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Alijagic, A., Södergren Seilitz, F., Bredberg, A., Hakonen, A., Larsson, M., Selin, E., . . . Engwall, M. (2025). Deciphering the phenotypic, inflammatory, and endocrine disrupting impacts of e-waste plastic-associated chemicals. Environmental Research, 269, Article ID 120929.
Open this publication in new window or tab >>Deciphering the phenotypic, inflammatory, and endocrine disrupting impacts of e-waste plastic-associated chemicals
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2025 (English)In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 269, article id 120929Article in journal (Refereed) Published
Abstract [en]

As the volume of plastic waste from electrical and electronic equipment (WEEE) continues to rise, a significant portion is disposed of in the environment, with only a small fraction being recycled. Both disposal and recycling pose unknown health risks that require immediate attention. Existing knowledge of WEEE plastic toxicity is limited and mostly relies on epidemiological data and association studies, with few insights into the underlying toxicity mechanisms. Therefore, this study aimed to perform comprehensive chemical screening and mechanistic toxicological assessment of WEEE plastic-associated chemicals. Chemical analysis, utilizing suspect screening based on high-resolution mass spectrometry, along with quantitative target chemical analysis, unveiled numerous hazardous compounds including polyaromatic compounds, organophosphate flame retardants, phthalates, benzotriazoles, etc. Toxicity endpoints included perturbation of morphological phenotypes using the Cell Painting approach, inflammatory response, oxidative stress, and endocrine disruption. Results demonstrated that WEEE plastic chemicals altered the phenotypes of the cytoskeleton, endoplasmic reticulum, and mitochondria in a dose-dependent manner. In addition, WEEE chemicals induced inflammatory responses in resting macrophages and altered inflammatory responses in lipopolysaccharide-primed macrophages. Furthermore, WEEE chemicals activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, indicating oxidative stress, and the aryl hydrocarbon receptor (AhR). Endocrine disruption was also observed through the activation of estrogenic receptor-α (ER-α) and the induction of anti-androgenic activity. The findings show that WEEE plastic-associated chemicals exert effects in multiple subcellular sites, via different receptors and mechanisms. Thus, an integrated approach employing both chemical and toxicological methods is essential for comprehensive assessment of the toxicity mechanisms and cumulative chemical burden of WEEE plastic-associated chemicals.

Place, publisher, year, edition, pages
Elsevier, 2025
Keywords
Waste from electrical and electronic equipment (WEEE), Plastic additives, Persistent organic pollutants, Suspect chemical screening, Cell Painting, Oxidative stress
National Category
Environmental Sciences
Identifiers
urn:nbn:se:oru:diva-118822 (URN)10.1016/j.envres.2025.120929 (DOI)001413779000001 ()39862959 (PubMedID)2-s2.0-85215971826 (Scopus ID)
Funder
Knowledge Foundation, 20160019; 20220122; 20230020; 20200017Vinnova, 2021-03968Afa Trygghetsförsäkringsaktiebolag, 230039Swedish National Infrastructure for Computing (SNIC), 2022/5-535; 2022/6-306Swedish Research Council, 2022-06725; 2018-05973
Note

This work was supported by the Swedish Knowledge Foundation [Grants No. 20160019; 20220122; 20230020], Vinnova, the Swedish Agency for Innovation Systems, [Grant No. 2021-03968], and AFA Forsakring [Grant No. 230039]. We acknowledge scientific support from the Exploring Inflammation in Health and Disease (X-HiDE) Consortium, which is a strategic research profile at Örebro University funded by the Knowledge Foundation [Grant No. 20200017]. The data handling was partially enabled by resources provided by the National Academic Infrastructure for Supercomputing in Sweden (NAISS) and the Swedish National Infrastructure for Computing (SNIC) partially funded by the Swedish Research Council [Grant No. 2022-06725 and 2018-05973], projects SNIC 2022/5-535 and SNIC 2022/6-306.

