Hepatic miRNA profiles and thyroid hormone homeostasis in rats exposed to dietary potassium perfluorooctanesulfonate (PFOS)
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE69522 | GEO | 2015/08/01
SECONDARY ACCESSION(S): PRJNA289357
REPOSITORIES: GEO
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Project description:Perfluorooctanesulfonate (PFOS) has been widely used in a variety of industrial and commercial applications as a surfactant and stain repellent. PFOS causes liver damage (including liver tumors) in experimental animals, primarily via interaction with PPARa and CAR/PXR. We investigated the involvement of microRNAs (miRNAs) in PFOS-induced hepatotoxicity, and mechanisms involved in abnormal TH homeostasis, in the livers of adult male rats exposed in feed to 50 mg PFOS/kg diet for 28 days. PFOS-treated rats exhibited expected histopathological and clinical chemistry changes. Global gene expression changes were consistent with the involvement of PPARα and CAR/PXR in PFOS-induced effects. Thirty-eight miRNAs were significantly altered. Three members of the miR-200 family were the most increased, while miR-122 and miR-21 were the most decreased, in PFOS-treated relative to control rats. Expression of the miR-23b/27b/24 cluster also decreased in PFOS-treated animals. Pathway analysis of miRNAs and associated gene expression changes demonstrated enrichment of transcripts involved in epithelial to mesenchymal transition (EMT), which is a primary process involved in tumor cell motility and cancer metastasis. Liver expression analysis revealed transcripts that may mediate PFOS effects on thyroid hormone (TH) homeostasis including: activation of the CAR/PXR pathway, phase II/III enzymes, and deiodinase. These changes are consistent with low serum TH due to enhanced metabolic clearance of TH. However, most TH hepatic target genes were not altered in a manner consistent with reduced TH signalling; suggesting that PFOS exposure did not induce functional hypothyroidism. Collectively, PFOS-induced miRNA perturbations were strongly associated with EMT suggesting an important role for miRNAs in PFOS-induced hepatotoxicity. The work also provides novel insights into the effects of PFOS on TH homeostasis.
2015-08-01 | GSE69521 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-08-01 | E-GEOD-69522 | biostudies-arrayexpress
Project description:Perfluorooctanesulfonate (PFOS) has been widely used in a variety of industrial and commercial applications as a surfactant and stain repellent. PFOS causes liver damage (including liver tumors) in experimental animals, primarily via interaction with PPARa and CAR/PXR. We investigated the involvement of microRNAs (miRNAs) in PFOS-induced hepatotoxicity, and mechanisms involved in abnormal TH homeostasis, in the livers of adult male rats exposed in feed to 50 mg PFOS/kg diet for 28 days. PFOS-treated rats exhibited expected histopathological and clinical chemistry changes. Global gene expression changes were consistent with the involvement of PPARα and CAR/PXR in PFOS-induced effects. Thirty-eight miRNAs were significantly altered. Three members of the miR-200 family were the most increased, while miR-122 and miR-21 were the most decreased, in PFOS-treated relative to control rats. Expression of the miR-23b/27b/24 cluster also decreased in PFOS-treated animals. Pathway analysis of miRNAs and associated gene expression changes demonstrated enrichment of transcripts involved in epithelial to mesenchymal transition (EMT), which is a primary process involved in tumor cell motility and cancer metastasis. Liver expression analysis revealed transcripts that may mediate PFOS effects on thyroid hormone (TH) homeostasis including: activation of the CAR/PXR pathway, phase II/III enzymes, and deiodinase. These changes are consistent with low serum TH due to enhanced metabolic clearance of TH. However, most TH hepatic target genes were not altered in a manner consistent with reduced TH signalling; suggesting that PFOS exposure did not induce functional hypothyroidism. Collectively, PFOS-induced miRNA perturbations were strongly associated with EMT suggesting an important role for miRNAs in PFOS-induced hepatotoxicity. The work also provides novel insights into the effects of PFOS on TH homeostasis. Total RNAs from liver samples (4 animals from each group) were labelled using the miRNA Complete Labelling and Hybridization kit (Agilent Technologies). Labelled RNA was hybridized on 8 X 15K Agilent rat miRNA microarray slides. Arrays were scanned using an Agilent G2505B scanner (5 μm resolution). Agilent Feature Extraction (version 10.7.3.1) was used to acquire the fluorescence intensity of each probe. The quality of the microarray data was evaluated using Agilent Feature Extraction quality control metrics. Data were normalized in R using cyclic-lowess (Bolstad et al., 2003). Ratio-intensity plots, boxplots and cluster analyses were used to identify potential outliers. One control sample failed the quality control tests and was eliminated for subsequent analyses. Statistically significantly altered miRNAs were identified using the methods described above for gene expression.
