Gene expression profiling in the lung and liver of low and high dose Perfluorooctanoic Acid exposed mouse fetuses
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE13044 | GEO | 2008/10/07
SECONDARY ACCESSION(S): PRJNA109955
REPOSITORIES: GEO
Similar Datasets
Project description:Exposure to PFOA during gestation altered the expression of genes related to fatty acid catabolism in both the fetal liver and lung. In the fetal liver, the effects of PFOA were robust and also included genes associated with lipid transport, ketogenesis, glucose metabolism, lipoprotein metabolism, cholesterol biosynthesis, steroid metabolism, bile acid biosynthesis, phospholipid metabolism, retinol metabolism, proteosome activation, and inflammation. These changes are consistent with activation of PPAR alpha. Non-PPAR alpha related changes were suggested as well. Experiment Overall Design: Experiment 1: High Dose: Thirty timed-pregnant CD-1 mice were orally dosed from gestation day 1-17 with either 0, 5, or 10 mg/kg/day PFOA in water. At term, fetal lung and liver were collected, total RNA prepared, and samples pooled from three fetuses per litter. Five biological replicates consisting of individual litter samples were then evaluated for treatment group using Affymetrix mouse 430_2 microarrays. Experiment Overall Design: Experiment 2: Low Dose: Thirty timed-pregnant CD-1 mice were orally dosed from gestation day 1-17 with either 0, 1, or 3 mg/kg/day PFOA in water. At term, fetal lung and liver were collected, total RNA prepared, and samples pooled from three fetuses per litter. Five biological replicates consisting of individual litter samples were then evaluated for treatment group using Affymetrix mouse 430_2 microarrays (note one microarray from the lung + 1mg/kg/day dose group was excluded from the study due to high background). Experiment Overall Design: Please note that each dose experiment had separate concurrent controls.
2008-10-26 | E-GEOD-13044 | biostudies-arrayexpress
Project description:We reported the hepatic gene expression profiling in male Sprague-Dawley rats treated by different concentrations of perfluorooctanoic acid (PFOA) for 7, 14, and 28 days. We confirmed that PFOA induced liver tumor formation was mainly through the activation of peroxisome proliferator-activated receptor α (PPARα). We identified a panel of 7 genes (Cyp4a1, Nr1d1, Acot2, Vnn, Ehhadh, and Acot1) that might serve as the biomarkers for PPARα activation. We also meausred the apical endpoints of PPARα activation and found a good correlation with the expression level of these biomarker genes. Consitituitive androstane receptor mediated Cyp2b enzymatic activity and gene expression was also upregulated by PFOA in a dose-response manner. On the other hand, acyl hydrocarbon receptor (AhR) target gene Cyp1a2 were significantly downregulated at all time points studied. To our surprise, results of KEGG and Reactome pathway analyses suggested that PFOA did not drive the cell cycles and proliferations in the liver. While some of the DNA replication genes such as Pold2 and Mcm8 were upregulated by PFOA treatment, several key cyclin-dependent cell growth genes, including Ccnd1, Ccne2, Ccnb1, and Ccna2 were all significantly downregulated by PFOA in a dose-dependent manner, especailly at 28 days. Ingenuity Pathway Analysis also indicated that PFOA led to a suppression of liver cancer related pathways at later time points studied. These results suggest that while PFOA clearly induced PPARα activation, the increased cell growth (the second key event in the tumor mode of action), was transient and tightly regulated by feedback mechanisms. Whether such changes will eventually cause the formation of preneoplastic foci and liver tumors in rats remains unclear.
2020-01-31 | GSE125762 | GEO
Project description:We reported the hepatic gene expression profiling in mice treated by perfluorooctanoate (PFOA) and high fat diet (HFD). Chronic HFD treatment was associated with gene expression changes in cholesterol biosynthetic process, lipid metabolic process, extracellular matrix, and inflammatory response pathways. Many chemokine related genes including Ccl2, Ccr2, Ccl3l3, Cx3cl1, Cx3cr1, Cxcl14, and toll-like receptor (TLR) related genes including Tlr2, Tlr7, Tlr8, Tlr13 were all significant upregulated comparing vehicle-treated HFD-fed mice to control diet (CD)-fed mice, suggesting their roles in the development of steatohepatitis. PFOA induced gene expression changes in PPAR signaling, fatty acid degradation, biosynthesis of unsaturated fatty acids, and chemical carcinogenesis pathways regardless of diet. However, we showed preexisting fatty liver enhanced the lipid clearance effect of PFOA compared to that in a normal liver. At last, chronic exposure to HFD and PFOA was found to interact on genes related to PPAR signaling, chemical carcinogenesis, and ABC transporter pathways.