Available from: 2025-01-24 Created: 2025-01-24 Last updated: 2025-02-19Bibliographically approved
Herring, M., Särndahl, E., Kotlyar, O., Scherbak, N., Engwall, M., Karlsson, R., . . . Alijagic, A. (2025). Exploring NLRP3-related phenotypic fingerprints in human macrophages using Cell Painting assay. iScience, Article ID 111961.
Open this publication in new window or tab >>Exploring NLRP3-related phenotypic fingerprints in human macrophages using Cell Painting assay
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2025 (English)In: iScience, E-ISSN 2589-0042, article id 111961Article in journal (Refereed) Epub ahead of print
Abstract [en]

Existing research has proven difficult to understand the interplay between upstream signalinge vents during NLRP3 inflammasome activation. Additionally, events downstream of inflammasome complex formation such as cytokine release and pyroptosis can exhibit variation, further complicating matters. Cell Painting has emerged as a prominent tool for unbiased evaluation of the effect of perturbations on cell morphological phenotypes. Using this technique, phenotypic fingerprints can be generated that reveal connections between phenotypes and possible modes of action. To the best of our knowledge, this was the first study that utilized Cell Painting on human THP-1 macrophages to generate phenotypic fingerprints in response to different endogenous and exogenous NLRP3 inflammasome triggers, and to identify phenotypic features specific to NLRP3 inflammasome complex formation. Our results demonstrated that not only can Cell Painting generate morphological fingerprints that are NLRP3 trigger-specific, but it can identify cellular fingerprints associated with NLRP3 inflammasome activation.

Place, publisher, year, edition, pages
Cell Press, 2025
Keywords
inflammasome, high-throughput imaging, cytokine profiling, THP-1 cells, morphological features
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:oru:diva-119201 (URN)10.1016/j.isci.2025.111961 (DOI)
Funder
Swedish Research Council
Available from: 2025-02-10 Created: 2025-02-10 Last updated: 2025-02-11Bibliographically approved
Alijagic, A., Russo, R., Scuderi, V., Ussia, M., Scalese, S., Taverna, S., . . . Pinsino, A. (2025). Sea urchin immune cells and associated microbiota co-exposed to iron oxide nanoparticles activate cellular and molecular reprogramming that promotes physiological adaptation. Journal of Hazardous Materials, 485, Article ID 136808.
Open this publication in new window or tab >>Sea urchin immune cells and associated microbiota co-exposed to iron oxide nanoparticles activate cellular and molecular reprogramming that promotes physiological adaptation
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2025 (English)In: Journal of Hazardous Materials, ISSN 0304-3894, E-ISSN 1873-3336, Vol. 485, article id 136808Article in journal (Refereed) Published
Abstract [en]

The innate immune system is the first player involved in the recognition/interaction with nanomaterials. Still, it is not the only system involved. The co-evolution of the microbiota with the innate immune system built an interdependence regulating immune homeostasis that is poorly studied. Herein, the simultaneous interaction of iron-oxide nanoparticles (Fe-oxide NPs), immune cells, and the microbiota associated with the blood of the sea urchin Paracentrotus lividus was explored by using a microbiota/immune cell model in vitro-ex vivo and a battery of complementary tools, including Raman spectroscopy, 16S Next-Generation Sequencing, high-content imaging, NanoString nCounter. Our findings highlight the P. lividus immune cells and microbiota dynamics in response to Fe-oxide NPs, including i) morphological rearrangement and immune cell health status maintenance (intracellular trafficking increasing, no phenotypic alterations or caspase 3/7 activation), ii) transcriptomic reprogramming in immune cells (Smad6, Lmo2, Univin, suPaxB, Frizzled-7, Fgfr2, Gp96 upregulation), iii) immune signaling unchanged (e.g., P-p38 MAPK, P-ERK, TLR4, IL-6 protein level unchanged), iv) enrichment in extracellular vesicle released in the co-culture medium, and v) a shift in the composition of microbial groups mainly in favor of Gram-positive bacteria (e.g., Firmicutes, Actinobacteria),. Our findings suggest that Fe-oxide NPs induce a multilevel immune cell-microbiota response restoring homeostasis.

