Perfluoroalkyl substances (PFAS) impact inflammation in lung cells and tissues
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE231602 | GEO | 2023/05/08
REPOSITORIES: GEO
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Project description:Perfluoroalkyl substances (PFAS) are a group of synthetic chemicals that are resistant to biodegradation and are environmentally persistent. PFAS are found in many consumer products including non-stick cookware, food packaging materials, upholstery, and personal care products. Accordingly, PFAS are a major source of water and soil contamination. Although use of many PFAS have been phased out, they continue to be detected in human and animal fluids, including human follicular fluid. This study investigated the effects of an environmentally relevant PFAS mixture [perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonic acid (PFHxS)] on the transcriptome and function of human granulosa cells (hGCs). PFOA, PFOS, and PFHxS were detected in 100% of follicle fluid samples. Increased cell proliferation was observed in hGCs treated with the PFAS mixture with no impacts on cellular apoptosis. The PFAS mixture also altered steroid hormone synthesis, increasing both FSH-stimulated and basal progesterone secretion and concomitant upregulation of STAR protein. RNA sequencing revealed inherent differences in transcriptomic profiles in hGCs after PFAS exposure. This study demonstrates functional and transcriptomic changes in hGCs after exposure to a PFAS mixture, improving our knowledge about the impacts of PFAS exposures and female reproductive health. These findings suggest that PFAS compounds have the potential to disrupt normal granulosa cell function with possible long-term consequences on overall reproductive health.
2024-07-03 | GSE246371 | GEO
Project description:Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants of concern due to their persistence and potential adverse health effects. Epidemiological studies have linked PFAS with an increased risk of uterine diseases including fibroids however, the mechanisms involved remain to be elucidated. This study investigated the effects of individual PFAS, including long-chain “legacy” PFAS [perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS)] and short-chain “alternative” PFAS compounds [undecafluoro-2-methyl-3-oxahexanoic acid (GENX/HFPO-DA), perfluorobutanesulfonic acid (PFBS)], as well as a mixture of these chemicals on the function and transcriptome of an immortalized human myometrial cell line (UT-TERT). UT-TERT cells exposed to individual PFAS displayed increased cell viability and proliferation. Flow cytometry analysis revealed that PFOS and the PFAS mixture altered cell cycle progression. Migration assays demonstrated that PFOS and the PFAS mixture significantly enhanced UT-TERT cell migration. Gap junction intercellular communication (GJIC) was impaired following PFOA, PFBS, and PFAS mixture exposure, indicating potential disruptions in cell-to-cell communication within the uterine environment. Transcriptomic analysis using RNA-seq identified substantial changes in gene expression after exposure to environmentally relevant levels of individual PFAS and PFAS mixture. Pathway analysis revealed common molecular pathways associated with PFAS exposure, including Cell-to-Cell Signaling, Lipid Metabolism, and Cell Death and Survival, while other pathways were unique to specific PFAS. These findings highlight the multifaceted effects of PFAS on myometrial cells, providing insights into the potential mechanisms underlying PFAS-associated health risks. Further research is necessary to elucidate the long-term implications of PFAS exposure on uterine function and overall reproductive health.
2024-10-18 | GSE279836 | GEO
Project description:The gut microbiota in our intestinal tract metabolizes non-digestible compounds into essential nutrients and signaling molecules (i.e. short-chain fatty acids), affecting our immune system and the development of various human diseases. Ingested environmental contaminants (xenobiotics) can disrupt the bacterial community and enzymatic activity, ultimately influencing the host. Pervasive xenobiotics include bisphenols and poly- and perfluoroalkyl substances (PFAS). Both classes of chemicals have been reported to affect the immune system and cause adverse effects on human metabolism. Since humans are exposed to a complex mixture of environmental contaminants it is critical to evaluate the effects of xenobiotics in mixtures. In our study, an in vitro bioreactor model system based on the simplified human microbiome model (SIHUMIx) was used to investigate the direct effects of either perfluorooctanoic acid (PFOA), perfluorohexanoic acid (PFHxA) and perfluorobutanoic acid (PFBA) or bisphenol S (BPS) and bisphenol F (BPF) or a combined mixture on the microbiota. We observed an increased production of the short-chain fatty acids (SCFAs) acetate and butyrate following PFAS exposure. A metaproteomics approach revealed changes in molecular pathways in all treatments, including alterations in vitamin and cofactor synthesis and an additional effect on fatty acid synthesis in BPX-treated reactors. This study highlights the need to assess the combined effects of xenobiotics and to better protect public health by considering adverse effects on the microbiome in the risk assessment of environmental chemicals.
