Mus musculus
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ABSTRACT:
PROVIDER: PRJNA128117 | ENA |
REPOSITORIES: ENA
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Project description:Perfluorooctane sulfonate (PFOS) is a perfluoroalkyl acid (PFAA) and a persistent environmental contaminant found in the tissues of humans and wildlife. Although blood levels of PFOS have begun to decline, health concerns remain because of the long half-life of PFOS in humans. Like other PFAAs, such as perfluorooctanoic acid (PFOA), PFOS is an activator of peroxisome proliferator-activated receptor-alpha (PPARα) and exhibits hepatocarcinogenic potential in rodents. PFOS is also a developmental toxicant in rodents where, unlike PFOA, it’s mode of action is independent of PPARα. Wild-type (WT) and PPARα-null (Null) mice were dosed with 0, 3, or 10 mg/kg/day PFOS for 7 days. Animals were euthanized, livers weighed, and liver samples collected for histology and preparation of total RNA. Gene profiling was conducted using Affymetrix 430_2 microarrays. In WT mice, PFOS induced changes that were characteristic of PPARα transactivation including regulation of genes associated with lipid metabolism, peroxisome biogenesis, proteasome activation, and inflammation. PPARα-independent changes were indicated in both WT and Null mice by altered expression of genes related to lipid metabolism, inflammation, and xenobiotic metabolism. Such results are similar to prior studies done with PFOA and are consistent with modest activation of the constitutive androstane receptor (CAR) and possibly PPARγ and/or PPARβ/δ. Unique treatment-related effects were also found in Null mice including altered expression of genes associated with ribosome biogenesis, oxidative phosphorylation and cholesterol biosynthesis. Of interest was up-regulation of Cyp7a1, a gene which is under the control of various transcription regulators. Hence, in addition to its ability to modestly activate PPARα, PFOS induces a variety of “off-target” effects as well. PPARalpha-null and wild-type male mice at 6-9 months of age were dosed by gavage for 7 consecutive days with either 0, 3, or 10 mg/kg PFOS (potassium salt) in 0.5% Tween 20. Five biological replicates consisting of individual animals were included in each dosage group. Data were compared to results previously published by our group for PFOA and Wy-14,643, a commonly used agonist of PPARalpha (Rosen et al., Toxicol Pathol. 36:592-607, 2008; GSE9796)
2010-10-01 | E-GEOD-22871 | biostudies-arrayexpress
Project description:Condition specific zebrafish metabolic models generated using the COBRA MetaboTools framework. The Wang et al., (2021) zebrafish genome-scale metabolic model (GEM) was constrained with experimental data from 5 days post fertilized (dpf) zebrafish to generate a 'base-model'.
In turn this 5 dpf zebrafish base-model was constrained with experimental (transcriptomics and metabolomics) data from 5 dpf zebrafish exposed to the environmental pollutant perfluorooctane sulfonate (PFOS), at three levels - Low (0.06 uM), Medium (0.6 uM), and High (2 uM) PFOS.
The MetaboTools framework was used to construct three condition-sepcific models: Low, Medium, and High PFOS.
Key simulation predictions of effects on the carnitine shuttle and lipid metabolism were confirmed in wild-caught fish and dolphins (stranded animals) sampled from the northern Gulf of Mexico - published in Nolen et al., (2024) https://doi.org/10.1016/j.cbpc.2023.109817
2024-03-04 | MODEL2403010004 | BioModels
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:Perfluorooctane sulfonate (PFOS) is a perfluoroalkyl acid (PFAA) and a persistent environmental contaminant found in the tissues of humans and wildlife. Although blood levels of PFOS have begun to decline, health concerns remain because of the long half-life of PFOS in humans. Like other PFAAs, such as perfluorooctanoic acid (PFOA), PFOS is an activator of peroxisome proliferator-activated receptor-alpha (PPARα) and exhibits hepatocarcinogenic potential in rodents. PFOS is also a developmental toxicant in rodents where, unlike PFOA, it’s mode of action is independent of PPARα. Wild-type (WT) and PPARα-null (Null) mice were dosed with 0, 3, or 10 mg/kg/day PFOS for 7 days. Animals were euthanized, livers weighed, and liver samples collected for histology and preparation of total RNA. Gene profiling was conducted using Affymetrix 430_2 microarrays. In WT mice, PFOS induced changes that were characteristic of PPARα transactivation including regulation of genes associated with lipid metabolism, peroxisome biogenesis, proteasome activation, and inflammation. PPARα-independent changes were indicated in both WT and Null mice by altered expression of genes related to lipid metabolism, inflammation, and xenobiotic metabolism. Such results are similar to prior studies done with PFOA and are consistent with modest activation of the constitutive androstane receptor (CAR) and possibly PPARγ and/or PPARβ/δ. Unique treatment-related effects were also found in Null mice including altered expression of genes associated with ribosome biogenesis, oxidative phosphorylation and cholesterol biosynthesis. Of interest was up-regulation of Cyp7a1, a gene which is under the control of various transcription regulators. Hence, in addition to its ability to modestly activate PPARα, PFOS induces a variety of “off-target” effects as well.