2015-08-01 | E-GEOD-69521 | biostudies-arrayexpress
Project description:Perfluorooctanesulfonate (PFOS) has been widely used in a variety of industrial and commercial applications as a surfactant and stain repellent. PFOS causes liver damage (including liver tumors) in experimental animals, primarily via interaction with PPARa and CAR/PXR. We investigated the involvement of microRNAs (miRNAs) in PFOS-induced hepatotoxicity, and mechanisms involved in abnormal TH homeostasis, in the livers of adult male rats exposed in feed to 50 mg PFOS/kg diet for 28 days. PFOS-treated rats exhibited expected histopathological and clinical chemistry changes. Global gene expression changes were consistent with the involvement of PPARα and CAR/PXR in PFOS-induced effects. Thirty-eight miRNAs were significantly altered. Three members of the miR-200 family were the most increased, while miR-122 and miR-21 were the most decreased, in PFOS-treated relative to control rats. Expression of the miR-23b/27b/24 cluster also decreased in PFOS-treated animals. Pathway analysis of miRNAs and associated gene expression changes demonstrated enrichment of transcripts involved in epithelial to mesenchymal transition (EMT), which is a primary process involved in tumor cell motility and cancer metastasis. Liver expression analysis revealed transcripts that may mediate PFOS effects on thyroid hormone (TH) homeostasis including: activation of the CAR/PXR pathway, phase II/III enzymes, and deiodinase. These changes are consistent with low serum TH due to enhanced metabolic clearance of TH. However, most TH hepatic target genes were not altered in a manner consistent with reduced TH signalling; suggesting that PFOS exposure did not induce functional hypothyroidism. Collectively, PFOS-induced miRNA perturbations were strongly associated with EMT suggesting an important role for miRNAs in PFOS-induced hepatotoxicity. The work also provides novel insights into the effects of PFOS on TH homeostasis.
2015-08-01 | GSE69520 | GEO
Project description:Perfluorooctanesulfonate (PFOS) has been widely used in a variety of industrial and commercial applications as a surfactant and stain repellent. PFOS causes liver damage (including liver tumors) in experimental animals, primarily via interaction with PPARa and CAR/PXR. We investigated the involvement of microRNAs (miRNAs) in PFOS-induced hepatotoxicity, and mechanisms involved in abnormal TH homeostasis, in the livers of adult male rats exposed in feed to 50 mg PFOS/kg diet for 28 days. PFOS-treated rats exhibited expected histopathological and clinical chemistry changes. Global gene expression changes were consistent with the involvement of PPARα and CAR/PXR in PFOS-induced effects. Thirty-eight miRNAs were significantly altered. Three members of the miR-200 family were the most increased, while miR-122 and miR-21 were the most decreased, in PFOS-treated relative to control rats. Expression of the miR-23b/27b/24 cluster also decreased in PFOS-treated animals. Pathway analysis of miRNAs and associated gene expression changes demonstrated enrichment of transcripts involved in epithelial to mesenchymal transition (EMT), which is a primary process involved in tumor cell motility and cancer metastasis. Liver expression analysis revealed transcripts that may mediate PFOS effects on thyroid hormone (TH) homeostasis including: activation of the CAR/PXR pathway, phase II/III enzymes, and deiodinase. These changes are consistent with low serum TH due to enhanced metabolic clearance of TH. However, most TH hepatic target genes were not altered in a manner consistent with reduced TH signalling; suggesting that PFOS exposure did not induce functional hypothyroidism. Collectively, PFOS-induced miRNA perturbations were strongly associated with EMT suggesting