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

ABSTRACT: Alternative splicing is a co-transcriptional mechanism by including or excluding exons in different combinations, thereby expanding the diversity of protein isoforms of a single gene. Abnormalities in this process can result in deleterious effects to human health, and several xenobiotics are known to interfere with splicing regulation through multiple mechanisms. These changes could lead to human diseases such as cancer, neurological disorders, autoimmune diseases, and developmental disorders. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant generated as a byproduct of various industrial activities. Exposure to this dioxin has been linked to a wide range of pathologies through the alteration of multiple cellular processes. However, the effects of TCDD exposure on alternative splicing have not yet been studied. Here, we investigate whether exposure to TCDD influenced hepatic alternative splicing in adult male C57BL/6J mice. We identified several genes whose alternative splicing of precursor messenger RNAs was modified following TCDD exposure. In particular, we demonstrated that alternative splicing of Cyp1a1, Ahrr, and Actn1 was significantly altered after TCDD treatment. These findings show that exposure to TCDD has an impact on alternative splicing, presumably through binding to the aryl hydrocarbon receptor, and suggest a new avenue for AhR-mediated pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE126328 | GEO | 2019/10/29

REPOSITORIES: GEO

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Project description:Oxidative stress is an important mechanism of chemical toxicity, contributing to teratogenesis as well as to cardiovascular and neurodegenerative diseases. Developing animals may be especially sensitive to chemicals causing oxidative stress. To assess the response to chemicals at different stages of development, zebrafish (Danio rerio) embryos at 1, 2, 3, 4, 5, and 6 days post-fertilization (dpf) were exposed to 0.1% dimethyl sulfoxide (DMSO), 2 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or 10 uM tert-butylhydroquinone (tBHQ) for 6 hr. Transcript abundance was assessed by real-time qRT-PCR and microarray (Agilent 22k). By microarray, 1477 probes were significantly different among the DMSO-, tBHQ-, and TCDD-treated embryos at 4 dpf. Of these, 220 were 2-fold or greater up-regulated and 108 were 2-fold or greater down-regulated by tBHQ. For TCDD, 17 probes were 2-fold or greater up-regulated and 6 were 2-fold or greater down-regulated. Genes induced by tBHQ, included genes involved in glutathione synthesis and utilization, signal transduction, and DNA damage / stress response. Keywords: Danio rerio, TCDD, tBHQ, oxidative stress, gene expression Separate groups of 30 embryos generated from TL adults were placed in 15 ml egg water in a 10-cm glass petri and at 1, 2, 3, 4, 5, and 6-dpf were exposed for 6 hr to 0.1% dimethyl sulfoxide (DMSO), 2 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or 10 uM tert-butylhydroquinone (tBHQ) (4 replicates per compound per time point). Embyros were frozen immediately after the 6 hr exposure and RNA isolated for microarray analysis. A Universal RNA Reference Sample was created by mixing equal amounts of total RNA from 2 replicates each from all toxicants (TCDD, tBHQ, DMSO) and timepoints (1, 2, 3, 4, 5, 6-dpf). Based on qRT-PCR results, the 4 dpf timepoint was selected for microarray analysis, in which the RNA samples (4 replicates per compound) were Cy3 labeled and co-hybridized with Cy5 labeled Universal RNA Reference Sample to generate data for analysis of variance.

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

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