PPARα/ACOX1 as a novel target for hepatic lipid metabolism disorders induced by per- and polyfluoroalkyl substances: An integrated approach

Environment International, Journal Year: 2023, Volume and Issue: 178, P. 108138 - 108138

Published: Aug. 1, 2023

Per- and polyfluoroalkyl substances (PFAS) are persistent ubiquitous environmental contaminants with well-documented hepatotoxicity. However, the mechanistic linkage between PFAS exposure non-alcoholic fatty liver disease (NAFLD) remains largely elusive.This study aimed to explore PFAS-to-NAFLD link relevant molecular mechanisms.The cross-sectional analyses using National Health Nutrition Examination Survey (NHANES) data were conducted investigate association NAFLD. A combination of in silico toxicological analyses, bioinformatics approaches, animal experiments, vitro assays was used initiating events (MIEs) key (KEs) PFAS-induced hepatic lipid metabolism disorders.The NHANES revealed significant steatosis/NAFLD. The showed that PPARα activation induced by perfluorooctanoic acid (PFOA) perfluorooctane sulfonic (PFOS), prototypical representatives PFAS, is critical MIE associated NAFLD-predominant diseases. Transcriptome-based bioinformatic annotation identified transcriptional upregulation acyl-CoA oxidase 1 (ACOX1) PPARα-regulated peroxisomal β-oxidation pathway KE involved PFOA/PFOS-perturbed metabolic pathways humans, mice rats. vivo further verified ACOX1-mediated oxidative stress contributed mitochondrial compromise accumulation PFOA/PFOS-exposed mouse hepatocytes, which could be mitigated co-treatment ACOX1 inhibitor mitochondria ROS scavenger. Additionally, we observed besides PFOA PFOS, exhibited good-fit response short-term exposures long-chain (C7-C10) perfluoroalkyl carboxylic acids (PFHpA, PFNA, PFDA) (PFHpS, PFDS) human hepatocyte spheroids through benchmark dose (BMD) modeling.Our unveils a novel target for disorders, shedding new light on prediction, assessment, mitigation

Language: Английский

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Early life exposure to low-dose perfluorooctane sulfonate disturbs gut barrier homeostasis and increases the risk of intestinal inflammation in offspring

Environmental Pollution, Journal Year: 2023, Volume and Issue: 329, P. 121708 - 121708

Published: April 24, 2023

Language: Английский

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Impact of perfluorooctanoic acid (PFOA) and perfluorobutanoic acid (PFBA) on oxidative stress and metabolic biomarkers in human neuronal cells (SH-SY5Y)

Environment International, Journal Year: 2024, Volume and Issue: 190, P. 108864 - 108864

Published: July 2, 2024

Perfluorinated alkyl substances (PFAS) are pervasive environmental contaminants that have attracted considerable attention due to their widespread utilization, resilient characteristics, adverse health implications, and regulatory scrutiny. Despite documented toxicity in living organisms, the precise molecular mechanisms governing induced effects remain unclear. This study aims elucidate of toxic action by collecting empirical data sets along oxidative stress metabolic disruption pathways. We investigated impact long-chain PFAS (perfluorooctanoic acid (PFOA)) its short-chain analog (perfluorobutanoic (PFBA)) on human neuronal cells (SH-SY5Y). The functionalities enzymes associated with (catalase glutathione reductase) cellular metabolism (lactate dehydrogenase pyruvate dehydrogenase) were also characterized. Our results reveal a 24-hour exposure PFOA PFBA generated significant levels reactive oxygen species. Correspondingly, there was notable decline catalase reductase activities, demonstrating more pronounced effect. High concentrations reduced activity. Lactate activity only impacted high concentration PFBA, while decreased increased exposure. findings from this contribute knowledge cell interactions potential underlying PFAS-induced toxicity.

Language: Английский

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Multi-omics reveal disturbance of glucose homeostasis in pregnant rats exposed to short-chain perfluorobutanesulfonic acid

Ecotoxicology and Environmental Safety, Journal Year: 2024, Volume and Issue: 278, P. 116402 - 116402

Published: May 9, 2024

Perfluorobutanesulfonic acid (PFBS), a short-chain alternative to perfluorooctanesulfonic (PFOS), is widely used in various products and increasingly present environmental media human bodies. Recent epidemiological findings have raised concerns about its potential adverse health effects, although the specific toxic mechanism remains unclear. This study aimed investigate metabolic toxicity of gestational PFBS exposure maternal rats. Pregnant Sprague Dawley (SD) rats were randomly assigned three groups administered either 3% starch gel (control), 5, or 50 mg/kg bw·d PFBS. Oral glucose tolerance tests (OGTT) lipid profiles measured, integrated omics analysis (transcriptomics non-targeted metabolomics) was employed identify changes genes metabolites their relationships with phenotypes. The results revealed that exposed exhibited significant decrease 1-h levels area under curve (AUC) OGTT compared group. Transcriptomics indicated alterations gene expression related cytochrome P450 exogenous metabolism, glutathione bile secretion, tumor pathways, retinol metabolism. Differentially expressed (DEMs) enriched pathways such as pyruvate glucagon signaling pathway, central carbon metabolism cancer, citric cycle. Co-enrichment pairwise correlation among genes, metabolites, outcomes identified several differentially (DEGs), including Gstm1, Kit, Adcy1, Gck, Ppp1r3c, Ppp1r3d, DEMs fumaric acid, L-lactic 4-hydroxynonenal, acetylvalerenolic acid. These DEGs may play role modulation glucolipid pathways. In conclusion, our suggest induce molecular perturbations homeostasis. provide insights into mechanisms contributing heightened risk abnormal associated exposure.

