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Integrated Spheroid-to-Population Framework for Evaluating PFHpA-Associated Metabolic Dysfunction and Steatotic Liver
Brittney O Baumert1, Ana C Maretti-Mira2, Douglas I Walker3
1Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
Insights
Exposure to perfluoroheptanoic acid (PFHpA), a type of PFAS chemical, significantly increases the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in obese adolescents. This study reveals key molecular pathways involved in PFHpA-induced liver damage.
Area of Science:
- Environmental Health
- Hepatology
- Toxicology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing, especially in children.
- Per- and polyfluoroalkyl substances (PFAS) are suspected contributors to liver damage, but their role in MASLD is unclear.
- Perfluoroheptanoic acid (PFHpA) is an unregulated, short-chain PFAS congener requiring investigation.
Purpose of the Study:
- To investigate the association between PFHpA exposure and MASLD risk in obese adolescents.
- To elucidate the molecular mechanisms underlying PFHpA-induced MASLD using in vitro models.
- To identify potential therapeutic targets for PFAS-induced liver disease.
Main Methods:
- Analysis of the Teen-LABS cohort (obese adolescents) including liver biopsies and plasma PFHpA levels.
- In vitro studies using 3D human liver spheroids and single-cell transcriptomics to assess PFHpA effects.
- Application of the latent unknown clustering with integrated data (LUCID) model for multiomic analysis.
Main Results:
- Doubling of plasma PFHpA levels was associated with an 80% increase in MASLD risk in adolescents.
- PFHpA exposure dysregulated pathways involved in innate immunity, inflammation, and lipid metabolism in both human and spheroid models.
- A specific proteome profile showed significantly higher odds of MASLD, while a metabolome profile showed lower odds, indicating critical protein dysregulation.
Conclusions:
- PFHpA is a significant risk factor for MASLD development in obese adolescents.
- PFHpA induces liver damage through the disruption of immune, inflammatory, and lipid metabolic pathways.
- Understanding these molecular mechanisms is crucial for developing targeted interventions against PFAS-induced MASLD.
Abstract:
The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), particularly among pediatric populations, requires identification of modifiable risk factors to control disease progression. Per- and polyfluoroalkyl substances (PFAS) have emerged as potential contributors to liver damage; however, their role in the etiology of MASLD remains underexplored. This study aimed to bridge the gap between human epidemiological data and in vitro experimental findings to elucidate the effect of perfluoroheptanoic acid (PFHpA), a short chain, unregulated PFAS congener on MASLD development. Our analysis of the Teen-LABS cohort, a national multi-site study on obese adolescents undergoing bariatric surgery, revealed that doubling of PFHpA plasma levels was associated with an 80% increase in MASLD risk (OR, 1.8; 95% CI: 1.3-2.5) based on liver biospies. To further investigate the underlying mechanisms, we used 3D human liver spheroids and single-cell transcriptomics to assess the effect of PFHpA on hepatic metabolism. Integrative analysis identified dysregulation of common pathways in both human and spheroid models, particularly those involved in innate immunity, inflammation, and lipid metabolism. We applied the latent unknown clustering with integrated data (LUCID) model to assess associations between PFHpA exposure, multiomic signatures, and MASLD risk. Our results identified a proteome profile with significantly higher odds of MASLD (OR = 7.1), whereas a distinct metabolome profile was associated with lower odds (OR = 0.51), highlighting the critical role of protein dysregulation in disease pathogenesis. A translational framework was applied to uncover the molecular mechanisms of PFAS-induced MASLD in a cohort of obese adolescents. Identifying key molecular mechanisms for PFAS-induced MASLD can guide the development of targeted prevention and treatment.