Place, publisher, year, edition, pages
Elsevier, 2025
Keywords
Nano-immune research, Innate immunity and bacterial community, Immune cell/bacteria co-culture, Advanced cellular system, High-throughput approach
National Category
Biological Sciences
Identifiers
urn:nbn:se:oru:diva-117736 (URN)10.1016/j.jhazmat.2024.136808 (DOI)001383331500001 ()39662349 (PubMedID)2-s2.0-85211364059 (Scopus ID)
Note

This work has been partially financed by the European Union (Next-generation EU), PNRR, M.4-C2–1.1 through the MUR-PNRR PRIN 2022 project “Betting on inter-species communication through extracellular vesicles of Paracentrotus lividus and Hermetia illucens for potential therapeutic use—SURPRISE (GA P2022LASKT: ST; AP, PI), and by the European Union (Next Generation EU) through the MUR-PNRR project “Sicilian MicronanoTech Research and Innovation Center-—SAMOTHRACE” (GA ECS00000022: VS; MU; SC, PI WP health; AP, PI IFT subunit).

Available from: 2024-12-11 Created: 2024-12-11 Last updated: 2025-01-20Bibliographically approved
Suljević, D., Fočak, M. & Alijagic, A. (2024). Assessing chromium toxicity across aquatic and terrestrial environments: a cross-species review. Drug and chemical toxicology (New York, N.Y. 1978), 47(6), 1312-1324
Open this publication in new window or tab >>Assessing chromium toxicity across aquatic and terrestrial environments: a cross-species review
2024 (English)In: Drug and chemical toxicology (New York, N.Y. 1978), ISSN 0148-0545, E-ISSN 1525-6014, Vol. 47, no 6, p. 1312-1324Article, review/survey (Refereed) Published
Abstract [en]

Chromium (cr) toxicity, even at low concentrations, poses a significant health threat to various environmental species. Cr is found in the environment in two oxidation states that differ in their bioavailability and toxicity. While cr(iii) is essential for glucose metabolism, the oxyanion chromate cr(vi) is mostly of anthropogenic origin, toxic, and carcinogenic. The sources of cr in the environment are multiple, including geochemical processes, disposal of industrial waste, and industrial wastewater. Cr pollution may consequently impact the health of numerous plant and animal species. Despite that, the number of published studies on cr toxicity across environmental species remained mainly unchanged over the past two decades. The presence of cr in the environment affects several plant physiological processes, including germination or photosynthesis, and consequently impacts growth, and lowers agricultural production and quality. Recent research has also reported the toxic effects of cr in different aquatic and terrestrial organisms. whereas some species showed sensitivity, others exhibited tolerance. Hence, this review discusses the understanding of the ecotoxicological effect of cr on different plant and animal groups and serves as a concise source of consolidated information and a valuable reference for researchers and policymakers in an understanding of cr toxicity. Future directions should focus on expanding research efforts to understand the mechanisms underlying species-specific responses to cr pollution.

Place, publisher, year, edition, pages
Taylor & Francis, 2024
Keywords
Hazardous materials, toxicity, aquatic organisms, terrestrial organisms, invertebrates, fish
National Category
Other Earth Sciences
Identifiers
urn:nbn:se:oru:diva-113661 (URN)10.1080/01480545.2024.2350660 (DOI)001218347800001 ()38727006 (PubMedID)2-s2.0-85192703673 (Scopus ID)
Available from: 2024-05-17 Created: 2024-05-17 Last updated: 2025-02-07Bibliographically approved
Alijagic, A. & Särndahl, E. (2024). Can evolutionary immunology decode micro and nanoplastic challenges?. Frontiers in Immunology, 15, Article ID 1404360.
Open this publication in new window or tab >>Can evolutionary immunology decode micro and nanoplastic challenges?
2024 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 15, article id 1404360Article, review/survey (Refereed) Published
Place, publisher, year, edition, pages
Frontiers Media S.A., 2024
Keywords
innate immunity, particles, environmental species, humans, pattern recognition receptors (PRRs)
National Category
Other Earth Sciences
Identifiers
urn:nbn:se:oru:diva-113663 (URN)10.3389/fimmu.2024.1404360 (DOI)001235827500001 ()38827731 (PubMedID)2-s2.0-85195010400 (Scopus ID)
Funder
Knowledge Foundation, 20220122; 20230020; 20200017
Note

This work was supported by the Swedish Knowledge Foundation (Grants No. 20220122; 20230020). Scientific support from the Exploring Inflammation in Health and Disease (X-HiDE) Consortium, which is a strategic research profile at Örebro University funded by the Knowledge Foundation (Grant No. 20200017) is also acknowledged.

