Metabolic and phenotypic changes induced by PFAS exposure in two human hepatocyte cell models DOI Creative Commons
Andi Alijagić,

Lisanna Sinisalu,

Daniel Duberg

и другие.

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

Exposure to per- and Polyfluoroalkyl Substances and Markers of Liver Injury: A Systematic Review and Meta-Analysis DOI Creative Commons
E. Jane Costello, Sarah Rock,

Nikos Stratakis

и другие.

Environmental Health Perspectives, Год журнала: 2022, Номер 130(4)

Опубликована: Апрель 1, 2022

Background: Experimental evidence indicates that exposure to certain pollutants is associated with liver damage. Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals widely used in industry consumer products bioaccumulate food webs human tissues, such as the liver. Objective: The objective of this study was conduct a systematic review literature meta-analysis evaluating PFAS injury from rodent epidemiological studies. Methods: PubMed Embase were searched for all studies earliest available indexing year through 1 December 2021 using keywords corresponding injury. For data synthesis, results limited humans rodents assessing following indicators injury: serum alanine aminotransferase (ALT), nonalcoholic fatty disease, steatohepatitis, or steatosis. studies, at least three observational per weighted z-score determine direction significance associations. synthesized qualitatively summarize effect. Results: Our search yielded 85 24 primarily people United States. Studies focused on legacy PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic (PFOS), perfluorononanoic (PFNA), perfluorohexanesulfonic acid. Meta-analyses revealed higher ALT levels PFOA (z-score= 6.20, p<0.001), PFOS 3.55, PFNA 2.27, p=0.023). also aspartate gamma-glutamyl transferase humans. In rodents, exposures consistently resulted Conclusion: There consistent hepatotoxicity supported by associations markers function This identifies need additional research next-generation PFAS, mixtures, early life exposures. https://doi.org/10.1289/EHP10092

Язык: Английский

Процитировано

242
The contribution of the exposome to the burden of cardiovascular disease DOI Creative Commons

Thomas Münzel,

Mette Sørensen, Omar Hahad

и другие.

Nature Reviews Cardiology, Год журнала: 2023, Номер 20(10), С. 651 - 669

Опубликована: Май 10, 2023

Large epidemiological and health impact assessment studies at the global scale, such as Global Burden of Disease project, indicate that chronic non-communicable diseases, atherosclerosis diabetes mellitus, caused almost two-thirds annual deaths in 2020. By 2030, 77% all are expected to be by diseases. Although this increase is mainly due ageing general population Western societies, other reasons include increasing effects soil, water, air noise pollution on health, together with environmental risk factors climate change, unhealthy city designs (including lack green spaces), lifestyle habits psychosocial stress. The exposome concept was established 2005 a new strategy study effect environment health. describes harmful biochemical metabolic changes occur our body owing totality different exposures throughout life course, which ultimately lead adverse premature deaths. In Review, we describe focus physical chemical their burden cardiovascular disease. We discuss selected highlight relevance for future research well preventive medicine. also challenges limitations studies. Münzel colleagues Additionally, they

Язык: Английский

Процитировано

84
Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort DOI
Jesse A. Goodrich, Douglas I. Walker, Xiangping Lin

и другие.

JHEP Reports, Год журнала: 2022, Номер 4(10), С. 100550 - 100550

Опубликована: Авг. 8, 2022

Язык: Английский

Процитировано

78
The exposome and liver disease - how environmental factors affect liver health DOI Creative Commons
Robert Barouki,

Michel Samson,

Étienne Blanc

и другие.

Journal of Hepatology, Год журнала: 2023, Номер 79(2), С. 492 - 505

Опубликована: Март 7, 2023

Since the initial development of exposome concept, much effort has been devoted to characterisation through analytical, epidemiological, and toxicological/mechanistic studies. There is now an urgent need link human diseases include exposomics in environment-linked pathologies together with genomics other omics. Liver are particularly well suited for such studies since major functions liver detection, detoxification, elimination xenobiotics, as inflammatory responses. It known that several associated i) addictive behaviours alcohol consumption, smoking, a certain extent dietary imbalance obesity, ii) viral parasitic infections, iii) exposure toxins occupational chemicals. Recent indicate environmental exposures also significantly diseases, these air pollution (particulate matter volatile chemicals), contaminants polyaromatic hydrocarbons, bisphenol A per-and poly-fluorinated substances, physical stressors radiation. Furthermore, microbial metabolites "gut-liver" axis play role diseases. Exposomics poised field pathology. Methodological advances exposomics-metabolomics framework, determination risk factors' genomic epigenomic signatures, cross-species biological pathway analysis should further delineate impact on liver, opening way improved prevention, identification new biomarkers effects, additional therapeutic targets.

