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Your Environment. Your Health.

Michigan State University: Dataset Details, ID=GSE206294

Superfund Research Program

Environmental, Microbial and Mammalian Biomolecular Responses to AhR Ligands

Center Director: Norbert E. Kaminski
Grant Number: P42ES004911
Funding Period: 1989-2027
View this project in the NIH Research Portfolio Online Reporting Tools (RePORT)

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Title: 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

Accession Number: GSE206294

Link to Dataset:

Repository: Gene Expression Omnibus (GEO)

Data Type(s): Gene Expression

Organism(s): Mus musculus

Summary: 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 percent 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/ -catenin signaling cascade in zonally resolved steatosis. Collectively, the integrated results suggest disruption of zonation contributes to the pattern of TCDD-elicited NAFLD pathologies.

Publication(s) associated with this dataset:
  • Nault R, Saha S, Bhattacharya S, Sinha S, Maiti T, Zacharewski TR. 2022. Single cell transcriptomics shows dose-dependent disruption of hepatic zonation by TCDD in mice. Toxicol Sci doi:10.1093/toxsci/kfac109 PMID:36222588
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