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

• Published in: Current research in toxicology 2021-01, Vol.2, p.30-41
• Main Authors: Chappell, G.A., Heintz, M.M., Haws, L.C.
• Format: Article
• Language: English
• Subjects: 1,4-Dioxane; Hepatotoxicity; Mechanisms; Mode of action; Transcriptomics
• ISSN: 2666-027X; 2666-027X
• DOI: 10.1016/j.crtox.2021.01.003

[Display omitted] •Minimal global gene expression changes at concentrations below 600 ppm of 1,4-dioxane.•Increased phase II metabolism genes and cellular cycle signaling at >600 ppm.•Increased cell cycle signaling occurred at 90 days, corroborating histopathology.•Data support the proposed cytotoxicity/regenerative hyperplasia mode of action (MOA)•Lack of DNA damage response at the mRNA level supports a non-mutagenic MOA. 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.