Exposure to environmental toxicants is associated with gut microbiome dysbiosis, insulin resistance and obesity

Environment International, Год журнала: 2024, Номер 186, С. 108569 - 108569

Опубликована: Март 20, 2024

Environmental toxicants (ETs) are associated with adverse health outcomes. Here we hypothesized that exposures to ETs linked obesity and insulin resistance partly through a dysbiotic gut microbiota changes in the serum levels of secondary bile acids (BAs). Serum BAs, per- polyfluoroalkyl substances (PFAS) additional twenty-seven were measured by mass spectrometry 264 Danes (121 men 143 women, aged 56.6 ± 7.3 years, BMI 29.7 6.0 kg/m

Язык: Английский

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Metabolic and phenotypic changes induced by PFAS exposure in two human hepatocyte cell models

Environment International, Год журнала: 2024, Номер 190, С. 108820 - 108820

Опубликована: Июнь 17, 2024

PFAS are ubiquitous industrial chemicals with known adverse health effects, particularly on the liver. The liver, being a vital metabolic organ, is susceptible to PFAS-induced dysregulation, leading conditions such as hepatotoxicity and disturbances. In this study, we investigated phenotypic responses of exposure using two hepatocyte models, HepG2 (male cell line) HepaRG (female line), aiming define alterations, disturbances at metabolite pathway levels. mixture composition was selected based epidemiological data, covering broad concentration spectrum observed in diverse human populations. Phenotypic profiling by Cell Painting assay disclosed predominant effects mitochondrial structure function both models well F-actin, Golgi apparatus, plasma membrane-associated measures. We employed comprehensive characterization liquid chromatography combined high-resolution mass spectrometry (LC-HRMS). dose-dependent changes profiles, lipid, steroid, amino acid sugar carbohydrate metabolism cells media, line showing stronger response. cells, most bile acids, acylcarnitines free fatty acids showed downregulation, while medium-chain carnosine were upregulated, media different response especially relation media. Importantly, also nonmonotonic for several features metabolites. On level, associated pathways indicating oxidative stress inflammatory responses. Taken together, our findings disruptions hepatocytes shed light potential mechanisms contributing broader comprehension PFAS-related risks.

Язык: Английский

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Impact of perfluoroalkyl substances (PFAS) and PFAS mixtures on lipid metabolism in differentiated HepaRG cells as a model for human hepatocytes

Archives of Toxicology, Год журнала: 2023, Номер 98(2), С. 507 - 524

Опубликована: Дек. 20, 2023

Abstract Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants with various adverse health effects in humans including disruption of lipid metabolism. Aim the present study was to elucidate molecular mechanisms PFAS-mediated on metabolism human cells. Here, we examined impact a number PFAS (PFOS, PFOA, PFNA, PFDA, PFHxA, PFBA, PFHxS, PFBS, HFPO-DA, PMPP) some exposure-relevant mixtures being composed PFOS, PFNA PFHxS HepaRG cells, an vitro model for hepatocytes. At near cytotoxic concentrations, selected induced triglyceride accumulation cells consistently affected expression marker genes steatosis, as well PPARα target related cholesterol metabolism, pointing common disrupting cellular homeostasis. activation by transactivation assay HEK293T synergistic were observed at sum concentrations higher than 25 µM, whereas additivity lower µM. Of note, any effect assays occurred that least four five magnitudes above real-life internal exposure levels general population.

Язык: Английский

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Effects of perfluorooctanoic acid (PFOA) on gene expression profiles via nuclear receptors in HepaRG cells: Comparative study with in vitro transactivation assays

Toxicology, Год журнала: 2023, Номер 494, С. 153577 - 153577

Опубликована: Июнь 10, 2023

Язык: Английский

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Risk-based prioritization of PFAS using phenotypic and transcriptomic data from human induced pluripotent stem cell-derived hepatocytes and cardiomyocytes