Available from: 2024-05-17 Created: 2024-05-17 Last updated: 2025-02-07Bibliographically approved
Alijagic, A., Wang, X., Vallabani, N. V., Melin, P., Särndahl, E., Karlsson, H. L. & Odnevall, I. (2024). Characteristics and health risks of the inhalable fraction of metal additive manufacturing powders. Nano Select, 5(4), Article ID 2300188.
Open this publication in new window or tab >>Characteristics and health risks of the inhalable fraction of metal additive manufacturing powders
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2024 (English)In: Nano Select, E-ISSN 2688-4011, Vol. 5, no 4, article id 2300188Article in journal (Refereed) Published
Abstract [en]

Metal additive manufacturing (AM) is gaining traction but raises worker health concerns due to micron-sized powders, including fine inhalable particles. This study explored particle and surface characteristics, electrochemical properties, metal release in artificial lysosomal fluid (ALF), and potential toxicity of virgin and sieved virgin Fe-based powders, stainless steel (316L), Fe, and two tooling steels. Virgin particles ranged in size from 1 to 100μm, while sieved particles were within the respirable size range (<5–10μm). Surface oxide composition differed from bulk composition. The Fe powder showed low corrosion resistance and high metal release due to a lack of protective surface oxide. Sieved particles of 316L, Fe, and one tooling steel released more metals into ALF than virgin particles, with the opposite was observed for the other tooling steel. Sieved particles had no notable impact on cell viability or micronuclei formation in human bronchial epithelial cells. Inflammatory response in human macrophages was generally low, except for the Fe powder and one tooling steel, which induced increased interleukin-8 (IL-8/CXCL-8) and monocyte chemoattractant protein-1 (MCP-1/CCL-2) secretion. This study underscores distinctions between virgin and sieved Fe-based powders and suggests relatively low acute toxicity.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2024
Keywords
AM manufacturing, exposure, genotoxicity, inflammation, inhalable metallic powders, particle dissolution
National Category
Other Earth Sciences Pharmacology and Toxicology
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-112113 (URN)10.1002/nano.202300188 (DOI)001186503300001 ()
Funder
Vinnova, 2021‐03968Knowledge Foundation, 20190107Knowledge Foundation, 20200017Knowledge Foundation, 20220122
Available from: 2024-03-05 Created: 2024-03-05 Last updated: 2025-02-01Bibliographically approved
Le Du-Carrée, J., Palacios, C. K., Rotander, A., Larsson, M., Alijagic, A., Kotlyar, O., . . . Almeda, R. (2024). Cocktail effects of tire wear particles leachates on diverse biological models: A multilevel analysis. Journal of Hazardous Materials, 471, Article ID 134401.
Open this publication in new window or tab >>Cocktail effects of tire wear particles leachates on diverse biological models: A multilevel analysis
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2024 (English)In: Journal of Hazardous Materials, ISSN 0304-3894, E-ISSN 1873-3336, Vol. 471, article id 134401Article in journal (Refereed) Published
Abstract [en]

Tire wear particles (TWP) stand out as a major contributor to microplastic pollution, yet their environmental impact remains inadequately understood. This study delves into the cocktail effects of TWP leachates, employing molecular, cellular, and organismal assessments on diverse biological models. Extracted in artificial seawater and analyzed for metals and organic compounds, TWP leachates revealed the presence of polyaromatic hydrocarbons and 4-tert-octylphenol. Exposure to TWP leachates (1.5 to 1000 mg peq L-1) inhibited algae growth and induced zebrafish embryotoxicity, pigment alterations, and behavioral changes. Cell painting uncovered pro-apoptotic changes, while mechanism-specific gene-reporter assays highlighted endocrine-disrupting potential, particularly antiandrogenic effects. Although heavy metals like zinc have been suggested as major players in TWP leachate toxicity, this study emphasizes water-leachable organic compounds as the primary causative agents of observed acute toxicity. The findings underscore the need to reduce TWP pollution in aquatic systems and enhance regulations governing highly toxic tire additives.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Cell painting, Endocrine disruption, In Vivo toxicity testing, Leachate cocktail toxicity, Tire wear particles
National Category
Environmental Sciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:oru:diva-113412 (URN)10.1016/j.jhazmat.2024.134401 (DOI)001236741400001 ()38678714 (PubMedID)2-s2.0-85191351412 (Scopus ID)
Note

