Chronic PFOA Exposure in vitro Causes Acquisition of Multiple Tumor Cell Characteristics in Rat Liver Cells
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PROVIDER: PRJNA918347 | ENA |
REPOSITORIES: ENA
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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 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: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: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:PFAS are persistent man-made chemicals considered to be emerging pollutants, with PFOA, PFOS, and PFHxS having associations with liver toxicity and steatosis. PFOA, PFOS, and PFHxS can undergo placental/lactational transfer, however, little is known about the impact of PFAS mixtures during the developmental window, nor maternal diet on PFAS adverse effects. It was hypothesized that gestational/lactational PFAS exposure would alter the pup liver proteome. The work herein evaluated the liver proteome in offspring, identifying potential biochemical/signaling pathways altered via maternal PFAS exposure. Timed-pregnant CD-1 dams were fed a standard chow or 60% kcal high-fat diet. From GD1 until PND20, dams were orally gavaged daily with either 0.5% Tween 20, individual PFOA, PFOS, PFHxS at 1 mg/kg, or a mixture (1 mg/kg each, totaling 3 mg/kg). Livers were collected from PND21 offspring and SWATH-MS pro-teomics was performed. IPA analysis revealed disease and biological function pathways involved in liver damage, xenobiotics, and lipid regulation were modulated by PFAS exposure in the PND21 liver: lipid transport, storage, oxidation, and synthesis, xenobiotic metabolism and transport, liver damage and inflammation, and fatty acid metabolism, oxidation and transport. This indicates the pup liver proteome is altered via maternal exposure and predisposes the pup to metabolic dysfunctions.
2024-05-09 | PXD052106 | Pride
Project description:synthesized of 2H,2Cl-PFOA from 2H,2H-PFOA or from 6:2 FTOH.
2024-03-12 | MSV000094292 | MassIVE
Project description:The objective of our study is to investigate the effect of PFOA and GenX on the gene expression levels in Monodelphis domestica whole blood cultures by RNA-seq and identify the major susceptible genes. We identified 578 differentially expressed genes (DEGs) in the PFOA treatment group and 148 DEGs in the GenX treatment group. 10 genes were selected for qRT-PCR validation and were confirmed to be DEGs. Pathway enrichment analysis revealed that several developmental processes were altered after PFOA exposure and showed an up-regulated pattern. And down-regulated DEGs after PFOA exposure were enriched for metabolic process and immune system process. GenX exposure is associated with up-regulated fatty acid transport pathways and inflammatory process. Our study is the first one to investigate the effects of PFASs on marsupial animals, providing supportive evidence of the similar transcriptomic alterations caused by PFOA and a fluorinated alternative GenX, which can work as a complement of the previous studies of PFASs effects on rodent or human.
2022-10-15 | GSE208237 | GEO
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. Experiment Overall Design: 129S1/SvlmJ wild-type and PPARalpha-null mice were exposed to 3 mg/kg/day PFOA or water for 7 days. Total RNA was isolated from liver samples and gene expression analyzed using Affymetrix Mouse 430 2.0 GeneChips. Data from 16 samples, with four mice in each of the 4 treatment groups, were analyzed.
2008-06-16 | E-GEOD-9786 | biostudies-arrayexpress