Transcription profiling of mouse wild-type and PPARalpha-null mutants response to PFOA
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Hongzu Ren
PROVIDER: E-GEOD-9786 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Toxicogenomic Dissection of the Perfluorooctanoic Acid (PFOA) Transcript Profile in Mouse Liver: Evidence for the Involvement of Nuclear Receptors PPARalpha and CAR We performed a toxicogenomics dissection of the transcript profiles in the mouse liver after exposure to PFOA. We uncovered classes of genes that were regulated independently of PPARalpha. Some of these genes, including those involved in lipid metabolism, may be regulated by PPARbeta/delta or PPARgamma, whereas others, such as those involved in xenobiotic metabolism are likely regulated through CAR. Keywords: toxicogenomic analysis
2008-02-04 | GSE9786 | 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:Humans and ecological species have been found to have detectable body burdens of a number of perfluorinated alkyl acids (PFAA) including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). In mouse and rat liver these compounds elicit transcriptional and phenotypic effects similar to peroxisome proliferator chemicals (PPC) that work through the nuclear receptor peroxisome proliferator activated receptor alpha (PPARalpha). Recent studies indicate that along with PPARalpha other nuclear receptors are required for transcriptional changes in the mouse liver after PFOA exposure including the constitutive activated receptor (CAR) and pregnane X receptor (PXR) that regulate xenobiotic metabolizing enzymes (XME). To determine the potential role of CAR/PXR in mediating effects of PFAAs in rat liver, we performed a meta-analysis of transcript profiles from published studies in which rats were exposed to PFOA or PFOS. We compared the profiles to those produced by exposure to prototypical activators of CAR (Phenobarbital (PB)), PXR (pregnenolone 16 alpha-carbonitrile (PCN)), or PPARalpha (WY-14,643 (WY)). As expected, PFOA and PFOS elicited transcript profile signatures that included many known PPARalpha target genes. Numerous XME genes were also altered by PFOA and PFOS but not WY. These genes exhibited expression changes shared with PB or PCN. Reexamination of the transcript profiles from the livers of chicken or fish exposed to PFAAs indicated that PPARalpha, CAR, and PXR orthologs were not activated. Our results indicate that PFAAs under these experimental conditions activate PPARalpha, CAR, and PXR in rats but not chicken and fish. Lastly, we discuss evidence that human populations with greater CAR expression have lower body burdens of PFAAs. Keywords: gene expression/microarray
2009-02-07 | GSE14712 | GEO
Project description:Perfluorooctanoic acid (PFOA) is a potent hepatocarcinogen and peroxisome proliferator (PP) in rodents. Humans are not susceptible to peroxisome proliferation and are thought to be refractory to carcinogenesis by PFOA and other PPs. However, previous studies with rainbow trout have shown that they are also insensitive to peroxisome proliferation by the PP, dehydroepiandrosterone (DHEA), but are still susceptible to enhanced hepatocarcinogenesis after chronic exposure. In this study, we determined whether PFOA is also a tumor promotor in trout and then examined hepatic gene expression profiles to further investigate possible mechanisms of action. Trout were initiated as fry to the hepatocarcinogen, aflatoxin B1, and then fed 200-1800 ppm PFOA in the diet for 30 weeks. Two structurally diverse PPs, clofibrate (CLOF) and DHEA, were included for comparison. Hepatic gene expression profiles were subsequently examined in animals exposed to similar doses of PFOA, DHEA and CLOF along with 5 ppm 17β-estradiol (E2; a known tumor promotor) in the diet. PFOA (1800 ppm) and DHEA treatments resulted in enhanced liver tumor incidence and multiplicity while CLOF showed no effect. Carcinogenesis seemed independent of peroxisome proliferation as no induction of peroxisomal β-oxidation and catalase activity were observed. Alternately, plasma VTG was elevated in fish fed PFOA and DHEA suggesting that estrogenic mechanisms may play a role. Both tumor promotors, PFOA and DHEA, resulted in strong correlation of transcriptional profiles with E2 by Pearson correlation (R=0.81 and 0.78, respectively). In comparison, CLOF regulated no genes in common with E2. Overall, these data suggest that the tumor promoting activities of DHEA and PFOA in trout are independent of peroxisome proliferation and may involve estrogenic mechanisms. Juvenile trout, 12-18 months old, were fed experimental diets containing 500 or 1800 ppm PFOA, 1800 ppm CLOF, 750 ppm DHEA, 5 ppm E2 or 0.15 % dimethyl sulfoxide vehicle control for 14 days. Liver samples were collected for microarray analysis. Hybridizations were performed using standard reference design with dye-swapping. For each sample, equal amounts of RNA (µg) were pooled from five fish per tank for every treatment (n=3 biological replicates per treatment). cDNA from two of the three biological replicates was dye-swapped and hybridized to two slides as technical replicates (5 arrays per treatment).
2007-08-31 | E-GEOD-7837 | 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
Project description:Perfluorooctanoic acid (PFOA) exposure is linked with tumorigenesis in rats, mice, and potentially tumorigenic in humans. Here, we studied long-term PFOA exposure with an in vitro transformation model using the rat liver epithelial cell, TRL 1215. Cells were cultured in 10 µM (T10), 50 µM (T50) and 100 µM (T100) PFOA for 38 weeks and compared to passage-matched control cells. T100 cells showed morphological changes, loss of cell contact inhibition, formation of multinucleated giant and spindle-shaped cells. T10, T50, and T100 cells increased LC50 values 20%, 29% to 35% above control with acute PFOA treatment, indicating a resistance to PFOA toxicity. PFOA-treated cells showed increases in Matrix metalloproteinase-9 secretion, cell migration, and developed more and larger colonies in soft agar. Microarray data showed Myc pathway activation at T50 and T100, associating Myc upregulation with PFOA-induced morphological transformation. Western blot confirmed that PFOA produced significant increases in c-MYC protein expression in a time- and concentration-dependent manner. Tumor invasion indicators MMP-2 and MMP-9, cell cycle regulator cyclin D1, and oxidative stress protein GST were all significantly overexpressed in T100 cells. Taken together, chronic in vitro PFOA exposure produced multiple cell characteristics of malignant progression and differential gene expression changes suggestive of rat liver cell transformation.
