A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Metabolic and phenotypic changes induced by PFAS exposure in two human hepatocyte cell models
Tekijät: Alijagic, Andi; Sinisalu, Lisanna; Duberg, Daniel; Kotlyar, Oleksandr; Scherbak, Nikolai; Engwall, Magnus; Orešič, Matej; Hyötyläinen, Tuulia
Kustantaja: Pergamon Press
Julkaisuvuosi: 2024
Journal: Environment International
Tietokannassa oleva lehden nimi: Environment international
Lehden akronyymi: Environ Int
Artikkelin numero: 108820
Vuosikerta: 190
ISSN: 0160-4120
eISSN: 1873-6750
DOI: https://doi.org/10.1016/j.envint.2024.108820
Verkko-osoite: https://doi.org/10.1016/j.envint.2024.108820
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/456967289
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.
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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).
