Replacement Per and Polyfluoroalkyl Substance GenX Induces Fibroinflammatory Gene Expression in Primary Human Hepatocytes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE187633 | GEO | 2022/07/21
REPOSITORIES: GEO
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Project description:Replacement Per and Polyfluoroalkyl Substance GenX Induces Fibroinflammatory Gene Expression in Primary Human Hepatocytes
| PRJNA777621 | ENA
Project description:Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals with several applications. Multiple adverse health effects are reported for longer carbon chain (≤C8) PFAS. Shorter carbon chain PFAS, [e.g., hexafluoropropylene oxide dimer acid (HFPO-DA; GenX) and perfluorobutanesulfonic acid (PFBS)] were introduced as alternatives. Past studies indicate that longer-chain PFAS are neurotoxic targeting the dopamine pathway, but it is not known if shorter-chain PFAS act similarly. This study aimed to evaluate developmental neurotoxicity and tissue uptake of GenX and PFBS using the zebrafish (Danio rerio). First, acute toxicity was assessed by measuring LC50 at 120 h postfertilization (hpf). Body burden was determined after embryonic exposure (1-72 hpf) to sublethal concentrations of GenX or PFBS by LC-ESI-MS/MS. Locomotor activity using a visual motor response assay at 120 hpf and dopamine levels at 72 hpf was assessed after embryonic exposure. PFBS was more acutely toxic and bioaccumulative than GenX. GenX and PFBS caused hyperactivity at 120 hpf, but stronger behavioral alterations were observed for PFBS. An increase in whole organism dopamine occurred at 40 ppb of GenX, while a decrease was observed at 400 ppb of PFBS. Differences detected in dopamine for these two PFAS indicate differential mechanisms of developmental neurotoxicity.
| S-EPMC11299994 | biostudies-literature
Project description:We investigated the effects of per- and polyfluroralkyl substance exposure on FRG liver-chimeric humanized mice on a C57Bl/6 background. These PFAS included PFOA, PFOS, and GenX. These mice were exposed to water ad libitum for 28 days to reach human relevant serum concentrations. We then performed RNA-Sequencing on isolated whole liver lysate to determine differentially expressed genes.
2023-07-14 | GSE208636 | GEO
Project description:BackgroundNeonatal per- and polyfluoroalkyl substance (PFAS) exposure can disrupt hormonal homeostasis and induce neuro- and immunotoxicity in children. In this exploratory study, we investigated associations between PFAS levels in neonatal dried blood spots and retinoblastoma risk.Materials and methodsThis study included 501 retinoblastoma cases born from 1983 to 2011 and 899 controls frequency-matched by birth year (20:1 matching ratio), born to 755 US-born and 366 Mexico-born mothers in California. Perfluorooctanesulfonic acid (PFOS), perflurooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) feature intensities were identified from neonatal blood spots from California newborn Genetic Disease Screening Program. Using logistic regression, we assessed whether an interquartile range (IQR) increase of PFAS levels or having above-mean levels of PFAS in blood affects retinoblastoma risk overall or its subtypes (i.e., unilateral, bilateral). We assessed children of US-born and Mexico-born mothers, separately.Results and discussionAmong all children, above-mean PFOS levels at birth increased the odds of retinoblastoma overall by 29% (95% Confidence Interval (CI): 1.00, 1.67) and unilateral retinoblastoma by 42% (95% CI: 1.03, 1.97). For children of Mexico-born mothers, we estimated the highest odds of retinoblastoma overall (adjusted odds ratio (aOR): 1.67; 95% CI: 1.06, 2.66) and bilateral retinoblastoma (aOR: 2.06; 95% CI: 1.12, 3.92) with above-mean PFOS levels. Among children of US-born mothers, higher PFOS levels increased the odds of unilateral retinoblastoma by 15% (95% CI: 0.99, 1.35) for each IQR increase and by 71% among children with above-mean PFOS levels (95% CI: 1.04, 2.90). In addition, for children of US-born mothers, PFOA increased the odds of retinoblastoma overall (aOR: 1.41; 95% CI: 1.00, 2.02 for above-mean levels, aOR: 1.06; 95% CI: 0.98, 1.16 per IQR increase). PFNA was not associated with retinoblastoma risk.ConclusionsOur results suggested that PFOS and PFOA might contribute to retinoblastoma risk in children born in California.