2010-10-01 | GSE22871 | GEO
Project description:The immunotoxicity of PFOS (perfluorooctane sulfonate) were reported previously, however, the detailed toxic mechanism remain unknown. Spleen is an important immune organ that controls the differentiation and development of immune cells including T cells, B cells, and macrophages etc. the disruption of the organ may result in altered immune functions and immunotoxicity. We used microarrays to snapshot the changes of global gene expression, and identified target genes underlying the immunotoxicity of PFOS exposure. 6-8 week old Balb/c female mice were exposed to 10mg/kg body weight PFOS per day for 3 weeks through intragastric administration, and then spleens were removed for RNA extraction and hybridization on Affymetrix microarrays. By comparing the gene expression of spleens with or without PFOS exposure, we sought to obtain differentially expressed genes in order to reveal the toxic mechanism of PFOS.
2013-08-20 | E-GEOD-50001 | biostudies-arrayexpress
Project description:During pregnancy, perfluorooctane sulfonate (PFOS) exposure is linked to increased risks of preeclampsia and fetal developmental complications. Although experimental and circumstantial data suggest that PFOS induces endothelial dysfunction, leading to decreased uterine arterial blood flow and gestational hypertension, the precise regulatory mechanisms responsible for this effect remain unknown. To address this issue, we treated human uterine artery endothelial cells (hUAECs) isolated from pregnant women with PFOS and conducted a comparative transcriptomic analyses to understand the underlying mechanism of PFOS-induced endothelial dysfunction.
2023-10-15 | GSE232176 | GEO
Project description:Recently it was discovered that the perfluorooctane sulfonate (PFOS) detected in wildlife, such as fish-eating birds, had a greater proportion of linear PFOS (L-PFOS) than the manufactured technical product (T-PFOS), which contains linear and branched isomers. This suggests toxicological studies based on T-PFOS data may inaccurately assess exposure risk to wildlife. To determine if PFOS effects were influenced by isomer content we compared the transcriptional profiles of cultured chicken embryonic hepatocytes (CEH) exposed to either L-PFOS or T-PFOS using Agilent microarrays. At equal concentrations (10 μM), T-PFOS altered the expression of more transcripts (340, >1.5 fold change, p<0.05) compared to L-PFOS (130 transcripts). Higher concentrations of L-PFOS (40 μM) were also less transcriptionally disruptive (217 transcripts) than T-PFOS at 10 μM. Functional analysis showed that L-PFOS and T-PFOS affected genes involved in lipid metabolism, hepatic system development and cellular growth and proliferation. Pathway and interactome analysis suggested that genes may be affected through the RXR receptor, oxidative stress response, TP53 signaling, MYC signaling, Wnt/β-catenin signaling and PPARγ and SREBP receptors. In all functional categories and pathways examined, the response elicited by T-PFOS was greater than L-PFOS. These data show that T-PFOS elicits a greater transcriptional response in CEH than L-PFOS alone and demonstrates the importance of considering the isomer-specific toxicological properties of PFOS when assessing exposure risk. Reference Design. Reference = pool of equal parts of all control and treated samples. Control groups and 5 treatment groups. Control samples were CEH exposed DMSO only (vehicle solvent). Treatments were: CEH exposed to 10 uM L-PFOS, 40 uM L-PFOS, 10 uM T-PFOS, 0.03 nM TCDD and 1 nM TCDD.
2011-10-28 | E-GEOD-33291 | biostudies-arrayexpress
Project description:The immunotoxicity of PFOS (perfluorooctane sulfonate) were reported previously, however, the detailed toxic mechanism remain unknown. Spleen is an important immune organ that controls the differentiation and development of immune cells including T cells, B cells, and macrophages etc. the disruption of the organ may result in altered immune functions and immunotoxicity. We used microarrays to snapshot the changes of global gene expression, and identified target genes underlying the immunotoxicity of PFOS exposure.
