine the role of inflammatory lipid mediators in TCDD-mediated hepatotoxicity, eicosanoid metabolism was investigated in female Sprague-Dawley (SD) rats. Rats were gavaged with sesame oil vehicle or 0.01-10 µg/kg TCDD every 4 days for 28 days. Hepatic RNA-Seq data from female SD rats was compared with data from female C57BL/6 mice and functionally annotated to determine key toxicogenomic differences between the two species regarding TCDD exposure. Hepatic RNA-Seq data from female SD rats integrated with untargeted metabolomics of liver, serum, and urine identified dose-dependent changes in linoleic acid (LA) and arachidonic acid (AA) metabolism. TCDD also elicited dose-dependent differential gene expression associated with cyclooxygenase, lipoxygenase, and cytochrome P450 epoxidation/ hydroxylation pathways with corresponding changes in omega-6 (e.g. AA and LA) and omega-3 polyunsaturated fatty acids (PUFAs) as well as their eicosanoid metabolites. Overall, total omega-6 PUFAs increased, while total omega-3 PUFAs decreased. Phospholipase A2 (Pla2g12a) was induced 6-fold consistent with increased AA metabolism, while AA utilization by lipoxygenases Alox5 (2-fold) and Alox15 (10-fold) increased leukotrienes (LTs), important mediators signaling an inflammatory response. More specifically, TCDD increased pro-inflammatory eicosanoids, including leukotriene (LT) B4 (3-fold), and LTB3 (5-fold), known signals for the recruitment of neutrophils to areas of tissue damage. Dose-response modeling of metabolite and gene expression changes suggests the cytochrome P450 hydroxylase/epoxygenase and the lipoxygenase pathways are the most sensitive to TCDD. While several differentially expressed genes (DEGs) associated with eicosanoid biosynthesis contained putative dioxin response elements (pDRE) within their regulatory region, ChIP-Seq analysis showed little AhR enrichment, suggesting TCDD-elicited induction of eicosanoid biosynthesis is not a direct effect of AhR activation.
2018-12-01 | GSE110293 | GEO
Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent aryl hydrocarbon receptor (AhR) agonist that elicits a broad spectrum of dose-dependent effects in the liver, including hepatic lipid accumulation coupled with inflammation. To determine the role of inflammatory lipid mediators in TCDD-mediated hepatotoxicity, eicosanoid metabolism was investigated in female Sprague-Dawley (SD) rats. Rats were gavaged with sesame oil vehicle or 0.01-10 µg/kg TCDD every 4 days for 28 days. Hepatic RNA-Seq data from female SD rats was compared with data from female C57BL/6 mice and functionally annotated to determine key toxicogenomic differences between the two species regarding TCDD exposure. Hepatic RNA-Seq data from female SD rats integrated with untargeted metabolomics of liver, serum, and urine identified dose-dependent changes in linoleic acid (LA) and arachidonic acid (AA) metabolism. TCDD also elicited dose-dependent differential gene expression associated with cyclooxygenase, lipoxygenase, and cytochrome P450 epoxidation/ hydroxylation pathways with corresponding changes in omega-6 (e.g. AA and LA) and omega-3 polyunsaturated fatty acids (PUFAs) as well as their eicosanoid metabolites. Overall, total omega-6 PUFAs increased, while total omega-3 PUFAs decreased. Phospholipase A2 (Pla2g12a) was induced 6-fold consistent with increased AA metabolism, while AA utilization by lipoxygenases Alox5 (2-fold) and Alox15 (10-fold) increased leukotrienes (LTs), important mediators signaling an inflammatory response. More specifically, TCDD increased pro-inflammatory eicosanoids, including leukotriene (LT) B4 (3-fold), and LTB3 (5-fold), known signals for the recruitment of neutrophils to areas of tissue damage. Dose-response modeling of metabolite and gene expression changes suggests the cytochrome P450 hydroxylase/epoxygenase and the lipoxygenase pathways are the most sensitive to TCDD. While several differentially expressed genes (DEGs) associated with eicosanoid biosynthesis contained putative dioxin response elements (pDRE) within their regulatory region, ChIP-Seq analysis showed little AhR enrichment, suggesting TCDD-elicited induction of eicosanoid biosynthesis is not a direct effect of AhR activation.
2018-12-01 | GSE110282 | 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. Adult male transgenic mice were treated by gavage with 0, 125, 250, 500, or 1000 µg/kg TCDD dissolved in corn oil vehicle. Mice were euthanized 4 days following treatment and liver tissue was harvested for analysis. RNA was isolated and the transcriptome for each animal assayed on separate microarrays.
2016-07-03 | E-GEOD-72270 | biostudies-arrayexpress