Dataset Information

Gene expression analysis of livers from female B6C3F1 mice exposed to carcinogenic and non-carcinogenic doses of furan, with or without bromodeoxyuridine (BrdU) treatment.

ABSTRACT: Standard methodology for identifying chemical carcinogens is both time-consuming and resource intensive. Researchers are actively investigating how new technologies can be used to identify chemical carcinogens in a more rapid and cost-effective manner. Here we performed a toxicogenomic case study of the liver carcinogen furan. Full study and mode of action details were previously published in the Journal of Toxicology and Applied Pharmacology. Female B6C3F1 mice were sub-chronically treated with two non-carcinogenic (1 and 2 mg/kg bw) and two carcinogenic (4 and 8 mg/kg bw) doses of furan for 21 days. Half of the mice in each dose group were also treated with 0.02% bromodeoxyuridine (BrdU) for five days prior to sacrifice [13]. Agilent gene expression microarrays were used to measure changes in liver gene and long non-coding RNA expression (published in Toxicological Sciences). Here we describe the experimental and quality control details for the microarray data. We also provide the R code used to analyze the raw data files, produce fold change and false discovery rate (FDR) adjusted p values for each gene, and construct hierarchical clustering between datasets.

SUBMITTER: Webster AF

PROVIDER: S-EPMC4536026 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Gene expression analysis of livers from female B6C3F1 mice exposed to carcinogenic and non-carcinogenic doses of furan, with or without bromodeoxyuridine (BrdU) treatment.

Webster Anna Francina AF Williams Andrew A Recio Leslie L Yauk Carole L CL Yauk Carole L CL

Genomics data 20140611

Standard methodology for identifying chemical carcinogens is both time-consuming and resource intensive. Researchers are actively investigating how new technologies can be used to identify chemical carcinogens in a more rapid and cost-effective manner. Here we performed a toxicogenomic case study of the liver carcinogen furan. Full study and mode of action details were previously published in the Journal of Toxicology and Applied Pharmacology. Female B6C3F1 mice were sub-chronically treated with ...[more]

PMID: 26484082

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Project description:Furan is an abundant food and environmental contaminant that is a potent liver carcinogen in rodent models. To determine if furan is genotoxic in vivo, female B6C3F1 Big Blue transgenic mice were treated with 15 mg/kg bw furan by gavage 5 days a week for 6 weeks, or once weekly for 3 weeks. Liver cII transgene mutation-frequency and mutation spectra were determined. Furan did not increase the mutation frequency under either treatment condition. In the 6-week treatment regimen, there was a change in the cII transgene mutation-spectrum, with the fraction of GC to AT transitions significantly reduced. The only other significant change was an increase in GC to CG transversions; these represented a minor contribution to the overall mutation spectrum. A much larger furan-dependent shift was observed in the 3-week study. There was a significant increase in transversion mutations, predominantly GC to TA transversions as well as smaller non-significant changes in GC to CG and AT to TA transversions. To determine if these mutations were caused by cis-2-butene-1,4-dial (BDA), a reactive metabolite of furan, the mutagenic activity and the mutation spectrum of BDA was determined in vitro, in Big Blue mouse embryonic fibroblasts. This compound did not increase the cII gene mutation-frequency but caused a substantial increase in AT to CG transversions. This increase, however, lost statistical significance when adjusted for multiple comparisons. Together, these findings suggest that BDA may not be directly responsible for the in-vivo effects of furan on mutational spectra. Histopathological analysis of livers from furan-treated mice revealed that furan induced multifocal, hepatocellular necrosis admixed with reactive leukocytes and pigment-laden Kupffer cells, enhanced oval-cell hyperplasia, and increased hepatocyte mitoses, some of which were atypical. An indirect mechanism of genotoxicity is proposed in which chronic toxicity followed by inflammation and secondary cell proliferation triggers cancer development in furan-exposed rodents.

Project description:ObjectiveExposure to persistent organic pollutants is consistently associated with increased diabetes risk in humans. We investigated the short- and long-term impact of transient low-dose dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) exposure during pregnancy and lactation on glucose homeostasis and beta cell function in female mice, including their response to a metabolic stressor later in life.MethodsFemale mice were injected with either corn oil (CO; vehicle control) or 20 ng/kg/d TCDD 2x/week throughout mating, pregnancy and lactation, and then tracked for 6-10 weeks after chemical exposure stopped. A subset of CO- and TCDD-exposed dams was then transferred to a 45% high-fat diet (HFD) or remained on a standard chow diet for an additional 11 weeks to assess the long-term effects of TCDD on adaptability to a metabolic stressor. To summarize, female mice were transiently exposed to TCDD and then subsequently tracked beyond when TCDD had been excreted to identify lasting metabolic effects of TCDD exposure.ResultsTCDD-exposed dams were hypoglycemic at birth but otherwise had normal glucose homeostasis during and post-TCDD exposure. However, TCDD-exposed dams on a chow diet were modestly heavier than controls starting 5 weeks after the last TCDD injection, and their weight gain accelerated after transitioning to a HFD. TCDD-exposed dams also had an accelerated onset of hyperglycemia, impaired glucose-induced plasma insulin levels, reduced islet size, increased MAFA-ve beta cells, and increased proinsulin accumulation following HFD feeding compared to controls. Overall, our study demonstrates that low-dose TCDD exposure during pregnancy has minimal effects on metabolism during the period of active exposure, but has detrimental long-term effects on metabolic adaptability to HFD feeding.ConclusionsOur study suggests that transient low-dose TCDD exposure in female mice impairs metabolic adaptability to HFD feeding, demonstrating that dioxin exposure may be a contributing factor to obesity and diabetes pathogenesis in females.

Dataset Information

Gene expression analysis of livers from female B6C3F1 mice exposed to carcinogenic and non-carcinogenic doses of furan, with or without bromodeoxyuridine (BrdU) treatment.

Publications

Gene expression analysis of livers from female B6C3F1 mice exposed to carcinogenic and non-carcinogenic doses of furan, with or without bromodeoxyuridine (BrdU) treatment.

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