2023-08-23 | GSE222106 | GEO
Project description:Perfluorooctanoic acid (PFOA) is a potent hepatocarcinogen and peroxisome proliferator (PP) in rodents. Humans are not susceptible to peroxisome proliferation and are thought to be refractory to carcinogenesis by PFOA and other PPs. However, previous studies with rainbow trout have shown that they are also insensitive to peroxisome proliferation by the PP, dehydroepiandrosterone (DHEA), but are still susceptible to enhanced hepatocarcinogenesis after chronic exposure. In this study, we determined whether PFOA is also a tumor promotor in trout and then examined hepatic gene expression profiles to further investigate possible mechanisms of action. Trout were initiated as fry to the hepatocarcinogen, aflatoxin B1, and then fed 200-1800 ppm PFOA in the diet for 30 weeks. Two structurally diverse PPs, clofibrate (CLOF) and DHEA, were included for comparison. Hepatic gene expression profiles were subsequently examined in animals exposed to similar doses of PFOA, DHEA and CLOF along with 5 ppm 17β-estradiol (E2; a known tumor promotor) in the diet. PFOA (1800 ppm) and DHEA treatments resulted in enhanced liver tumor incidence and multiplicity while CLOF showed no effect. Carcinogenesis seemed independent of peroxisome proliferation as no induction of peroxisomal β-oxidation and catalase activity were observed. Alternately, plasma VTG was elevated in fish fed PFOA and DHEA suggesting that estrogenic mechanisms may play a role. Both tumor promotors, PFOA and DHEA, resulted in strong correlation of transcriptional profiles with E2 by Pearson correlation (R=0.81 and 0.78, respectively). In comparison, CLOF regulated no genes in common with E2. Overall, these data suggest that the tumor promoting activities of DHEA and PFOA in trout are independent of peroxisome proliferation and may involve estrogenic mechanisms. Keywords: treatment effect
2007-08-31 | GSE7837 | GEO
Project description:Background: Previously, we reported that perfluorooctanoic acid (PFOA) promotes liver cancer in manner similar to that of 17β-estradiol (E2) in rainbow trout. Also, other perfluoroalkyl acids (PFAAs) are weakly estrogenic in trout and bind the trout liver estrogen receptor (ER). Objectives: The primary objective of this study was to determine whether multiple PFAAs enhance hepatic tumorigenesis in trout, an animal model that represents human insensitivity to peroxisome proliferators. Methods: A two-stage chemical carcinogenesis model was employed in trout to evaluate PFOA, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorooctane sulfonate (PFOS) and 8:2 fluorotelomer alcohol (8:2FtOH) as complete carcinogens or promoters of aflatoxin B1 (AFB1)- and/or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced liver cancer. A custom trout DNA microarray was used to assess hepatic transcriptional response to these dietary treatments in comparison to E2 and the classic peroxisome proliferator clofibrate (CLOF). Results: Incidence, multiplicity and size of liver tumors in trout fed diets containing E2, PFOA, PFNA and PFDA were significantly higher compared to AFB1-initiated animals fed control diet, whereas PFOS caused a minor increase in liver tumor incidence. E2 and PFOA also enhanced MNNG-initiated hepatocarcinogenesis. Pearson correlation analyses, unsupervised hierarchical clustering and principal components analyses showed that the hepatic gene expression profiles for E2 and PFOA, PFNA, PFDA and PFOS were overall highly similar, though distinct patterns of gene expression were evident for each treatment, particularly for PFNA. Conclusions: Overall, these data suggest that multiple PFAAs can promote liver cancer and that the mechanism of promotion may be similar to that for E2. A total of 40 samples were analyzed using a a dye-swap, reference sample hybridization protocol. Rainbow trout were exposed to the following experimental treatments via the diet for two weeks (number in parenthesis is assigned group #): (1) Control; (2) 5 mg/kg diet estradiol (E2); (3) 2000 mg/kg diet perfluorooctanoic acid (PFOA); (4) 2000 mg/kg diet perfluorononanoic acid (PFNA); (5) 2000 mg/kg diet perfluorodecanoic acid (PFDA); (6) 200 mg/kg diet perfluorooctane sulfonate; (7) 2000 mg/kg 8:2 fluorotelomer alcohol (FTOH); and (8) 2000 mg/kg diet clofibrate. A total of 40 total hepatic mRNA samples were analyzed using a dye-swap, reference sample hybridization protocol. A reference RNA pool was made by combining equal amounts of RNA from all control RNA samples, with one exception. A separate time-matched reference pool was utilized for group 6 samples (PFOS treatment). Five hybridizations were performed for each treatment group in the following pattern: Replicate A Cy5/Reference Cy3; Replicate A Cy3/Reference Cy 5; Replicate B Cy5/Reference Cy3; Replicate B Cy3/Reference Cy5; Replicate C Cy5/Reference Cy3. Thus, the experiment consisted of three biological replicates, for two of which were replicated technically.
2011-08-01 | E-GEOD-31085 | biostudies-arrayexpress
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