| S-EPMC10842486 | biostudies-literature
Project description:Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals utilized in various industrial settings, and include products such as flame retardants, artificial film-forming foams, cosmetics, non-stick cookware among others. Epidemiological studies suggest a link between increased blood PFAS levels and prostate cancer incidence, but the mechanism through which PFAS impact cancer development is unclear. To investigate the link between PFAS and prostate cancer, we evaluated the impact of metabolic alterations resulting from a high-fat diet combined with PFAS exposure on prostate tumor progression. Our studies are the first in the field to provide new and clinically relevant insights regarding novel metabolic and epigenetic states and support future development of effective preventative and therapeutic strategies for PFAS-induced prostate cancers. Our findings enhance understanding of how PFAS synergize with high-fat diets to contribute to prostate cancer development and establish an important basis to mitigate PFAS exposure.
2021-12-01 | GSE185183 | GEO
Project description:Per- and polyfluoroalkyl substances (PFAS) are a class of environmental toxicants, and some, such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), have been associated with hepatic steatosis in rodents and monkeys. It was hypothesized that perfluorosulfonic acids (C4, 6, 8), perfluorocarboxylic acids (C4-14), perfluoro(2-methyl-3-oxahexanoic) acid (HFPO-DA), 1H, 1H, 2H, 2H-perfluorooctanesulfonic acid (6:2 FTS) along with 3 PFOS precursors could induce expression of lipid metabolism genes and lipid deposition in human hepatocytes. Five-donor pooled cryopreserved human hepatocytes were cultured and treated with 0.1% DMSO vehicle or various PFAS (0.25 to 25 μM) in media. After a 48-h treatment, mRNA transcripts related to lipid transport, metabolism, and synthesis were measured using a Quantigene Plex assay. After 72-h treatments, hepatocytes were stained with Nile Red dye to quantify intracellular lipids. Overall, PFAS were transcriptionally active at 25 μM. In this model, lipid accumulation was not observed with C8-C12 treatments. Shorter chain PFAS (C4-C5), 6:2 FTS, and PFOS precursor, metFOSA, induced significant liver lipid accumulation, and gene activation at lower concentrations than legacy PFAS. In summary short chain PFAS and other alternative PFAS were more potent gene inducers, and potential health effects of replacement PFAS should be critically evaluated in humans.
| S-EPMC9036616 | biostudies-literature
Project description:Primary human hepatocytes (PHH) are a main instrument in drug metabolism research and in the prediction of drug-induced phase I/II enzyme induction in humans. The HepG2 liver-derived cell line is commonly used as a surrogate for human hepatocytes, but their use in ADME and toxicity studies can be limited because of lowered basal levels of metabolizing enzymes. Despite their widespread use, the transcriptome of HepG2 cells compared to PHH is not well characterized. In this study, microarray analysis was conducted to ascertain the differences and similarities in mRNA expression between HepG2 cells and human hepatocytes before and after exposure to a panel of fluoroquinolone compounds. Comparison of the naïve HepG2 cell and PHH transcriptomes revealed a substantial number of basal gene expression differences. When HepG2 cells were dosed with a series of fluoroquinolones, trovafloxacin, which has been associated with human idiosyncratic hepatotoxicity, induced substantially more gene expression changes than the other quinolones, similar to previous observations with PHH. While TVX-treatment resulted in many gene expression differences between HepG2 cells and PHH, there were also a number of TVX-induced commonalities, including genes involved in RNA processing and mitochondrial function. Taken together, these results provide insight for interpretation of results from drug metabolism and toxicity studies conducted with HepG2 cells in lieu of PHH, and could provide further insight into the mechanistic evaluation of TVX-induced hepatotoxicity. Keywords: Cell Type Comparison
2007-10-30 | GSE9166 | GEO
