2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase (TIPARP/PARP7) catalytic mutant mice (TiparpH532A) have increased sensitivity to TCDD-induced hepatotoxicity and lethality
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA703925 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13762403_1.fastq.gz | Fastqsanger.gz | |||
| SRR13762403_2.fastq.gz | Fastqsanger.gz | |||
| SRR13762404_1.fastq.gz | Fastqsanger.gz | |||
| SRR13762404_2.fastq.gz | Fastqsanger.gz | |||
| SRR13762405_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 32 |
Similar Datasets
Project description:Typical rodent toxicology experiments are performed at human thermoneutral temperatures (thermostandard; TS = 20 – 24° C). Reports have indicated that investigation of metabolic endpoints at mouse thermoneutral temperatures (TNM = 28 – 30° C) improves translation to humans when they are not chronically cold-stressed. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to dose-dependently induce metabolic disease in mice at including liver steatosis, steatohepatitis, and periportal fibrosis. To test whether dose-dependent hepatotoxicity caused by TCDD is altered by housing temperature we gavaged male C57BL/6 mice every 4 days for 28 days with TCDD (0.03 – 30 µg/kg) or sesame oil vehicle at TS and TNM. Mice held at TNM exhibited less marked relative liver weight gain and histopathology with milder steatosis, immune cell infiltration, hepatocellular hypertrophy, and an absence of biliary hyperplasia compared to mice held at Ts. Mice housed in both temperature conditions had a similar dose-dependent decrease in total cholesterol, but mice at TS had more elevated serum ALT and decreased glucose and triglycerides at 30 µg/kg TCDD. Mice at TNM had fewer differentially expressed genes (DEGs) than TS, although most of the DEGs at TNM were shared with the DEGs at TS. Benchmark Dose (BMD) analysis performed on the DEGs revealed largely similar trends, however, the most induced DEGs, which constituted some of the AhR-battery genes (e.g. Cyp1a1), exhibited lower BMDs at TNM. Moreover, at 30 µg/kg TCDD both sets of mice had increased pro-inflammatory cytokines. The only cytokine which was clearly different between the two sets of mice irrespective of dose was VEGF-A. Overall, mice held at TNM showed reduced severity at equivalent doses to mice held at TS.
2023-09-18 | GSE203300 | GEO
Project description:Dose-dependent jejunal epithelial gene expression was examined following repeated exposure (every 4 days for 28 days) to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These data were used to examine the effect of repeated TCDD exposure on jejunal differential gene expression, in order to investigate the role of the jejunum in TCDD-elicited steatohepatitis in C57BL/6.
2015-10-01 | GSE70379 | GEO
Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that disrupts normal hepatic function. This disruption leads to the development and progression of non-alcoholic fatty liver disease (NAFLD) pathologies, including steatosis, steatohepatitis, and fibrosis. TCDD exerts hepatotoxic effects through activation of the aryl hydrocarbon receptor (AHR) eliciting transcriptional changes. Although diverse liver cell types contribute to TCDD-induced hepatotoxicity, cell-specific transcriptional changes in response to acute TCDD exposure remain unclear. The objective of this project was to elucidate the cell-specific outcomes of AHR activation following acute TCDD exposure. We conducted liver single-nuclei RNA-sequencing from male C57BL/6 mice administered 30 μg/kg of TCDD or sesame oil and sacrificed at 2, 4, 8, 12, 18, 24, or 72 hours post-oral gavage. Leiden clustering and annotation identified 10 major liver cell types, and 2 macrophage and 8 endothelial cell (EC) subtypes. While most cell types maintained their relative abundance, neutrophils exhibited an increase at 72 hours in response to TCDD. Hepatocytes, ECs, and hepatic stellate cells (HSCs) were the only cell types with cell-specific gene expression changes with known AHR binding sites (1,550, 102, and 40, respectively). Functional enrichment analysis in response to TCDD revealed disruptions in the metabolism of steroids, primary bile acids, vitamins, retinols, and glutathione in addition to one-carbon metabolism. EC differential gene expression was associated with PI3-AKT signaling, as well as protein processing and transport pathways. HSCs were enriched in protein processing, ABC transporters, and the dysregulation of tryptophan and linoleic acid metabolism. Altogether, these results suggest that early responses to TCDD trigger cell-specific changes in gene expression in the liver, contributing to hepatotoxicity and the emergence of hepatic pathologies related to NAFLD.