2024-06-13 | PXD048273 | Pride
Project description:Per- and polyfluoroalkyl substances (PFAS) are some of the most prominent organic contaminants in human blood that have the potential to disrupt biological processes and pathways in the liver. Although the toxicological implications from human exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are well established, data on other, lesser-understood PFAS are limited. A challenge for regulatory authorities is to determine acceptable levels of human exposure to large, diverse classes of environmental contaminants. New approach methodologies (NAMs) that apply bioinformatics tools to interpret biological data are being increasingly considered to inform risk assessment when traditional toxicology methodologies are not amenable. The aim of the current investigation was to identify the biological responses relevant to PFAS mode of action as the concentration (benchmark dose) that these effects take place in order to utililze this information to inform/facilitate read-across for risk assessment of data-poor PFAS. A TempO-Seq platform (BioSpyder) measured gene expression changes in human liver microtissues (i.e., spheroids) after 1-day and 10-day exposures to increasing concentrations of PFAS. A bioinformatics framework was applied to 23 PFAS sub-classed into carboxylates (PFCAs), sulfonates (PFSAs), or PFAS precursors that were analyzed for the total altered transcripts, the concentration where effects take place, and identifying target genes of interest. Both PFCAs and PFSAs exhibited a trend toward increased transcriptional changes with carbon chain-length. Specifically, longer-chain compounds (7 to 10 carbons) were more likely to surpass liver-toxic transcriptomic thresholds established from previous studies than shorter chain PFAS. Longer-chain PFAS were also more potent, inducing transcriptional effects at lower concentrations. However, PFOS was the most potent PFAS and of all precursors, only PFOSA (a PFOS precursor) induced a response. The combined high-throughput transcriptomic and bioinformatics analyses revealed the capability of NAMs to assess the effects of PFAS in liver microtissues; such data improves our understanding of PFAS-related effects in humans and facilitates the use of read-across in human health risk assessment for other data-poor chemicals.
2021-11-08 | GSE145239 | GEO
Project description:Background: Previous epidemiological studies have repeatedly found per- and polyfluoroalkyl substances (PFAS) exposure associated with higher circulating cholesterol, one of the greatest risk factors for development of coronary artery disease. The main route of cholesterol catabolism is through its conversion to bile acids, which circulate between the liver and ileum via enterohepatic circulation. Patients with coronary artery disease have decreased bile acid excretion, indicating that PFAS-induced changes of enterohepatic circulation may play a critical role in cardiovascular risk. Objectives: Using a mouse model with high LDL-VLDL cholesterol and aortic lesion development similar to humans, the current study investigates mechanisms linking exposure to a PFAS mixture with increased cholesterol. Methods: Male and female Ldlr-/- mice were fed an atherogenic diet (Clinton/Cybulsky low fat, 0.15% cholesterol) and exposed to a mixture of 5 PFAS representing legacy, replacement, and emerging subtypes (i.e., PFOA, PFOS, PFNA, PFHxS, GenX), each at a concentration of 2 mg/L, for 7 weeks. Blood was collected longitudinally for cholesterol measurements and mass spectrometry was used to measure circulating and fecal bile acids. Transcriptomic analysis of ileal samples was performed via RNA-sequencing. Results: After 7 weeks of PFAS exposure, average circulating PFAS levels were measured at 21.6, 20.1, 31.2, 23.5, and 1.5 µg/mL in PFAS-exposed females and 12.9, 9.7, 23, 14.3, and 1.7 µg/mL in PFAS-exposed males for PFOA, PFOS, PFHxS, PFNA, and GenX, respectively. PFAS exposure led to elevated circulating cholesterol levels after 7 weeks compared to vehicle mice, with females increasing 18% and males increasing 24%. Total circulating bile acid levels were elevated in PFAS-exposed mice by 230% in males and 290% in females compared to vehicle. PFAS decreased fecal bile acid levels by 62% in females and 59% in males. In the ileum, expression levels of the bile acid reuptake transporter ASBT were increased due to PFAS exposure. Discussion: Mice exposed to a PFAS mixture display increased circulating cholesterol and bile acids perhaps due to changes in enterohepatic circulation. This study implicates PFAS-mediated effects at the site of the ileum as a possible critical mediator of increased cardiovascular risk due to PFAS.
