Comparative genomic analysis of Fischer F344 rat livers exposed for 90 days to 3-methylfuran or its parental compound furan.
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE249626 | GEO | 2024/01/08
REPOSITORIES: GEO
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Project description:Furan is a widely used industrial chemical and a common contaminant in heated foods. Chronic furan exposure has been shown to cause cholangiocarcinoma and hepatocellular tumors at doses of 2 mg/kg bw/day with gender differences in frequency and severity. The hepatic transcriptional alterations induced by low doses of furan (doses below those inducing liver tumors) and the potential mechanisms underlying gender differences are largely unexplored. We used DNA microarrays to examine the global hepatic mRNA and microRNA transcriptional profiles of male and female rats exposed to 0, 0.03, 0.12, 0.5 or 2 mg/kg bw/day furan over 90 days. Marked gender differences in gene expression responses to furan were observed, with many more altered genes in exposed males than females, confirming the increased sensitivity of males even at the low doses. Pathway analysis supported that key events in furan-induced hepatotoxicity in males included gene expression changes related to oxidative stress, apoptosis and inflammatory response, while pathway changes in females were consistent with primarily adaptive responses (regeneration). Pathway benchmark doses (BMDs) were estimated and compared to relevant apical endpoints. Transcriptional BMDs could be examined in males, they ranged from 0.08 – 1.43 mg/kg bw/day and approximated those derived from traditional histopathology. MiR-34a (a target of P53 signalling) was the only microRNA significantly increased at the 2 mg/kg bw/day, providing evidence in support of the importance of apoptosis and cell proliferation in furan hepatotoxicity. Overall, this study demonstrates the use of transcriptional profiling to discern mode of action and mechanisms involved in gender differences.
2014-10-30 | GSE62807 | GEO
Project description:Furan is a widely used industrial chemical and a common contaminant in heated foods. Chronic furan exposure has been shown to cause cholangiocarcinoma and hepatocellular tumors at doses of 2 mg/kg bw/day with gender differences in frequency and severity. The hepatic transcriptional alterations induced by low doses of furan (doses below those inducing liver tumors) and the potential mechanisms underlying gender differences are largely unexplored. We used DNA microarrays to examine the global hepatic mRNA and microRNA transcriptional profiles of male and female rats exposed to 0, 0.03, 0.12, 0.5 or 2 mg/kg bw/day furan over 90 days. Marked gender differences in gene expression responses to furan were observed, with many more altered genes in exposed males than females, confirming the increased sensitivity of males even at the low doses. Pathway analysis supported that key events in furan-induced hepatotoxicity in males included gene expression changes related to oxidative stress, apoptosis and inflammatory response, while pathway changes in females were consistent with primarily adaptive responses (regeneration). Pathway benchmark doses (BMDs) were estimated and compared to relevant apical endpoints. Transcriptional BMDs could be examined in males, they ranged from 0.08 – 1.43 mg/kg bw/day and approximated those derived from traditional histopathology. MiR-34a (a target of P53 signalling) was the only microRNA significantly increased at the 2 mg/kg bw/day, providing evidence in support of the importance of apoptosis and cell proliferation in furan hepatotoxicity. Overall, this study demonstrates the use of transcriptional profiling to discern mode of action and mechanisms involved in gender differences.
