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Dose-dependent disruption of hepatic zonation by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice: integration of single-nuclei RNA sequencing and spatial transcriptomics

ABSTRACT: Dose-dependent disruption of hepatic zonation by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice: integration of single-nuclei RNA sequencing and spatial transcriptomics

PROVIDER: PRJNA849972 | ENA |

REPOSITORIES: ENA

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Dose-dependent disruption of hepatic zonation by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice: integration of single-nuclei RNA sequencing and spatial transcriptomics

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

Application of singe nuclei RNA sequencing to assess the hepatic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin

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

Transcription profiling by array of mouse liver from three strains with identical AhRb2 genotype treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

Project description:Differences in gene expression in the liver of three strains of female mice with identical AhRb2 genotype treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

2008-03-21 | E-MEXP-1231 | biostudies-arrayexpress

Dose-response hepatic single nuclei RNA sequencing of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treated mice

Project description:Dose-response hepatic single nuclei RNA sequencing of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treated mice

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2,3,7,8-tetrachlorodibenzo-p-dioxin modifies alternative splicing in mouse liver

Project description:2,3,7,8-tetrachlorodibenzo-p-dioxin modifies alternative splicing in mouse liver

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Dose-response hepatic single nuclei RNA sequencing of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treated mice

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

Application of singe nuclei RNA sequencing to assess the hepatic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Project description:Application of singe nuclei RNA sequencing to assess the hepatic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin

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Expression profiling of human neuroblastoma cells SK-N-SH after treatment with low dose of 2,3,7,8- tetrachlorodibenzo-p-dioxin

Project description:Exposure to dioxins has been associated with impaired development of the nervous system and losses of brain functions. However, the precise cellular events and related molecular basis underlining these adverse effects has not been fully understood. We aimed to reveal global alterations of mRNA expression and potential cellular events by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure.

2020-07-12 | GSE101464 | GEO

2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Alters Lipid Metabolism and Depletes Immune Cell Populations in the Jejunum of C57BL/6 Mice

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

Cross-Species Comparisons of Transcriptomic Alterations in Human and Rat Primary Hepatocytes Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin: rat samples

Project description:A toxicogenomics approach was used to qualitatively and quantitatively compare the gene expression changes in human and rat primary hepatocytes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Hepatocytes from five individual rats and five individual humans were exposed for 24 hours to 11 concentrations of TCDD ranging from 0.00001 nM to 100 nM and a vehicle control. Gene expression changes were analyzed using whole genome microarrays.

2012-02-03 | GSE34250 | GEO

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