Language: Английский

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Relationship between per-fluoroalkyl and polyfluoroalkyl substance exposure and insulin resistance in nondiabetic adults: Evidence from NHANES 2003–2018

Ecotoxicology and Environmental Safety, Journal Year: 2024, Volume and Issue: 287, P. 117260 - 117260

Published: Nov. 1, 2024

Studies have linked per- and polyfluoroalkyl substances (PFAS) to chronic metabolic diseases. However, the relationship between PFAS exposure insulin resistance (IR), a key pathophysiological basis of these diseases, in nondiabetic individuals yet be determined.

Language: Английский

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Insights into Toxicological Mechanisms of Per-/polyfluoroalkyl Substances by Using Omics-centered Approaches

Environmental Pollution, Journal Year: 2025, Volume and Issue: unknown, P. 125634 - 125634

Published: Jan. 1, 2025

Language: Английский

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Angelica sinensis polysaccharide as potential protectants against recurrent spontaneous abortion: focus on autophagy regulation

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 15, 2025

Recurrent spontaneous abortion (RSA) represents a significant clinical challenge, with its underlying mechanisms yet to be fully elucidated. Despite advances in understanding, the precise pathophysiology driving RSA remains unclear. Angelica sinensis, traditional herbal remedy, is frequently used as an adjunctive treatment for miscarriage. However, it uncertain whether primary active component, sinensis polysaccharide (ASP), plays definitive role therapeutic effects. The specific function and mechanism of ASP context require further investigation. In this study, we sought evaluate autophagy levels at maternal-fetal interface patients mouse model treated ASP, complemented by comprehensive metabolomic analysis. Autophagy flux decidua was compared between eight healthy pregnant women. Additionally, changes were assessed following treatment, embryos placental tissues collected subsequent profiling. Our results revealed reduction Beclin 1 protein normal pregnancy group. Conversely, restored autophagy-related expression, including ATG7, ATG16L, 1, higher than those observed untreated Metabolomic analyses identified phosphatidylethanolamine ASP-treated control groups, differential metabolites enriched pathways related glycolysis/gluconeogenesis, glycerolipid metabolism, glycine, serine, threonine metabolism. Functional assays that enhances trophoblast cell proliferation, migration, invasion. summary, our findings demonstrate diminished activity patients, while appears restore regulate key metabolic pathways, glycolysis/gluconeogenesis. These provide new insights into protective RSA, suggesting potential intervention condition.

Language: Английский

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Maternal per- and polyfluoroalkyl substances exposure, cord blood lipidomics and infant anthropometry: A mediation analysis

Environmental Research, Journal Year: 2025, Volume and Issue: 271, P. 121074 - 121074

Published: Feb. 7, 2025

Language: Английский

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Effects of Serum Insulin and Insulin-Like Growth Factor 1 Levels on the Association between Fetal Growth and Per- and Polyfluoroalkyl Substance Exposure Based on a Nested Case–Control Study

Environmental Science & Technology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Insulin and insulin-like growth factor 1 (IGF1) play key roles in fetal development. However, their the association between perfluoroalkyl polyfluoroalkyl substance (PFAS) exposure remain unclear. In this study, levels of 34 PFAS, IGF1, insulin were measured 258 paired mother-infant serum samples collected from a nested case-control study Maoming city. Isomeric perfluorooctanesulfonate (PFOS) significantly increased preterm birth or low weight (PTB/LBW) risk, odds ratios for ∑2m, 3+4+5m, iso, branched PFOS 1.50, 1.72, 1.61, 1.77, respectively. Cord IGF1 could explain 15.4, 13.4, 9.7, 11.9% these associations, Additionally, cord mediated 12.3 to 44.6% associations isomers, perfluorooctanoate acid (PFOA), its alternative (perfluorobutanoic acid: PFBA) with index. For instance, contributed 42.0% (95% Cl: 0.8, 140.0%), 42.7% 13.0, 110.0%), 43.0% 8.4, 130.0%) z-scores PFOS, PFOA, PFBA, These findings suggest that plays mediating role PFAS growth.

Language: Английский

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Impact of PFOS Exposure on Murine Fetal Hematopoietic Stem Cells, Associated with Intrauterine Metabolic Perturbation

Environmental Science & Technology, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

This study hypothesized that perfluorooctanesulfonate (PFOS) exposure disrupts maternal-fetal metabolism, affecting fetal liver hematopoietic stem cell (FL-HSC) development. Pregnant mice received PFOS (0.3 and 3 μg/g bw) were sacrificed on gestation day 14.5. Metabolomic analysis of maternal plasma revealed disruptions in steroid hormone, purine, carbohydrate, amino acid which aligned with the enriched pathways amniotic fluid (AF). FL indicated increased purine metabolism disrupted glucose metabolism. exhibited higher levels polyunsaturated fatty acids, glycolytic TCA metabolites, pro-inflammatory cytokine IL-23, crucial for hematopoiesis regulation. Transcriptomic FL-HSCs disturbances PPAR signaling pathway, pyruvate oxidative phosphorylation, correlating metabolic changes. significant rises glycerophospholipid vitamin B6 related to HSC expansion differentiation. Flow cytometric confirmed populations progenitor activation megakaryocyte, erythrocyte, lymphocyte lineages. The CFU assay showed a increase BFU-E CFU-G, but decrease CFU-GM from H-PFOS group, indicating altered differentiation potential. These findings provide first time insights into effects hematopoiesis, highlighting implications pollution-affected immune functions.

Language: Английский

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