2014-10-30 | GSE62806 | GEO
Project description:Toxicogenomic Assessment of Liver Responses following subchronic exposure to furan in Fischer F344 rats
| PRJNA265192 | ENA
Project description:Furan is a widely used industrial chemical and a common contaminant in heated foods. Chronic furan exposure has been shown to cause cholangiocarcinoma and hepatocellular tumors at doses of 2 mg/kg bw/day with gender differences in frequency and severity. The hepatic transcriptional alterations induced by low doses of furan (doses below those inducing liver tumors) and the potential mechanisms underlying gender differences are largely unexplored. We used DNA microarrays to examine the global hepatic mRNA and microRNA transcriptional profiles of male and female rats exposed to 0, 0.03, 0.12, 0.5 or 2 mg/kg bw/day furan over 90 days. Marked gender differences in gene expression responses to furan were observed, with many more altered genes in exposed males than females, confirming the increased sensitivity of males even at the low doses. Pathway analysis supported that key events in furan-induced hepatotoxicity in males included gene expression changes related to oxidative stress, apoptosis and inflammatory response, while pathway changes in females were consistent with primarily adaptive responses (regeneration). Pathway benchmark doses (BMDs) were estimated and compared to relevant apical endpoints. Transcriptional BMDs could be examined in males, they ranged from 0.08 M-bM-^@M-^S 1.43 mg/kg bw/day and approximated those derived from traditional histopathology. MiR-34a (a target of P53 signalling) was the only microRNA significantly increased at the 2 mg/kg bw/day, providing evidence in support of the importance of apoptosis and cell proliferation in furan hepatotoxicity. Overall, this study demonstrates the use of transcriptional profiling to discern mode of action and mechanisms involved in gender differences. A total of 50 RNA samples (5 female and 5 male rats per dose group, 5 dose groups total) were labelled with Cyanine 5-CTP using Low Input Quick Amp Labelling kits (Agilent Technologies Inc.) following the manufacturerM-bM-^@M-^Ys instruction. Universal rat reference total RNA (Agilent Technologies Inc.) was labelled with Cyanine 3-CTP. Cy5-sample cRNA and Cy3-reference cRNA were hybridized to Agilent G4853A SurePrint G3 Rat GE 8 X 60K microarrays (Agilent Technologies Inc.). One microarray from the male group did not pass the quality control and was eliminated from further analyses
2014-10-30 | E-GEOD-62806 | biostudies-arrayexpress
Project description:Furan is a widely used industrial chemical and a common contaminant in heated foods. Chronic furan exposure has been shown to cause cholangiocarcinoma and hepatocellular tumors at doses of 2 mg/kg bw/day with gender differences in frequency and severity. The hepatic transcriptional alterations induced by low doses of furan (doses below those inducing liver tumors) and the potential mechanisms underlying gender differences are largely unexplored. We used DNA microarrays to examine the global hepatic mRNA and microRNA transcriptional profiles of male and female rats exposed to 0, 0.03, 0.12, 0.5 or 2 mg/kg bw/day furan over 90 days. Marked gender differences in gene expression responses to furan were observed, with many more altered genes in exposed males than females, confirming the increased sensitivity of males even at the low doses. Pathway analysis supported that key events in furan-induced hepatotoxicity in males included gene expression changes related to oxidative stress, apoptosis and inflammatory response, while pathway changes in females were consistent with primarily adaptive responses (regeneration). Pathway benchmark doses (BMDs) were estimated and compared to relevant apical endpoints. Transcriptional BMDs could be examined in males, they ranged from 0.08 – 1.43 mg/kg bw/day and approximated those derived from traditional histopathology. MiR-34a (a target of P53 signalling) was the only microRNA significantly increased at the 2 mg/kg bw/day, providing evidence in support of the importance of apoptosis and cell proliferation in furan hepatotoxicity. Overall, this study demonstrates the use of transcriptional profiling to discern mode of action and mechanisms involved in gender differences. Total RNAs from 16 liver samples (4 males and 4 females from control and 2 mg/kg bw/day dose groups) were processed using the miRNA Complete Labelling and Hybridization kit (Agilent Technologies Inc.). Labelled RNA was hybridized on 8 X 15K Agilent rat miRNA microarray slides. Arrays were scanned using an Agilent G2505B scanner (5 ?M resolution). Feature extraction (version 10.7.3.1, Agilent Tech. Inc.) was used to acquire the fluorescence intensity of each probe.
