Associations between perfluoroalkyl substances and the severity of non-alcoholic fatty liver disease

David, Norma; Antignac, Jean-Philippe; Roux, Marine; Marchand, Philippe; Michalak, Sophie; Oberti, Fréderic; Fouchard, Isabelle; Lannes, Adrien; Blanchet, Odile; Cales, Paul; Blanc, Etienne B.; Boursier, Jérôme; Canivet, Clémence M.

doi:10.1016/j.envint.2023.108235

Cited by 11 publications

(2 citation statements)

References 37 publications

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“…In our study, transcriptomic data in iPSC-derived hepatocytes confirmed the disruption of lipoprotein transport as the most prominent molecular event elicited by many of the tested PFAS. This observation aligns well with previous in vivo animal and epidemiological studies that established linkages between PFAS and alterations in serum lipoproteins and liver steatosis (Ho et al, 2022;David et al, 2023;Bijland et al, 2011). Indeed, a number of in vivo (Bijland et al, 2011;Curran et al, 2008;Das et al, 2017;Menger et al, 2020;Wan et al, 2012) and in vitro (Bjork et al, 2011;Hickey et al, 2009;Naile et al, 2012;Reardon et al, 2021;Rowan-Carroll et al, 2021) studies documented the disruptive impact of PFAS on lipid metabolism in the liver.…”

Section: Mechanistic Similarity In the Transcriptomic Effects Of Pfassupporting

confidence: 90%

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

2024

ALTEX

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Per-and polyfluoroalkyl substances (PFAS) are chemicals with important applications; they are persistent in the environment and may pose human health hazards. Regulatory agencies are considering restrictions and bans of PFAS; however, little data exists for informed decisions. Several prioritization strategies were proposed for evaluation of potential hazards of PFAS. Structure-based grouping could expedite the selection of PFAS for testing; still, the hypothesis that structure-effect relationships exist for PFAS requires confirmation. We tested 26 structurally diverse PFAS from 8 groups using human-induced pluripotent stem cell-derived hepatocytes and cardiomyocytes, and tested concentration-response effects on cell function and gene expression. Few phenotypic effects were observed in hepatocytes, but negative chronotropy was observed for 8 of the 26 PFAS. Substance-and cell type-dependent transcriptomic changes were more prominent but lacked substantial group-specific effects. In hepatocytes, we found up-regulation of stress-related and extracellular matrix organization pathways, and down-regulation of fat metabolism. In cardiomyocytes, contractilityrelated pathways were most affected. We derived phenotypic and transcriptomic points of departure and compared them to predicted PFAS exposures. The conservative estimates for bioactivity and exposure were used to derive bioactivityto-exposure ratio (BER) for each PFAS, most (23 of 26) PFAS had BER>1. Overall, these data suggests that structurebased grouping of PFAS may not be sufficient to predict their biological effects. Testing of individual PFAS may be needed for scientific-based decision-making. Our proposed strategy of using two human cell types and considering phenotypic and transcriptomic effects, combined with dose-response analysis and calculation of BER, may be used for PFAS prioritization.

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Section: Mechanistic Similarity In the Transcriptomic Effects Of Pfassupporting

confidence: 90%

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

2024

ALTEX

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“…Although PFHpA has gained attention in recent years, the relatively few studies investigating it may reflect a combination of factors including historical research priorities, technical challenges, and resource limitations. While previous research has established a connection between PFHpA exposure, along with other short and long-chain PFAS, and severity of liver steatosis and fibrosis in MASLD among adults 32 , our study marks the first time that exposure to PFHpA has been associated with MASLD in adolescents. Beyond the association with histological markers of MASLD, our findings indicate that adolescents with obesity exposed to PFHpA also exhibit alterations in plasma levels of proteins and metabolites that signal inflammation and dysfunction in lipid metabolism.…”

Section: Discussionmentioning

confidence: 44%

PFHpA alters lipid metabolism and increases the risk of metabolic dysfunction-associated steatotic liver disease in youth—a translational research framework

Baumert,

Maretti-Mira,

et al. 2024

Preprint

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To address the growing epidemic of liver disease, particularly in pediatric populations, it is crucial to identify modifiable risk factors for the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Per- and polyfluoroalkyl substances (PFAS) are persistent ubiquitous chemicals and have emerged as potential risk factors for liver damage. However, their impact on the etiology and severity of MASLD remains largely unexplored in humans. This study aims to bridge the gap between human and in vitro studies to understand how exposure to perfluoroheptanoic acid (PFHpA), one of the emerging PFAS replacements which accumulates in high concentrations in the liver, contributes to MASLD risk and progression. First, we showed that PFHpA plasma concentrations were significantly associated with increased risk of MASLD in obese adolescents. Further, we examined the impact of PFHpA on hepatic metabolism using 3D human liver spheroids and single-cell transcriptomics to identify major hepatic pathways affected by PFHpA. Next, we integrated thein vivoandin vitromulti-omics datasets with a novel statistical approach which identified signatures of proteins and metabolites associated with MASLD development triggered by PFHpA exposure. In addition to characterizing the contribution of PFHpA to MASLD progression, our study provides a novel strategy to identify individuals at high risk of PFHpA-induced MASLD and develop early intervention strategies. Notably, our analysis revealed that the proteomic signature exhibited a stronger correlation between both PFHpA exposure and MASLD risk compared to the metabolomic signature. While establishing a clear connection between PFHpA exposure and MASLD progression in humans, our study delved into the molecular mechanisms through which PFHpA disrupts liver metabolism. Ourin vitrofindings revealed that PFHpA primarily impacts lipid metabolism, leading to a notable increase of lipid accumulation in human hepatocytes after PFHpA exposure. Among the pathways involved in lipid metabolism in hepatocytes, regulation of lipid metabolism by PPAR-a showed a remarkable activation. Moreover, the translational research framework we developed by integrating human and in vitro data provided us biomarkers to identify individuals at a high risk of MASLD due to PFHpA exposure. Our framework can inform policies on PFAS-induced liver disease and identify potential targets for prevention and treatment strategies.

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Polluants éternels et contamination humaine : état des lieux et enjeux autour des substances per- et polyfluoroalkylées (PFAS)

Gaillard,

Bernal,

Coumoul

et al. 2024

Cahiers de Nutrition et de Diététique

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Associations between perfluoroalkyl substances and the severity of non-alcoholic fatty liver disease

Cited by 11 publications

References 37 publications

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

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

PFHpA alters lipid metabolism and increases the risk of metabolic dysfunction-associated steatotic liver disease in youth—a translational research framework

Polluants éternels et contamination humaine : état des lieux et enjeux autour des substances per- et polyfluoroalkylées (PFAS)

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