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

Environment International, Год журнала: 2023, Номер 178, С. 108138 - 108138

Опубликована: Авг. 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

Язык: Английский

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Ecosurveillance reveals subtle metabolic effects on the non-native cane toad (Rhinella marina) from low levels of accumulated environmental per- and polyfluoroalkyl substances

Environmental Pollution, Год журнала: 2025, Номер 372, С. 125968 - 125968

Опубликована: Март 4, 2025

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment, bioaccumulate, may have toxic effects. This study used non-native cane toads (Rhinella marina) to examine PFAS metal accumulation impacts large terrestrial amphibians from urban peri-urban areas. We quantified 38 compounds 36 environmental legacy metal(loid)s 52 adult toad livers collected six locations around Southeast Queensland, Australia, along a known gradient. Associations among PFAS, metal(loid) concentrations, whole-organism metrics were assessed. An omics-led approach assessed biochemical responses liver, muscle, fat gonad/egg tissues associated with these concentrations. Liver concentrations ranged 0.5 82.1 μg/kg ww, one male outlier at 452 ww (mean: 18 ± 21 SD excluding outlier). PFOS was most dominant (60 26 SD% of total), followed by PFDoDA (13 9 SD%). The liver statistically significant variation sex Al, As, Ca, Cu, Mn, Ni, Se, Sn, Sr V. Total had no associations metrics, body condition relative femur length showed weak interaction effect between Ni. Metabolic profiling revealed sex-specific differences linked total females showing broader metabolic perturbation. strongest signals glycerolipid metabolism, ether lipid fatty acid biosynthesis, though effects weak. levels low compared those previously recorded tertiary consumers aquatic vertebrates contaminated Despite minor metabolomic changes, overall health impact minimal. These findings contribute development tissue guideline values for wild amphibians, but further studies on higher additional amphibian species needed.

Язык: 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, Год журнала: 2023, Номер 329, С. 121708 - 121708

Опубликована: Апрель 24, 2023

Язык: 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, Год журнала: 2024, Номер 190, С. 108864 - 108864

Опубликована: Июль 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.

Язык: Английский

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Transcriptomics integrated with metabolomics reveals perfluorobutane sulfonate (PFBS) exposure effect during pregnancy and lactation on lipid metabolism in rat offspring

Chemosphere, Год журнала: 2023, Номер 341, С. 140120 - 140120

Опубликована: Сен. 9, 2023

Язык: 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, Год журнала: 2024, Номер 278, С. 116402 - 116402

Опубликована: Май 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.

Язык: 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, Год журнала: 2024, Номер 287, С. 117260 - 117260

Опубликована: Ноя. 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.

Язык: Английский

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Insights into the effect of benzotriazoles in liver using integrated metabolomic and transcriptomic analysis

Environment International, Год журнала: 2024, Номер 187, С. 108716 - 108716

Опубликована: Май 1, 2024

Benzotriazoles (BTRs) are a class of benzoheterocyclic chemicals that frequently used as metal-corrosive inhibitors, both in industry and daily use. However, the exposure effect information on BTRs remains relatively limited. In this study, an integrated metabolomic transcriptomic approach was utilized to evaluate three BTRs, benzotriazole, 6-chloro-1-hydroxi-benzotriazole, 1-hydroxy-benzotriazole, mouse liver with results showing disrupted basal metabolic processes vitamin cofactor metabolism after 28 days. The expression several genes related inflammatory response aryl hydrocarbon receptor pathways, such Gstt2 Arntl, altered by BTRs. Exposure also affected metabolites involved immune system xenobiotic responses. cytochrome P450 family reveal potential detoxification mechanism liver. Taken together, our findings provide new insights into multilayer well resource for further exploration molecular mechanisms which occurs.

Язык: Английский

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Hunting Metabolic Biomarkers for Exposure to Per- and Polyfluoroalkyl Substances: A Review

Metabolites, Год журнала: 2024, Номер 14(7), С. 392 - 392

Опубликована: Июль 19, 2024

Per- and polyfluoroalkyl substances (PFAS) represent a class of persistent synthetic chemicals extensively utilized across industrial consumer sectors, raising substantial environmental human health concerns. Epidemiological investigations have robustly linked PFAS exposure to spectrum adverse outcomes. Altered metabolites stand as promising biomarkers, offering insights into the identification specific pollutants their deleterious impacts on health. However, elucidating metabolic alterations attributable ensuing effects has remained challenging. In light this, this review aims elucidate potential biomarkers by presenting comprehensive overview recent metabolomics-based studies exploring toxicity. Details types, sources, patterns are provided. Furthermore, PFAS-induced liver toxicity, reproductive developmental cardiovascular glucose homeostasis disruption, kidney carcinogenesis synthesized. Additionally, thorough examination utilizing metabolomics delineate toxicity blood, liver, urine specimens is presented. This endeavors advance our understanding regarding associated toxicological effects.

Язык: Английский

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

Environmental Pollution, Год журнала: 2025, Номер unknown, С. 125634 - 125634

Опубликована: Янв. 1, 2025

Язык: Английский

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