2014-10-30 | E-GEOD-62807 | biostudies-arrayexpress
Project description:The carcinogenic effect of furan, a potent hepatotoxicant and rodent liver carcinogen, has been attributed to genotoxic and non-genotoxic, including epigenetic, changes in the liver; however, the mechanisms of the furan liver tumorigenicity are still unclear. The goal of the present study was to investigate the role of transcriptomic and epigenetic events in the development of hepatic lesions in Fischer (F344) rats induced by furan treatment in a classic two-year rodent tumorigenicity bioassay. Male F344 rats were distributed randomly into control and experimental groups. Rats from the experimental groups were treated by gavage 5 days/week with either 0.92 or 2.0 mg furan/kg body weight (bw) in corn oil for 104 weeks. Rats from control group received corn oil only. High-throughput whole genome microarray analyses demonstrated distinctive dose-dependent alterations in gene expression in the furan-induced liver lesions. A total of 2073 and 2422 genes was found to be differentially expressed in the furan-induced liver lesions in rats treated with 0.92 and 2.0 mg furan/kg bw, respectively, as compared to normal liver tissue. Approximately 60% (1340) of the differentially expressed genes were common to both treatment groups. In silico analysis of the common differentially expressed genes revealed the presence of CpG island in 51% (679) of the genes, suggesting that they may be epigenetically regulated. Promoter methylation analysis of individual differentially expressed CpG island-containing genes demonstrated dose-dependent gene-specific methylation changes that were highly correlated with gene expression. Our findings illustrate that gene-specific DNA methylation changes have functional consequences and may contribute to the development of furan-induced pathologic liver lesions.
2015-07-18 | GSE71055 | GEO
Project description:This study was performed to characterize the gene expression profile of rat peritoneal mesothelioma (RPM) formation following treatment of Fischer 344 rats with o-nitrotoluene (o-NT) or bromochloracetic acid (BCA). Keywords: Rat, Mesotheliomas, Bromochloractetic acid, o-Nitrotoluene, Carcinogenesis, Microarray
2006-04-20 | GSE4682 | GEO
Project description:Furan is a heterocyclic organic compound produced in the chemical manufacturing industry and also found in a broad range of food products, including infant formulas and baby foods. Previous reports have indicated that the adverse biological effects of furan, including its liver tumorigenicity, may be associated with epigenetic abnormalities. In the present study we investigated the persistence of epigenetic alterations in rat liver. Male Fisher 344 (F344) rats were treated by gavage 5 days per week with 8 mg furan/kg body weight (bw)/day for 90 days. After the last treatment, rats were divided randomly into four groups; one group of rats was sacrificed 24 hours after the last treatment, while other groups were maintained without further furan treatment for an additional 90, 180, or 360 days. Treatment with furan for 90 days resulted in alterations in histone lysine methylation and acetylation, oxidative damage to DNA, and changes in the gene expression in the livers. A majority of these furan-induced molecular changes was transient and disappeared after the cessation of furan treatment. In contrast, histone H3 lysine 9, H3 lysine 27, and H3 lysine 56 showed a sustained and time-depended decrease in acetylation, which was associated with formation of heterochromatin and altered gene expression. These results indicate that furan-induced adverse effects may be mechanistically related to sustained changes in histone lysine acetylation that compromise the ability of cells to maintain and control properly the expression of genetic information.
2014-12-02 | GSE63740 | GEO
Project description:Diethylnitrosamine is used as initiator carcinogen in the modiffied resistan model but is not known its effect on gene expression profile on this stage. In other way, CAPE is compound with anticarcinogenic propertie when is administered 12 h before DEN and with the aim to characterize its effect on gene expression profile when is administered alone and in combination with diethylnitrosamine, these analysis were made. Male Fischer-344 rats were we used 4 animal per each treatment and all treatments are compared with not treated rats. Were identified groups of genes related with Carcinogens metabolism, oxidative stress and cell regulation with important differences between treatments.
2009-06-30 | GSE12030 | GEO
Project description:Diethylnitrosamine is used as initiator carcinogen in the modiffied resistan model but is not known its effect on gene expression profile on this stage. In other way, CAPE is compound with anticarcinogenic propertie when is administered 12 h before DEN and with the aim to characterize its effect on gene expression profile when is administered alone and in combination with diethylnitrosamine, these analysis were made. Male Fischer-344 rats were we used 4 animal per each treatment and all treatments are compared with not treated rats. Were identified groups of genes related with Carcinogens metabolism, oxidative stress and cell regulation with important differences between treatments. RT-PCR, enzyme activities, wester blots, metabolism assays were performed to validate these results.
2009-06-30 | E-GEOD-12030 | biostudies-arrayexpress