ALTEX, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

Per- and polyfluoroalkyl substances (PFAS) are chemicals with important applications; they persistent in the environment may pose human health hazards. Regulatory agencies considering restrictions bans of PFAS; however, little data exists for informed decisions. Several prioritization strategies were proposed evaluation potential hazards PFAS. Structure-based grouping could expedite selection PFAS testing; still, hypothesis that structure-effect relationships exist requires confirmation. We tested 26 structurally diverse from 8 groups using human-induced pluripotent stem cell-derived hepatocytes cardiomyocytes, concentration-response effects on cell function gene expression. Few phenotypic observed hepatocytes, but negative chronotropy was Substance- type-dependent transcriptomic changes more prominent lacked substantial group-specific effects. In we found up-regulation stress-related extracellular matrix organization pathways, down-regulation fat metabolism. contractility-related pathways most affected. derived points departure compared them to predicted exposures. The conservative estimates bioactivity exposure used derive bioactivity-to-exposure ratio (BER) each PFAS, (23 26) had BER>1. Overall, these suggests structure-based not be sufficient predict their biological Testing individual needed scientific-based decision-making. Our strategy two types effects, combined dose-response analysis calculation BER, prioritization. Plain language summaryPer- man-made many products. However, have been safety, concerns harmful and/or environment. This study aimed use cell-based models investigate if some exhibit hazardous properties similarities among observed. liver cells, a decrease beating frequency heart cells Gene expression substance- type-dependent. did find convincing this testing necessary future inform showed test types, heart, without need animals.

Язык: Английский

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DNA adductomics aided rapid screening of genotoxic impurities using nucleosides and 3D bioprinted human liver organoids

Talanta, Год журнала: 2024, Номер 273, С. 125902 - 125902

Опубликована: Март 15, 2024

Язык: Английский

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Comparative steroidogenic effects of hexafluoropropylene oxide trimer acid (HFPO-TA) and perfluorooctanoic acid (PFOA): Regulation of histone modifications

Environmental Pollution, Год журнала: 2024, Номер 350, С. 124030 - 124030

Опубликована: Апрель 23, 2024

Язык: Английский

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Exposure to PFAS chemicals induces sex-dependent alterations in key rate-limiting steps of lipid metabolism in liver steatosis

Frontiers in Toxicology, Год журнала: 2024, Номер 6

Опубликована: Июнь 5, 2024

Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due their association multiple diseases organ injuries. Per- polyfluoro alkyl substances (PFAS) polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that associated steatosis liver. Although PFAS PAH classified as molecular mechanisms toxicity remain be explored detail. In this study, we aimed identify by which an acute exposure can induce lipid accumulation whether responses depend on chemical class, dose, sex. To end, analyzed beginning binding initiating event (MIE) consequent transcriptomic alterations. We collated MIEs using predictions from our previously developed ToxProfiler tool published adverse outcome pathways. Most transcription factors, collected target genes mining TRRUST database. analyze effects mechanisms, performed computational MIE-target gene analysis high-throughput measurements liver tissue male female rats exposed either or PAH. The results showed peroxisome proliferator-activated receptor (PPAR)-α targets most dysregulated, being upregulated. Furthermore, disrupted several metabolism genes, including upregulation fatty acid oxidation ( Acadm , Acox1 Cpt2 Cyp4a1 - 3 ) downregulation transport Apoa1 Apoa5 Pltp ). also identified sex-specific behavior. Notably, rate-limiting gluconeogenesis Pck1 bile synthesis Cyp7a1 were specifically downregulated compared rats, while Scd PFAS-specific upregulation. suggest PPAR signaling pathway plays major role PFAS-induced rats. Together, these show induces multi-factorial mechanism involving could lead activation steatosis.

Язык: Английский

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PFAS: The Journey from Wonder Chemicals to Environmental Nightmares and the Search for Solutions

Applied Sciences, Год журнала: 2024, Номер 14(19), С. 8611 - 8611

Опубликована: Сен. 24, 2024

Per- and polyfluoroalkyl substances (PFAS) are diverse synthetic chemicals manufactured over seven decades. It is an aliphatic molecule with a basic hydrophobic structure of carbon fluorine linked to hydrophilic end group. Due their physicochemical properties associated the unique structure, PFAS has been used in wide variety applications including aqueous film-forming foams (AFFF), paper, carpets, non-stick cookware, etc. as they make products resistant water, heat, stains. These molecules have drawn great attention recently for properties, high stability low degradability, so-called “Forever Chemicals”. strongest carbon-fluorine bond which makes them persistent environment. Hence it contaminates natural resources endangers public health. This review discusses discovery, development, evolution from wonder chemical era nightmare era, exposure its impacts on human health environment, current remediation techniques, future trends related products. The primary objective this identify knowledge gaps contamination, methods, possible alternatives.

Язык: Английский

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Effects of per- and polyfluoroalkyl substances on the liver: Human-relevant mechanisms of toxicity

The Science of The Total Environment, Год журнала: 2024, Номер 954, С. 176717 - 176717

Опубликована: Окт. 9, 2024

Язык: Английский

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