2024-08-20 | GSE254121 | GEO
Project description:We previously reported that TCDD-inducible poly-ADP-ribose polymerase (TIPARP), an aryl hydrocarbon receptor (AHR) target gene and mono-ADP-ribosyltransferase, acts as part of a negative feedback loop to repress AHR signalling, a process that prevented by a single H532A mutation that destroys TIPARP catalytic activity. Moreover, whole body or hepatocyte specific-deletion of, increases the sensitivity of mice to dioxin-induced toxicities. Based on these findings, we hypothesized that the loss of TIPARP catalytic activity would increase sensitivity to TCDD-induced toxicity in vivo. To test the hypothesis, we created a catalytically deficient mouse line (TiparpH532A) by introducing a single H532A mutation in Tiparp. Treatment of mouse embryonic fibroblasts (MEFs) or hepatocytes isolated from TiparpH532A mice confirmed the increased TCDD-induced expression of the AHR target genes, Cyp1a1, Cyp1b1 and Tiparp. We also confirmed TCDD-dependent increases in Tiparp protein levels, as well as increased protein stabilization of TiparpH532A compared Tiparp+/+ protein. TiparpH532A mice given a single injection of 10 ug/kg dioxin, a non-lethal dose in Tiparp+/+ mice, did not survive beyond day 10. All Tiparp+/+ mice survived the 30-day treatment. Dioxin treated TiparpH532A mice displayed increased expression of Ahr target genes, increased steatohepatitis and hepatotoxicity as indicated by increased alanine aminotransferase activity compared with wildtypes. Taken together, these data further support TIPARP as a key negative regulator of AHR activity and its specific loss of its catalytic activity is sufficient to increase the sensitivity to dioxin-induced hepatosteatosis and lethality. TIPARP has recently emerged as a potential anti-cancer therapeutic; however, AHR signalling and toxicity will need to be carefully considered in determining the consequences of TIPARP inhibition.
2021-09-08 | GSE167205 | GEO
Project description:Effect of thermoneutral housing conditions on the hepatotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in male C57BL/6 mice
| PRJNA839384 | ENA
Project description:Cell-specific transcriptional responses are lost in the averages of bulk RNA sequencing. We performed single nuclei RNA sequencing (snSeq) on frozen liver samples from male C57BL/6 mice in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Approximately 19,907 hepatic genes were detected across 16,015 sequenced nuclei from control and treated samples. Eleven cell-(sub)types were identified including distinct hepatocyte sub-populations, consistent with the cell diversity of the liver. TCDD increased macrophages from 0.5% to 24.7%, while neutrophils were only present in treated samples. The number of differentially expressed genes correlated with the basal expression level of Ahr. In addition to expected functional enrichments within each cell-(sub)type, RAS signaling was enriched in nonparenchymal cells. snSeq also identified a Kupffer cell subtype highly expressing Gpnmb, consistent with a dietary NASH model. Overall, snSeq distinguished cell-specific transcriptional changes and population shifts consistent with the hepatotoxicity of TCDD.
2020-09-01 | GSE148339 | 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: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: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:The objective of the study was to characterize gene expression cascade involved in the suppression of B-cell activation and differentiation by 2,3,7,8-tetrachlorodibenzo-p-dixoxin (TCDD). The underlying hypothesis was that multiple nodes in the B-cell differentiation network are directly or indirectly regulated by TCDD through its receptor, the AHR.
2010-10-21 | GSE21272 | GEO