2013-08-20 | GSE50001 | GEO
Project description:This series was used for two studies: Study 1: Recently it was discovered that the perfluorooctane sulfonate (PFOS) detected in wildlife, such as fish-eating birds, had a greater proportion of linear PFOS (L-PFOS) than the manufactured technical product (T-PFOS), which contains linear and branched isomers. This suggests toxicological studies based on T-PFOS data may inaccurately assess exposure risk to wildlife. To determine if PFOS effects were influenced by isomer content we compared the transcriptional profiles of cultured chicken embryonic hepatocytes (CEH) exposed to either L-PFOS or T-PFOS using Agilent microarrays. At equal concentrations (10 ?M), T-PFOS altered the expression of more transcripts (340, >1.5 fold change, p<0.05) compared to L-PFOS (130 transcripts). Higher concentrations of L-PFOS (40 ?M) were also less transcriptionally disruptive (217 transcripts) than T-PFOS at 10 ?M. Functional analysis showed that L-PFOS and T-PFOS affected genes involved in lipid metabolism, hepatic system development and cellular growth and proliferation. Pathway and interactome analysis suggested that genes may be affected through the RXR receptor, oxidative stress response, TP53 signaling, MYC signaling, Wnt/?-catenin signaling and PPAR? and SREBP receptors. In all functional categories and pathways examined, the response elicited by T-PFOS was greater than L-PFOS. These data show that T-PFOS elicits a greater transcriptional response in CEH than L-PFOS alone and demonstrates the importance of considering the isomer-specific toxicological properties of PFOS when assessing exposure risk. Study 2: In many bird populations, concentrations of perfluoroundanoic acid (PFUdA) are second only to perfluorooctane sulfonate (PFOS) among perfluoroalkyl compounds. Here, we used microarrays to characterize the transcriptional response of cultured chicken embryonic hepatocytes (CEH) to PFUdA and compared it to the response induced by PFOS. At non-cytotoxic doses, PFUdA (1 or 10 ?M) disrupted the expression of more genes (854) than PFOS (447, at 10 or 40 ?M) in CEH. Using functional, pathway and interactome analysis we identified several potentially important modes-of-action (MoAs) for PFUdA and some associated key events, including the suppression of the acute-phase response (APR) through peroxisome proliferator activated receptor activation. We then measured the expression of five APR genes, fibrinogen alpha (fga), fibrinogen gamma (fgg), thrombin (f2), plasminogen (plg), and protein C (proC), in the liver of chicken embryos exposed in ovo to PFUdA. The expression of fga, f2, and proC were down-regulated in embryo livers (100 or 1000 ng/g, p<0.1) as predicted from microarray analysis, whereas fibrinogen gamma (fgg) was up-regulated and plg was not significantly affected. Our results demonstrate PFUdA is more transcriptionally disruptive than PFOS in CEH. Additionally, we identified APR suppression as a potentially important and environmentally relevant MoA. These findings suggest in ovo exposure of birds to PFUdA could lead to post-hatch developmental deficiencies, such as impaired immune response.
2011-10-29 | GSE33291 | GEO
Project description:The effect of perfluoroalkyl sulfonates on lipoprotein metabolism was investigated in APOE*3-Leiden.CETP mice with a humanized lipoprotein profile. Perfluorohexane sulfonate and perfluorooctane sulfonate markedly reduced both plasma TG and TC by decreasing nonHDL-C and HDL-C accompanied by a reduction in apoAI. Mechanistic studies showed that these effects were mainly caused by impaired lipoprotein production. Male E3L.CETP mice on a C57Bl/6 background were fed a Western-type diet, containing 0.25% (w/w) cholesterol, 1% (w/w) corn oil and 14% (w/w) bovine fat (Western-type diet) (Hope Farms, Woerden, The Netherlands) for 4 to 6 weeks in three independent experiments. Upon randomization according to total plasma cholesterol (TC) and TG levels, mice received the Western-type diet without or with PFBS (30 mg/kg/day), PFHxS (6 mg/kg/day) or PFOS (3 mg/kg/day) during 4-6 weeks. The effects of these PFAS on plasma lipids and lipoproteins were determined. In addition, PFAS levels were determined in plasma and livers were isolated for hepatic lipid analysis and hepatic gene expression analysis using an Affymetrix technology platform and Affymetrix GeneChip® mouse genome 430 2.0 arrays.
2011-01-01 | E-GEOD-22940 | biostudies-arrayexpress