This study was funded by the Spanish Ministry of Science and Innovation and the National Agency of Research through the MICROPLEACH project (Agencia Estatal de Investigación, PID2020–120479 GA-I00/AEI/10.13039/501100011033) to RA. It was also supported by a “Juan de la Cierva” grant from the Spanish Ministry of Science and Innovation to JLD and a ”Ramón y Cajal” grant from the Spanish Ministry of Science (RYC2018–025770-I) to RA.

Available from: 2024-04-29 Created: 2024-04-29 Last updated: 2024-06-13Bibliographically approved
Alijagic, A., Södergren Seilitz, F., Bredberg, A., Hakonen, A., Larsson, M., Sjöberg, V., . . . Engwall, M. (2024). Comprehensive chemical and toxicological screening of e-waste plastic chemicals. Paper presented at 58th Congress of the European Societies of Toxicology (EUROTOX 2024), Copenhagen, Denmark, September 8-11, 2024. Toxicology Letters, 399(Suppl. 2), S66-S66, Article ID OS03-08.
Open this publication in new window or tab >>Comprehensive chemical and toxicological screening of e-waste plastic chemicals
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2024 (English)In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 399, no Suppl. 2, p. S66-S66, article id OS03-08Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

This study presents a comprehensive chemical and toxicological screening of chemicals extracted from WEEE (waste from electrical and electronic equipment) plastics. Chemical identification was conducted through suspect and target screening methods, revealing a diverse array of hazardous compounds including polycyclic aromatic compounds (PACs), organophosphate flame retardants (OPFRs), phthalates, benzotriazoles, and others. Toxicological endpoints included cell morphological phenotypes, inflammatory response, aryl hydrocarbon receptor (AhR) activation, activation of estrogenic receptor, and anti-androgenic activity. Results demonstrated that WEEE plastic chemicals significantly altered cell morphological phenotypes, particularly affecting the cytoskeleton, endoplasmic reticulum (ER), and mitochondrial measures. Moreover, WEEE chemicals induced inflammatory responses in resting human macrophages and altered ongoing inflammatory responses in lipopolysaccharide (LPS)-primed macrophages. Furthermore, WEEE chemicals exhibited potent AhR agonistic activity, activated estrogen receptor-α (ERα), and inhibited androgen receptor (AR) activation. The findings suggest that WEEE plastic chemicals exert their effects through multiple modes of action, targeting various subcellular sites. Thus, a combined approach utilizing non-target and target screening tools is essential for comprehensively assessing the toxic effects and health hazards associated with WEEE plastic chemicals.

Place, publisher, year, edition, pages
Elsevier, 2024
National Category
Environmental Sciences
Research subject
Enviromental Science
Identifiers
urn:nbn:se:oru:diva-116256 (URN)10.1016/j.toxlet.2024.07.181 (DOI)001325675700156 ()
Conference
58th Congress of the European Societies of Toxicology (EUROTOX 2024), Copenhagen, Denmark, September 8-11, 2024
Available from: 2024-09-24 Created: 2024-09-24 Last updated: 2024-11-11Bibliographically approved
Alijagic, A., Kotlyar, O., Larsson, M., Salihovic, S., Hedbrant, A., Eriksson, U., . . . Särndahl, E. (2024). Immunotoxic, genotoxic, and endocrine disrupting impacts of polyamide microplastic particles and chemicals. Environment International, 183, Article ID 108412.
Open this publication in new window or tab >>Immunotoxic, genotoxic, and endocrine disrupting impacts of polyamide microplastic particles and chemicals
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2024 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 183, article id 108412Article in journal (Refereed) Published
Abstract [en]

