Characterizing the Impact of Simvastatin on TCDD-Induced Liver Injury Utilizing Single-Nuclei RNA Sequencing
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ABSTRACT:
PROVIDER: PRJNA868699 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21016617.fastq.gz | Fastqsanger.gz | |||
| SRR21016618.fastq.gz | Fastqsanger.gz | |||
| SRR21016619.fastq.gz | Fastqsanger.gz | |||
| SRR21016620.fastq.gz | Fastqsanger.gz | |||
| SRR21016621.fastq.gz | Fastqsanger.gz |
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Project description:Objective: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with metabolic syndrome (MetS) in humans and hepatic effects similar to non-alcoholic fatty liver disease through activation of the aryl hydrocarbon receptor (AHR) pathway. Dysregulation of cholesterol homeostasis, an aspect of MetS, is linked to NAFLD pathogenesis, and TCDD exposure is also linked to the suppression of genes that encode key cholesterol biosynthesis steps and changes in serum cholesterol levels. In a previous experiment, treating mice with TCDD in the presence of simvastatin, a 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) competitive inhibitor, increased toxicity in male mice, compared to TCDD alone. The aim of this study was to deduce a possible mechanism(s) for this increased liver injury. Methods: Male C57Bl/6 mice were treated with vehicle control or TCDD via oral gavage and were fed either standard or simvastatin-laced chow. Single nuclei RNA sequencing (snRNASeq) was performed in mouse liver to investigate the impact of treatment on distinct liver cell (sub)types that may explain differences in pathology between treatments. Results: We demonstrated that co-treated mice experienced exacerbated wasting and increased AHR activation compared to TCDD alone. Furthermore, relative proportions of cell (sub)types were different between TCDD alone and co-treated mice including important mediators of NAFLD progression such as hepatocytes and Kupffer cells. Co-treated mice promoted upregulation of lipid metabolism in hepatocytes, which is consistent with decreased fat accumulation seen in previous studies. Interestingly, the proportion of plasmacytoid dendritic cells (pDCs) increased in only co-treated mice, which may play an important role in the differences in immune cell infiltration between treatment groups. Conclusions: Our results suggest simvastatin co-treatment promotes a worse prognosis of TCDD-induced injury in mice and alterations in immune infiltration between treatments may influence liver injury severity.
2023-10-11 | GSE211018 | 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.
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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: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:Single nuclei RNA sequencing (snRNA-seq) dataset characterizing nuclei from a putative astrocyte enrichment method: SOX9-positive sorting.
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Project description:Transcriptional profiling of mouse Hepa1c1c7 cells comparing control TCDD-treated cells with Hepa1c1c7 cells treated with TCDD plus blebbistatin. The latter causes dysfunction of MYH9. Goal was to determine the effects of blebbistatin on global Hepa1c1c7 gene expression. Two-condition experiment, TCDD treated Hepa1c1c7 vs. TCDD plus blebbistatin. Biological replicates: 1 TCDD sample, 1 TCDD plus blebbistatin sample.
2013-04-16 | E-GEOD-46061 | biostudies-arrayexpress
Project description:Dose-response hepatic single nuclei RNA sequencing of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treated mice
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Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dose-dependently induces the development of hepatic fat accumulation and inflammation with fibrosis in mice initially in the portal region. Conversely, differential gene and protein expression is first detected in the central region. To further investigate cell-specific and spatially resolved dose-dependent changes in gene expression elicited by TCDD, single-nuclei RNA sequencing and spatial transcriptomics were used for livers of male mice gavaged with TCDD every 4 days for 28 days. The proportion of 11 cell (sub)types across 131,613 nuclei dose-dependently changed with 68% of all portal and central hepatocyte nuclei in control mice being overtaken by macrophages following TCDD treatment. We identified 368 (portal fibroblasts) to 1,339 (macrophages) differentially expressed genes. Spatial analyses revealed initial loss of portal identity that eventually spanned the entire liver lobule with increasing dose. Induction of R-spondin 3 (Rspo3) and pericentral Apc, suggested dysregulation of the Wnt/β-catenin signaling cascade in zonally resolved steatosis. Collectively, the integrated results suggest disruption of zonation contributes to the pattern of TCDD-elicited NAFLD pathologies.
2022-10-21 | GSE206294 | GEO
Project description:Transcriptional profiling of mouse Hepa1c1c7 cells comparing control TCDD-treated cells with Hepa1c1c7 cells treated with TCDD plus blebbistatin. The latter causes dysfunction of MYH9. Goal was to determine the effects of blebbistatin on global Hepa1c1c7 gene expression.
2013-04-16 | GSE46061 | GEO
Project description:Dose-response is the cornerstone of safety assessments to determine risk. Innovations in transcriptomic technologies has recently led to the ability to profile gene expression at the single-cell level, enabling comprehensive assessment of adaptive and adverse responses at unprecedented resolution. To demonstrate its application of dose dependent study designs, we performed single nuclei sequencing of livers from male C57BL/6 mice gavaged with the persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at doses of 0.01, 0.03, 0.1, 0.3, 1, 3, 10, or 30 µg/kg or sesame oil vehicle. Following quality control, a total of 131,613 nuclei were sequenced representing 11 distinct cell (sub)types. Our findings reveal dose-dependent changes in relative levels of distinct cell (sub)types such as hepatocytes and macrophages, including the emergence of NASH-associated macrophages (NAMs) characterized by elevated Gpnmb expression. Zonally resolved hepatocytes could also be characterized demonstrating initial induction of aryl hydrocarbon receptor (AhR) target genes such as Cyp1a1 in the central region of the liver lobule while central and portal induction is observed at higher doses. Moreover, we show that zero-inflation inherent to single-cell technologies pose challenges for dose-dependent differential expression analysis and present a novel single-cell Bayesian test method that outperforms common two-group test methods. Collectively, our results demonstrate that single-cell technology can be used to further elucidate mechanisms associated within specific-cell (sub)types and interactions between different cell (sub)types to support the risk assessment paradigm.
2022-05-10 | GSE184506 | GEO