2024-08-14 | GSE263158 | GEO
Project description:Perfluoroalkyl substances (PFAS) impact inflammation in lung cells and tissues
| PRJNA966988 | ENA
Project description:Humans can be exposed to per- and polyfluoroalkyl substances (PFASs) via many exposure routes, including diet, which may lead to several adverse health effects. So far, little is known about PFAS transport across the human intestinal barrier. In the current study, we aimed to assess the transport of 5 PFASs (PFOS, PFOA, PFNA, PFHxS and HFPO-DA) in a human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cell (IEC) model. This model was extensively characterized and compared with the widely applied human colonic adenocarcinoma cell line Caco-2 and a human primary IEC-based model, described to most closely resemble in vivo tissue. The hiPSC-derived IEC layers demonstrated polarized monolayers with tight junctions and a mucus layer. The monolayers consisted of enterocytes, stem cells, goblet cells, enteroendocrine cells, and Paneth cells that are also present in native tissue. Transcriptomics analysis revealed distinct differences in gene expression profiles where the hiPSC-derived IECs showed highest expression of intestinal tissue-specific genes relative to the primary IEC-based model, whereas the Caco-2 cells clustered closer to the primary IEC-based model than the hiPSC-derived IECs. The order of PFAS transport was largely similar between the models and the apparent permeability (Papp) values of PFAS in apical to basolateral direction in the hiPSC-derived IEC model were in the following order: PFHxS>PFOA>HFPO-DA>PFNA>PFOS. In conclusion, the hiPSC-derived IEC model highly resembles human intestinal physiology and is therefore a promising novel in vitro model to study transport of chemicals across the intestinal barrier for risk assessment of chemicals.
2024-06-05 | GSE268603 | GEO
Project description:Multiple per- and polyfluoroalkyl substances (PFAS) have been associated with adverse liver outcomes in adult humans and toxicological models, but effects on the developing liver or biologic pathways involved are not known. We performed whole-transcriptome gene expression analysis to investigate the molecular mechanisms of liver toxicity in the dam and female fetuses after exposure to two different PFAS, perfluorooctanoic acid (PFOA) and its replacement, hexafluoropropylene oxide-dimer acid (HFPO-DA, commonly referred to as GenX).
2022-11-29 | GSE199233 | 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:Perfluoroalkyl substances (PFAS) are man-made chemicals with suspected endocrine-disrupting properties. Exposure to perfluorooctanoic acid (PFOA) has been linked to disturbed metabolism via the liver, although the exact mechanism is not clear. Moreover, information on the metabolic effects of the new PFAS alternative GenX is limited. We tested whether low-dose exposure to PFOA and GenX induces metabolic disturbances, including NAFLD, dyslipidemia, and glucose tolerance in mice and studied the involvement of PPARα. To this end, male C57BL/6J wildtype and PPARα−/− mice were given 0.05 or 0.3 mg/kg bw/day PFOA, or 0.3 mg/kg bw/day GenX next to a high-fat diet for 20 weeks. RNA sequencing was performed on liver, next to thorough assesment of metabolic parameters. RNA sequencing revealed that whereas the effects of GenX are entirely dependent on PPARα, effects of PFOA are mostly dependent on PPARα. In the absence of PPARα, the involvement of PXR/CAR becomes more prominent. Exposure to high-dose PFOA in mice decreased body weights and increased liver weights in wildtype and PPARα−/− mice. High-dose but not low-dose PFOA reduced plasma triglycerides and cholesterol, which for triglycerides, showed PPARα dependency. PFOA and GenX increased hepatic triglycerides in a PPARα-dependent manner. Overall, we show that long-term and low-dose exposure to PFOA and GenX disrupts lipid metabolism in mice. Whereas the effects of PFOA are mediated by multiple nuclear receptors, effects of GenX are entirely mediated by PPARα. Our data underscore the potential of PFAS to disrupt metabolism by altering signaling pathways in the liver.
2022-09-02 | GSE212294 | GEO