2020-09-02 | GSE119441 | GEO
Project description:Ketone bodies, intermediates in energy metabolism and signaling, have attracted significant attention due to their role in health and disease. We performed around the clock study on ketone bodies and ketogenesis with mice on different diets. We found that caloric restriction, a dietary intervention that improves metabolism and longevity, induced high amplitude circadian rhythms in blood βOHB. The blood βOHB rhythms resulted from rhythmic ketogenesis in the liver controlled by the interaction between the circadian clock and PPAR transcriptional networks. This interaction results in transcriptional reprogramming of in beta-oxidation and ketogenesis enzymes. The reprogramming is impaired in circadian clock mutant mice. The circadian clock gated ketogenesis contributes to the diet impact on health and longevity.
2022-08-31 | GSE211975 | GEO
Project description:Unlike the PPARalpha agonist W14,643, PFOA is capable of inducing effects independently of PPARa. Genes altered in the PPARalpha-null mouse following exposure to PFOA included those associated with fatty acid metabolism, inflammation, xenobiotic metabolism, and cell cycle progression. The specific signaling pathway(s) responsible for these effects is not readily apparent but it is conceivable that other members of the nuclear receptor superfamily such as PPARbeta/delta and CAR may be involved. Keywords: dose response Wild-type and PPARa-null mice were orally dosed for 7 days with either PFOA (1 or 3 mg/kg), the PPARalpha agonist WY-14,643 (50 mg/kg), or compound vehicle. Gene profiling analysis was conducted on 4 animals per group using Applied Biosystems Mouse Genome Survey Microarrays.
2008-05-22 | E-GEOD-9796 | biostudies-arrayexpress
Project description:Unlike the PPARalpha agonist W14,643, PFOA is capable of inducing effects independently of PPARa. Genes altered in the PPARalpha-null mouse following exposure to PFOA included those associated with fatty acid metabolism, inflammation, xenobiotic metabolism, and cell cycle progression. The specific signaling pathway(s) responsible for these effects is not readily apparent but it is conceivable that other members of the nuclear receptor superfamily such as PPARbeta/delta and CAR may be involved. Keywords: dose response
2008-05-22 | GSE9796 | GEO
Project description:ChIP-Seq analyses of GR and PPARa occupancy in mouse E14.5 fetal liver BFU-E cells untreated or treated by DEX with or without GW7647 ChIP-Seq on GR and PPAR alpha in purified 10^7 mouse BFU-E cells purified from E14.5 fetal livers with or without treatment of Dexamethasone and/or GW7647
2015-06-08 | E-GEOD-62788 | biostudies-arrayexpress
Project description:Perfluorooctanoic acid (PFOA) is one of the most used perfluorinated compounds in numerous applications and can be detected in environmental samples from around the globe. The aquatic environment is an important site for PFOA deposit. Nevertheless, the exact mode of action and its resulting toxicological effects on aquatic organisms remain largely unknown. To gain a more extensive understanding of the mode of action of teleost PFOA toxicity, transcriptomics, proteomics, biochemical parameters and reproduction were integrated in the present study. Male and female zebrafish were exposed to nominal concentrations of 0.1; 0.5 and 1 mg/l PFOA for 4 and 28 days resulting in an accumulation which was higher in males compared to females. These gender-related differences were likely caused by different elimination rates due to distinct hormone levels and differences in transport activity by solute carriers. The general mode of action of PFOA was believed to be an increase of the mitochondrial membrane permeability which caused effects on the electron transport system at the biochemical level and resulted in alterations of the oxidative phosphorylation, oxidative stress and apoptosis at the gene transcript and protein level. As a consequence, evidence for the replacement of the affected cells and organelles to sustain tissue homeostasis was found at the molecular level. The higher energy demand, due to these adverse effects, was provided by lowering the glycogen stores. Despite this increase in metabolic expenditure, no effects on reproduction were found indicating that the fish seemed to cope with exposure to the tested concentrations of PFOA.
