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Transcriptomic analyses of the liver in female mice exposed to 1,4-dioxane in drinking water

ABSTRACT: We evaluated liver tissues of B6D2F1/Crl mice exposed to 0, 40, 200, 600, 2000, or 6000 ppm 1,4-dioxane in drinking water for 7, 28, or 90 days in support of an investigation of the mode of action for 1,4-dioxane-induced murine liver tumors. TempO-Seq technology was used to measure global hepatic gene expression. Exposure-induced transcriptional responses increased by dose and exposure duration, with few differentially expressed genes at 40 and 200 ppm regardless of exposure duration. Pathway enrichment analysis identified significant perturbations in pathways associated with xenobiotic metabolism, complement and coagulation cascades and fatty acid metabolism in 600, 2000, and 6000 ppm groups at all timepoints compared to time-matched control groups. A significant transcriptomic proliferative response was only observed in 6000 ppm exposed mice at 90 days. Differential gene expression and pathway enrichment analysis results suggest 600 ppm as a potential threshold concentration for hepatic transcriptomic response to 1,4-dioxane in female mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE154899 | GEO | 2021/01/21

REPOSITORIES: GEO

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Project description:1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States (US). While it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, we performed chronic and short-term dosing studies in female BDF-1 mice to explore the toxic effects of 1,4-DX. Histopathology studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Mice were exposed to various concentrations of 1,4-DX (0, 50, 500 and 5,000 mg/L) in their drinking water for one or four weeks. Immunohistochemical analysis of the liver revealed an increase in the number of H2AXγ-positive hepatocytes (a marker of DNA double strand breaks) in mice exposed to 5,000 mg/L 1,4-DX for one and four weeks. In addition, an expansion of precholangiocytes was observed after four weeks of 5,000 mg/L 1,4-DX exposure, as reflected by CK-7 immunostaining. An increase in these markers reflect both DNA damage and repair mechanisms. Liver transcriptomics profiling showed that exposure to 5,000 mg/L 1,4-DX for four weeks resulted in the differential expression of 65 genes compared to controls. Pathway analysis of the transcriptomic data revealed 1,4-DX-induced perturbations in multiple signaling pathways in the liver, including those involved in xenobiotic metabolism, nicotine degradation and glutathione-mediated detoxification. Changes to these pathways as a result of 1,4-DX exposure reflect would be predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, stool and urine metabolomics profiling revealed no effect of 5,000 mg/L 1,4-DX exposure for one or four weeks on metabolites. We speculate that this may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death, but have activated the repair systems in response to 1,4-DX exposure

Project description:ß-chloroprene (2-chloro-1,3-butadiene), a monomer used in the production of neoprene elastomers, is of regulatory interest due to the production of multi-organ tumors in mouse and rat cancer bioassays. A significant increase in female mouse lung tumors was observed at the lowest exposure concentration of 12.8 ppm while a small, but not statistically significant, increase was observed in female rats only at the highest exposure concentration of 80 ppm. The metabolism of chloroprene results in the generation of reactive epoxides and the rate of overall chloroprene metabolism is highly species dependent. To identify potential key events in the mode-of-action of chloroprene lung tumorigenesis, dose response and time course gene expression microarray measurements were made in the lungs of female mice and female rats. The gene expression changes were analyzed using both a traditional analysis of variance approach followed by pathway enrichment analysis and a pathway-based benchmark dose (BMD) analysis approach. Pathways related to glutathione biosynthesis and metabolism were the primary pathways consistent with cross-species differences in tumor incidence and transcriptional BMD values for the pathway were more similar to differences in tumor response than were estimated target tissue dose surrogates based on the total amount of chloroprene metabolized per unit mass of lung tissue per day. The closer correspondence of the transcriptional changes with the tumor response are likely due to their reflection of the overall balance between metabolic activation and detoxication reactions whereas the current tissue dose surrogate reflects only oxidative metabolism. Female mice (B6C3F1/Crl) were exposed to chloroprene (CAS 126-99-8) by whole-body inhalation exposure at 0, 0.3, 2, 13, or 90 ppm. Exposures were performed for 6 hr/day, 5 days per week. The animals were sacrified at 5 days or 19 days (15 exposure days) post initiation of exposure. The right lung was excised and gene expression microarray analysis was performed using Affymetrix Mouse 430_2 arrays. Female rats (F344/NCrl) were exposed to chloroprene (CAS 126-99-8) by whole-body inhalation exposure at 0, 5, 30, 90, or 200 ppm. Exposures were performed for 6 hr/day, 5 days per week. The animals were sacrified at 5 days or 19 days (15 exposure days) post initiation of exposure. The right lung was excised and gene expression microarray analysis was performed using Affymetrix Rat 230_2 arrays.

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Transcriptomic analyses of the liver in female mice exposed to 1,4-dioxane in drinking water

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