an important role for miRNAs in PFOS-induced hepatotoxicity. The work also provides novel insights into the effects of PFOS on TH homeostasis. Four RNA samples from control and four from PFOS treated rats were labelled with Cyanine 5-CTP (Cy5) using Low Input Quick Amp Labelling kits (Agilent Technologies Inc.) following the manufacturer’s instruction. Universal rat reference total RNA (Agilent Technologies Inc.) was labelled with Cyanine 3-CTP (Cy3). Cy5-sample cRNA and Cy3-reference cRNA were hybridized to Agilent G4853A SurePrint G3 Rat GE 8 X 60K microarrays (Agilent Technologies Inc.) at 65°C overnight with Agilent hybridization solution. Slides were washed and scanned on an Agilent G2505B microarray scanner at 5 μm resolution, and the data were acquired with Agilent Feature Extraction software version 10.7.3.1. Microarray data quality was confirmed using Agilent Feature Extraction quality control metrics and in-house metrics (boxplots, cluster analyses, and MA plots to identify poor quality outlier arrays). All samples passed the quality control tests and were used for subsequent analyses.
2015-08-01 | E-GEOD-69520 | biostudies-arrayexpress
Project description:An oral dose study with perfluorooctanesulfonate (PFOS) was undertaken to identify potential associations between serum PFOS and changes in serum clinical chemistry parameters in purpose-bred young adult cynomolgus monkeys (Macaca fascicularis). In this study, control group (n = 6/sex) was sham-dosed with vehicle (0.5% Tween 20 and 5% ethanol in water), low-dose group (n = 6/sex) received 1 single K+PFOS dose (9 mg/kg), and high-dose group (n = 4-6/sex) received 3 separate K+ PFOS doses (11-17.2 mg/kg). Monkeys were given routine checkups and observed carefully for health problems on a daily basis. Scheduled blood samples were drawn from all monkeys prior to, during, and after K+PFOS administration for up to 1 year and they were analyzed for PFOS concentrations and clinical chemistry markers for coagulation, lipids, hepatic, renal, electrolytes, and thyroid-related hormones. No mortality occurred during the study. All the monkeys were healthy, gained weight, and were released back to the colony at the end of the study. The highest serum PFOS achieved was approximately 165 μg/ml. When compared with time-matched controls, administration of K+PFOS to monkeys did not result in any toxicologically meaningful or clinically relevant changes in serum clinical measurements for coagulation, lipids, hepatic, renal, electrolytes, and thyroid-related hormones. A slight reduction in serum cholesterol (primarily the high-density lipoprotein fraction), although not toxicologically significant, was observed. The corresponding lower-bound fifth percentile benchmark concentrations (BMCL1sd) were 74 and 76 μg/ml for male and female monkeys, respectively. Compared to the 2013-2014 geometric mean serum PFOS level of 4.99 ng/ml (0.00499 μg/ml) in US general population reported by CDC NHANES, this represents 4 orders of magnitude for margin of exposure.
| S-EPMC5412069 | biostudies-literature
Project description:Perfluorooctanesulfonic acid (PFOS) is a persistent anthropogenic chemical that can affect the thyroid hormone system in humans. In experimental animals, PFOS exposure decreases thyroxine (T4) and triiodothyronine (T3) levels, without a compensatory upregulation of thyroid stimulating hormone (TSH). In adults, THs are regulated by the hypothalamus-pituitary-thyroid (HPT) axis, but also organs such as the liver and potentially the gut microbiota. PFOS and other xenobiotics can therefore potentially disrupt the TH system through various entry points of disruption. To start addressing this issue, we performed a PFOS exposure study to identify effects in multiple organs and pathways simultaneously.
