Gene expression profiling in the lung and liver of Perfluorooctane sulfonate (PFOS) exposed mouse fetuses
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE13302 | GEO | 2009/05/12
SECONDARY ACCESSION(S): PRJNA109877
REPOSITORIES: GEO
Similar Datasets
Project description:Most of the transcriptional changes induced by PFOS in the fetal mouse liver and lung were related to activation of PPARalpha. When compared to the transcript profiles induced by PFOA (Pubmed ID 17681415), few remarkable differences were found other than up-regulation of Cyp3a genes. Because PFOS and PFOA have been shown to differ in their mode of action in the murine neonate, these data suggest that changes related to PFOS-induced neonatal toxicity may not be evident in the fetal transcriptome at term. Experiment Overall Design: Thirty timed-pregnant CD-1 mice were orally dosed from gestation day 1-17 with either 0, 5, or 10 mg/kg/day PFOS in 0.5% Tween 20. 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 each treatment group using Affymetrix mouse 430_2 microarrays.
2009-05-16 | E-GEOD-13302 | biostudies-arrayexpress
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: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: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: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: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: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:Perfluorooctanesulfonic acid (PFOS) is a persistent, bio-accumulative pollutant that has been used for the last 60+ years in numerous industrial and commercial applications. In mice, PFOS administration is known to induce hepatomegaly and hepatic steatosis. The aim of the present study was to evaluate potential PFOS and diet interactions and explore the mechanism of PFOS induced liver lipid accumulation. Prior to PFOS administration, mice were fed either a standard chow diet (SD) or 60% kCal high fat diet (HFD) for 4 weeks to establish significant body weight increase. After 4 weeks of diet acclimation, the treatment groups received 0.0003% PFOS in diet for an additional 10 weeks. In addition, a subset of the mice fed HFD were switched to a SD (H-SD) to mimic weight-loss induced improvement of hepatic steatosis. A total of six treatment groups: i) SD, ii) HSD, iii) HFD (H), iv) SD +PFOS(SDP), v) H-SD +PFOS (HSDP), and vi) HFD +PFOS (HP) were included. PFOS and lipid concentrations were measured in both serum and liver. Relative liver mRNA expression was determined by targeted bead array and proteins were quantified using untargeted mass spectrometry. PFOS exposure increased liver weight, and in the HFD increased liver triglycerides and liver cholesterol content. Gene and protein expression in the liver demonstrated that PFOS exposure induced lipid utilization and xenobiotic metabolism pathways, and in a HFD, induced lipid synthesis. The data suggests that PFOS exposure acts on lipid utilization genes and exacerbates hepatic steatosis in mice fed a HFD.
2020-09-30 | PXD016161 | Pride
Project description:Perfluoroalkyl acid carboxylates and sulfonates (PFAAs) have many consumer and industrial applications. The persistence and widespread distribution of these compounds in humans have brought them under intense scrutiny. Limited pharmacokinetic data is available in humans; however, human data exists for two communities with drinking water contaminated by PFAAs. Also, there is toxicological and pharmacokinetic data for monkeys, which can be quite useful for cross-species extrapolation to humans. The goal of this research was to develop a physiologically-based pharmacokinetic (PBPK) model for PFOA and PFOS for monkeys and then scale this model to humans in order to describe available human drinking water data. The monkey model simulations were consistent with available PK data for monkeys. The monkey model was then extrapolated to the human and then used to successfully simulate the data collected from residents of two communities exposed to PFOA in drinking water. Human PFOS data is minimal; however, using the half-life estimated from occupational exposure, our model exhibits reasonable agreement with the available human serum PFOS data. It is envisioned that our PBPK model will be useful in supporting human health risk assessments for PFOA and PFOS by aiding in understanding of human pharmacokinetics.
Model is encoded by Ruby and submitted to BioModels by Ahmad Zyoud
2020-03-20 | MODEL2003190002 | BioModels
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. Keywords: gene expression, microarray,PFOA, mouse, fetus, liver
2008-10-07 | GSE13044 | GEO