Project description:Primary human hepatocytes (PHH) are a main instrument in drug metabolism research and in the prediction of drug-induced phase I/II enzyme induction in humans. The HepG2 liver-derived cell line is commonly used as a surrogate for human hepatocytes, but their use in ADME and toxicity studies can be limited because of lowered basal levels of metabolizing enzymes. Despite their widespread use, the transcriptome of HepG2 cells compared to PHH is not well characterized. In this study, microarray analysis was conducted to ascertain the differences and similarities in mRNA expression between HepG2 cells and human hepatocytes before and after exposure to a panel of fluoroquinolone compounds. Comparison of the naïve HepG2 cell and PHH transcriptomes revealed a substantial number of basal gene expression differences. When HepG2 cells were dosed with a series of fluoroquinolones, trovafloxacin, which has been associated with human idiosyncratic hepatotoxicity, induced substantially more gene expression changes than the other quinolones, similar to previous observations with PHH. While TVX-treatment resulted in many gene expression differences between HepG2 cells and PHH, there were also a number of TVX-induced commonalities, including genes involved in RNA processing and mitochondrial function. Taken together, these results provide insight for interpretation of results from drug metabolism and toxicity studies conducted with HepG2 cells in lieu of PHH, and could provide further insight into the mechanistic evaluation of TVX-induced hepatotoxicity. Experiment Overall Design: HepG2 cells were obtained from the American Type Culture Collection (Rockville, MD). The cells were cultured in Minimum Essential Medium (Invitrogen Life Technologies, Carlsbad,CA) with 10% Fetal Bovine Serum under a humidified 5% CO2 atmosphere using T-162 plastic culture flasks. The cells were split when they reached approximately 70-85% confluence after washing with sterile phosphate buffered saline and detachment of the cells with trypsin (Invitrogen Life Technologies, Carlsbad, CA). The HepG2 cells were cultured in 6-well plastic plates upon exposure to quinolone compounds. Primary human hepatocytes, obtained from In Vitro Technologies (IVT, Baltimore, MD) in 6-well type I collagen coated plates, were cultured with 2 mL of Hepatocyte Incubation Media (IVT) at 37°C with 5% CO2 for 24 hours after receipt. Experiment Overall Design: For the genomic experiments, quinolone compounds, dissolved in 0.1 N KOH (Sigma Chemical Co., St. Louis, MO), were added to the wells with fresh media at levels of 100 µM (HepG2) or 400 µM (primary human hepatocytes) for 24 hours using at least two technical replicates. Trovafloxacin was dosed using two separate preparations of HepG2 cells and two separate donors of human hepatocytes. Vehicle control cells were dosed with an equivalent volume of 0.1N KOH as the experimental samples. For intracellular comparison (HepG2 cells vs PHH), naïve cells were harvested using TRIzol� reagent (Invitrogen Life Technologies, Carlsbad, CA). Experiment Overall Design: Total RNA was isolated from the TRIzol� extracts using the standard procedure from the manufacturer. O.D. at 260 nm determined RNA concentrations. RNA quality was accessed using an Agilent Technologies bioanalyzer before proceeding to microarray sample preparation. Microarray analysis was performed using the standard protocol provided by Affymetrix Inc. (Santa Clara, CA) and as previously described, starting with 5 µg of total RNA (Richert et al., 2006). Experiment Overall Design: Fragmented, labeled cRNA was hybridized to an Affymetrix human genome U133A array, which contains sequences corresponding to roughly 22,200 transcripts at 45°C overnight. The arrays were washed, developed, and scanned.
2008-06-16 | E-GEOD-9166 | biostudies-arrayexpress
Project description:Hepatocytes isolated from DILI patient's liver (#2064) were cultured for a long term using irrMEF and EMUKK-05, and comprehensive gene expression was compared between Puromycin-treated and non-treated groups. In addition, comprehensive gene expression analysis of human mature hepatocytes, primary cultured cells, and ips cell-derived hepatocyte-like cells were performed as controls. Two-condition experiment, Proliferating hepatocytes (ProilHH) vs. puromycin-treated ProliHH. Primary human hepatocytes (PHH) and isolated humen mature hepatocytes (MH) and human iPSC-derived hepatocyte-like cells (HLC) as controls.
2021-12-30 | GSE192653 | GEO