Transcriptomic analyses of livers from mice exposed to 1,4-dioxane for up to 90 days to assess potential mode(s) of action underlying liver tumor development
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Updated: Oct 25, 2025
Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
G A Chappell1, M M Heintz1, L C Haws2
1ToxStrategies, Inc., Asheville, NC, United States.
Abstract:
1,4-Dioxane is a volatile organic compound with industrial and commercial applications as a solvent and in the manufacture of other chemicals. 1,4-Dioxane has been demonstrated to induce liver tumors in chronic rodent bioassays conducted at very high doses. The available evidence for 1,4-dioxane-induced liver tumors in rodents aligns with a threshold-dependent mode of action (MOA), with the underlying mechanism being less clear in the mouse than in rats. To gain a better understanding of the underlying molecular mechanisms related to liver tumor development in mice orally exposed to 1,4-dioxane, transcriptomics analysis was conducted on liver tissue collected from a 90-day drinking water study in female B6D2F1/Crl mice (Lafranconi et al., 2020). Using tissue samples from female mice exposed to 1,4-dioxane in the drinking water at concentrations of 0, 40, 200, 600, 2,000 or 6,000 ppm for 7, 28, and 90 days, transcriptomic analyses demonstrate minimal treatment effects on global gene expression at concentrations below 600 ppm. At higher concentrations, genes involved in phase II metabolism and mitotic cell cycle checkpoints were significantly upregulated. There was an overall lack of enrichment of genes related to DNA damage response. The increase in mitotic signaling is most prevalent in the livers of mice exposed to 1,4-dioxane at the highest concentrations for 90 days. This finding aligns with phenotypic changes reported by Lafranconi et al. (2020) after 90-days of exposure to 6,000 ppm 1,4-dioxane in the same tissues. The transcriptomics analysis further supports overarching study findings demonstrating a non-mutagenic, threshold-based, mitogenic MOA for 1,4-dioxane-induced liver tumors.
Insights
1,4-Dioxane exposure induces liver tumors in mice via a threshold-based, non-mutagenic mechanism. Transcriptomics reveals increased mitotic signaling at high doses, supporting a mitogenic mode of action for 1,4-dioxane liver tumor development.
Area of Science:
- Toxicology
- Molecular Biology
- Genomics
Background:
- 1,4-Dioxane is a common industrial solvent linked to liver tumors in rodents at high doses.
- Evidence suggests a threshold-dependent mode of action (MOA) for 1,4-dioxane-induced liver tumors, but mechanisms in mice are unclear.
- Understanding the molecular basis of 1,4-dioxane's hepatocarcinogenicity in mice is crucial for risk assessment.
Purpose of the Study:
- To investigate the molecular mechanisms underlying 1,4-dioxane-induced liver tumor development in female mice.
- To analyze transcriptomic changes in liver tissue following sub-chronic oral exposure to 1,4-dioxane.
- To determine if 1,4-dioxane exposure triggers DNA damage response pathways.
Main Methods:
- Transcriptomics analysis of liver tissue from female B6D2F1/Crl mice exposed to 1,4-dioxane (0-6,000 ppm) for 7, 28, and 90 days.
- Gene expression profiling to identify molecular pathways affected by 1,4-dioxane exposure.
- Comparison of transcriptomic data with phenotypic changes and known toxicological MOAs.
Main Results:
- Minimal global gene expression changes were observed at 1,4-dioxane concentrations below 600 ppm.
- Significant upregulation of phase II metabolism and mitotic cell cycle checkpoint genes occurred at higher concentrations.
- No significant enrichment of DNA damage response genes was detected.
- Increased mitotic signaling was most pronounced in mice exposed to the highest 1,4-dioxane concentrations for 90 days.
Conclusions:
- Transcriptomics data support a non-mutagenic, threshold-based, mitogenic MOA for 1,4-dioxane-induced liver tumors in mice.
- The findings align with observed phenotypic changes and suggest cell proliferation as a key driver.
- This study enhances the understanding of 1,4-dioxane's hepatocarcinogenic mechanisms in a rodent model.