2013-07-20 | GSE19908 | GEO
Project description:Perfluorooctanoic acid (PFOA) is one of the most used perfluorinated compounds in numerous applications and can be detected in environmental samples from around the globe. The aquatic environment is an important site for PFOA deposit. Nevertheless, the exact mode of action and its resulting toxicological effects on aquatic organisms remain largely unknown. To gain a more extensive understanding of the mode of action of teleost PFOA toxicity, transcriptomics, proteomics, biochemical parameters and reproduction were integrated in the present study. Male and female zebrafish were exposed to nominal concentrations of 0.1; 0.5 and 1 mg/l PFOA for 4 and 28 days resulting in an accumulation which was higher in males compared to females. These gender-related differences were likely caused by different elimination rates due to distinct hormone levels and differences in transport activity by solute carriers. The general mode of action of PFOA was believed to be an increase of the mitochondrial membrane permeability which caused effects on the electron transport system at the biochemical level and resulted in alterations of the oxidative phosphorylation, oxidative stress and apoptosis at the gene transcript and protein level. As a consequence, evidence for the replacement of the affected cells and organelles to sustain tissue homeostasis was found at the molecular level. The higher energy demand, due to these adverse effects, was provided by lowering the glycogen stores. Despite this increase in metabolic expenditure, no effects on reproduction were found indicating that the fish seemed to cope with exposure to the tested concentrations of PFOA. Adult zebrafish (Danio rerio) were exposed to nominal concentrations of 0mg/l; 0.1mg/l; 1mg/l PFOA (perfluorooctanoic acid) for 28 days. Three different 25 litre aquaria per exposure concentration were used resulting in 3 biological replicates with each aquarium containing 8 male and 8 female zebrafish. The livers of 6 male fish and 6 female fish were pooled separately and snap frozen in liquid nitrogen. A reference sample was made by pooling equal amounts of RNA from all samples. A carriage wheel design was used in which all samples were connected to the reference sample and the main contrasts of interest were made directly on the same microarrays as frequently as possible. This design resulted in technical triplicates of each sample.
2013-07-20 | E-GEOD-19908 | biostudies-arrayexpress
Project description:Perfluoroalkyl substances (PFAS) are man-made chemicals with suspected endocrine-disrupting properties. Exposure to perfluorooctanoic acid (PFOA) has been linked to disturbed metabolism via the liver, although the exact mechanism is not clear. Moreover, information on the metabolic effects of the new PFAS alternative GenX is limited. We tested whether low-dose exposure to PFOA and GenX induces metabolic disturbances, including NAFLD, dyslipidemia, and glucose tolerance in mice and studied the involvement of PPARα. To this end, male C57BL/6J wildtype and PPARα−/− mice were given 0.05 or 0.3 mg/kg bw/day PFOA, or 0.3 mg/kg bw/day GenX next to a high-fat diet for 20 weeks. RNA sequencing was performed on liver, next to thorough assesment of metabolic parameters. RNA sequencing revealed that whereas the effects of GenX are entirely dependent on PPARα, effects of PFOA are mostly dependent on PPARα. In the absence of PPARα, the involvement of PXR/CAR becomes more prominent. Exposure to high-dose PFOA in mice decreased body weights and increased liver weights in wildtype and PPARα−/− mice. High-dose but not low-dose PFOA reduced plasma triglycerides and cholesterol, which for triglycerides, showed PPARα dependency. PFOA and GenX increased hepatic triglycerides in a PPARα-dependent manner. Overall, we show that long-term and low-dose exposure to PFOA and GenX disrupts lipid metabolism in mice. Whereas the effects of PFOA are mediated by multiple nuclear receptors, effects of GenX are entirely mediated by PPARα. Our data underscore the potential of PFAS to disrupt metabolism by altering signaling pathways in the liver.
2022-09-02 | GSE212294 | GEO