2022-05-04 | GSE196133 | GEO
Project description:Thyroid hormones play an essential role in regulating whole-body homeostasis. Deiodinases are known to convert thyroid hormone from the prohormone thyroxine (T4) to the bioactive hormone tri-iodothyronine (T3) and convert both T4 and T3 toward their inactive metabolites 3,3',5'-tri-iodothyronine (rT3) and 3,3'-di-iodothyronine (3,3'-T2). Deiodinases are thus important for the regulation of intracellular thyroid hormone concentrations. This is known to be crucial both during development and adult life in regulating thyroid hormone-related gene transcription. This review discusses the importance of liver deiodinases in determining serum and liver thyroid hormone concentrations, liver metabolism and liver disease.
| S-EPMC10160546 | biostudies-literature
Project description:The role of organic anion transporting polypeptides (OATPs), particularly the members of OATP1B subfamily, in hepatocellular handling of endogenous and exogenous compounds is an important and emerging area of research. Using a mouse model lacking Slco1b2, the murine ortholog of the OATP1B subfamily, we have demonstrated previously that genetic ablation causes reduced hepatic clearance capacity for substrates. In this study, we focused on the physiological function of the hepatic OATP1B transporters. First, we studied the influence of the Oatp1b2 deletion on bile acid (BA) metabolism, showing that lack of the transporter results in a significantly reduced expression of Cyp7a1, the key enzyme of BA synthesis, resulting in elevated cholesterol levels after high dietary fat challenge. Furthermore, Slco1b2-/- mice exhibited delayed clearance after oral glucose challenge resulting from reduced hepatic glucose uptake. In addition to increased hepatic glycogen content, Slco1b2-/- mice exhibited reduced glucose output after pyruvate challenge. This is in accordance with reduced hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK) in knockout mice. We show that this phenotype is due to the loss of liver-specific Oatp1b2-mediated hepatocellular thyroid hormone entry, which then leads to reduced transcriptional activation of target genes of hepatic thyroid hormone receptor (TR), including Cyp7a1 and Pepck but also Dio1 and Glut2. Importantly, we assessed human relevance using a cohort of archived human livers in which OATP1B1 expression was noted to be highly associated with TR target genes, especially for glucose facilitating transporter 2 (GLUT2). Furthermore, GLUT2 expression was significantly decreased in livers harboring a common genetic polymorphism in SLCO1B1.Our findings reveal that OATP1B-mediated hepatic thyroid hormone entry is a key determinant of cholesterol and glucose homeostasis.
| S-EPMC3164486 | biostudies-literature
Project description:Hepatic steatosis increases risk of fatty liver and cardiovascular disease. Perfluorooctanesulfonic acid (PFOS) is a persistent, bio-accumulative pollutant that has been used in industrial and commercial applications. PFOS administration induces hepatic steatosis in rodents and increases lipogenic gene expression signatures in cultured hepatocytes. We hypothesized that PFOS treatment interferes with lipid loss when switching from a high fat diet (HFD) to a standard diet (SD), and augments HFD-induced hepatic steatosis. Male C57BL/6 N mice were fed standard chow diet or 60% kCal high-fat diet (HFD) for 4 weeks to increase body weight. Then, some HFD mice were switched to SD and mice were further divided to diet only or diet containing 0.0003% PFOS, for six treatment groups: SD, HFD to SD (H-SD), HFD, SD + PFOS, H-SD + PFOS, or HFD + PFOS. After 10 weeks on study, blood and livers were collected. HFD for 14 weeks increased body weight and hepatic steatosis, whereas H-SD mice returned to SD measures. PFOS administration reduced body weight in mice fed a SD, but not H-SD or HFD. PFOS administration increased liver weight in H-SD + PFOS and HFD + PFOS mice. PFOS increased hepatic steatosis in H-SD and HFD groups. Hepatic mRNA expression and SWATH-MS proteomic analysis revealed that PFOS induced lipid and xenobiotic transporters, as well as metabolism pathways. Overall, the findings herein suggest that PFOS treatment did interfere with lipid loss associated with switch to a SD and similarly augmented hepatic lipid accumulation in mice established on an HFD.
| S-EPMC8386191 | biostudies-literature