Язык: Английский

Процитировано

72
PPARα/ACOX1 as a novel target for hepatic lipid metabolism disorders induced by per- and polyfluoroalkyl substances: An integrated approach DOI Creative Commons
Yang Wang, Xi Ling, Shijun He

и другие.

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

Процитировано

72
Association of per- and polyfluoroalkyl substance exposure with fatty liver disease risk in US adults DOI Creative Commons
Xinyuan Zhang, Longgang Zhao, Alan Ducatman

и другие.

JHEP Reports, Год журнала: 2023, Номер 5(5), С. 100694 - 100694

Опубликована: Фев. 3, 2023

Per- and polyfluoroalkyl substances (PFAS) are widespread pollutants with demonstrated hepatotoxicity. Few studies have examined the association between PFAS fatty liver disease (FLD) risk in an adult population.

Язык: Английский

Процитировано

62
Metabolic Signatures of Youth Exposure to Mixtures of Per- and Polyfluoroalkyl Substances: A Multi-Cohort Study DOI
Jesse A. Goodrich, Douglas I. Walker,

Jingxuan He

и другие.

Environmental Health Perspectives, Год журнала: 2023, Номер 131(2)

Опубликована: Фев. 1, 2023

Exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous has been associated with an increased risk of several cardiometabolic diseases. However, the metabolic pathways linking PFAS exposure human disease are unclear.

Язык: Английский

Процитировано

48
Reproductive toxicity of PFOA, PFOS and their substitutes: A review based on epidemiological and toxicological evidence DOI

Wenshan Shi,

Zengli Zhang, Mei Li

и другие.

Environmental Research, Год журнала: 2024, Номер 250, С. 118485 - 118485

Опубликована: Фев. 17, 2024

Язык: Английский

Процитировано

38
Pathogenesis of MASLD and MASH – role of insulin resistance and lipotoxicity DOI
Shalini Bansal, Meena B. Bansal

Alimentary Pharmacology & Therapeutics, Год журнала: 2024, Номер 59(S1)

Опубликована: Март 7, 2024

Summary Background Insulin resistance and lipotoxicity are extremely interconnected but fundamental in setting the stage for development of MASLD/MASH. Aim/Methods A comprehensive literature search was performed key themes were synthesised to provide insight into underlying molecular mechanisms insulin liver, muscle, pancreas adipose tissue how organ cross‐talk is driving disease pathogenesis. Results Classical thinking postulates that excess FFA load exceeds storage capacity tissue, which predicated upon both genetic environmental factors. This results compensatory hyperinsulinaemia by pancreatic beta cells overcome target resistance. As adipocyte dysfunction worsens, not only delivered other organs, including skeletal liver a pro‐inflammatory milieu established with increases IL‐6, TNF‐α changes adipokine levels (increased leptin decreased adiponectin). With increased intramuscular lipid accumulation, lipotoxic species decrease signalling, reduce glucose uptake downregulation GLUT4 glycogen synthesis. this additional reduced capacity, hyperglycaemia further exacerbated liver. The has largest oxidise fat adapt these stressors and, therefore, become last line defence utilisation, may be impacted However, when can no longer keep up increasing delivery DNL, accumulate ensuing mitochondrial dysfunction, ER stress, oxidant stress inflammasome activation, all drive hepatocyte injury apoptosis. resulting wound healing response, marked stellate cell drives collagen progressive fibrosis, ultimately, end failure death. vicious cycle complex interplay between resistance, hyperinsulinaemia, multi‐directional among different organs critical drivers Conclusions Targeting tissue‐specific while decreasing (lipotoxicity) through dietary lifestyle remain best upstream interventions.

Язык: Английский

Процитировано

26
An exposome atlas of serum reveals the risk of chronic diseases in the Chinese population DOI Creative Commons
Lei You,

Jing Kou,

Mengdie Wang

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 13, 2024

Although adverse environmental exposures are considered a major cause of chronic diseases, current studies provide limited information on real-world chemical and related risks. For this study, we collected serum samples from 5696 healthy people patients, including those with 12 in China completed biomonitoring 267 chemicals via gas liquid chromatography-tandem mass spectrometry. Seventy-four highly frequently detected were used for exposure characterization risk analysis. The results show that region is the most critical factor influencing human levels, followed by age. Organochlorine pesticides perfluoroalkyl substances associated multiple some them exceed safe ranges. Multi-exposure models reveal significant effects hyperlipidemia, metabolic syndrome hyperuricemia. Overall, study provides comprehensive exposome atlas disease information, which can guide subsequent in-depth cause-and-effect between health.

Язык: Английский

Процитировано

23