Due to their exceptional properties and cost effectiveness, polyamides or nylons have emerged as widely used materials, revolutionizing diverse industries, including industrial 3D printing or additive manufacturing (AM). Powder-based AM technologies employ tonnes of polyamide microplastics to produce complex components every year. However, the lack of comprehensive toxicity assessment of particulate polyamides and polyamide-associated chemicals, especially in the light of the global microplastics crisis, calls for urgent action. This study investigated the physicochemical properties of polyamide-12 microplastics used in AM, and assessed a number of toxicity endpoints focusing on inflammation, immunometabolism, genotoxicity, aryl hydrocarbon receptor (AhR) activation, endocrine disruption, and cell morphology. Specifically, microplastics examination by means of field emission scanning electron microscopy revealed that work flow reuse of material created a fraction of smaller particles with an average size of 1-5 µm, a size range readily available for uptake by human cells. Moreover, chemical analysis by means of gas chromatography high-resolution mass spectrometry detected several polyamide-associated chemicals including starting material, plasticizer, thermal stabilizer/antioxidant, and migrating slip additive. Even if polyamide particles and chemicals did not induce an acute inflammatory response, repeated and prolonged exposure of human primary macrophages disclosed a steady increase in the levels of proinflammatory chemokine Interleukin-8 (IL-8/CXCL-8). Moreover, targeted metabolomics disclosed that polyamide particles modulated the kynurenine pathway and some of its key metabolites. The p53-responsive luciferase reporter gene assay showed that particles per se were able to activate p53, being indicative of a genotoxic stress. Polyamide-associated chemicals triggered moderate activation of AhR and elicited anti-androgenic activity. Finally, a high-throughput and non-targeted morphological profiling by Cell Painting assay outlined major sites of bioactivity of polyamide-associated chemicals and indicated putative mechanisms of toxicity in the cells. These findings reveal that the increasing use of polyamide microplastics may pose a potential health risk for the exposed individuals, and it merits more attention.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Additive manufacturing, GC-HRMS, High-throughput morphological profiling, Metabolomics, Nylon, Plastic additives
National Category
Environmental Sciences
Identifiers
urn:nbn:se:oru:diva-110605 (URN)10.1016/j.envint.2023.108412 (DOI)001153657900001 ()38183898 (PubMedID)2-s2.0-85183378556 (Scopus ID)
Funder
Knowledge Foundation, 20160019; 20190107; 20220122; 20200017Swedish Research Council, 2022-06725; 2018-05973
Available from: 2024-01-09 Created: 2024-01-09 Last updated: 2024-03-05Bibliographically approved
Alijagic, A., Sinisalu, L., Duberg, D., Kotlyar, O., Scherbak, N., Engwall, M., . . . Hyötyläinen, T. (2024). Metabolic and phenotypic changes induced by PFAS exposure in two human hepatocyte cell models. Environment International, 190, Article ID 108820.
Open this publication in new window or tab >>Metabolic and phenotypic changes induced by PFAS exposure in two human hepatocyte cell models
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2024 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 190, article id 108820Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Bile acids, Cell Painting, HepG2, HepaRG, Lipidomics, Metabolomics, PFAS
National Category
Cell Biology
Identifiers
urn:nbn:se:oru:diva-114390 (URN)10.1016/j.envint.2024.108820 (DOI)001333743400001 ()38906088 (PubMedID)2-s2.0-85196525679 (Scopus ID)
Funder
Swedish Research Council, 2020-03674; 2016-05176Swedish Research Council Formas, 2019-00869Novo Nordisk Foundation, NNF20OC0063971; NNF21OC0070309EU, Horizon Europe, 101136259Knowledge Foundation, 20160019; 20190107; 20220122
Note

This study was supported by the Swedish Research Council (grants no. and 2020-03674 and 2016-05176 to T.H and M.O) , Formas (grant no. 2019-00869 to T.H and M.O) , Novo Nordisk Foundation (Grants no. NNF20OC0063971 and NNF21OC0070309 to T.H. and M.O.) , and by the "Investigation of endocrine-disrupting chemicals as contributors to progression of metabolic dysfunction-associated steatotic liver disease" (EDC-MASLD) consortium funded by the Horizon Europe Program of the European Union under Grant Agreement 101136259 (to MO and TH) . The study was also partially supported by grants from the Swedish Knowledge Foundation (Grants. no. 20160019; 20190107; 20220122) .

Available from: 2024-06-25 Created: 2024-06-25 Last updated: 2024-10-24Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-2403-7989

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