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Embryotoxicity and mixture effects of legacy PFAS in a human iPSC-based 3D model
Andreas Frederik Treschow1, Elisa Martiny1, Claudia Torero Gutierrez1
1National Food Institute, Technical University of Denmark, Kgs. Lyngby, 2800, Denmark.
Cell Biology and Toxicology
|January 19, 2026
Summary
Four per- and polyfluoroalkyl substances (PFAS) demonstrated embryotoxicity by impairing cardiomyocyte differentiation. Their combined effects followed concentration addition, indicating shared molecular actions in human development.
Area of Science:
- Environmental Science
- Toxicology
- Developmental Biology
Background:
- Humans face continuous exposure to exogenous chemicals, including persistent per- and polyfluoroalkyl substances (PFAS).
- PFAS are linked to adverse human developmental effects, necessitating robust toxicity testing models.
- Legacy PFAS (PFOS, PFOA, PFNA, PFHxS) are of particular concern due to their persistence and widespread presence.
Purpose of the Study:
- To assess the individual and mixture embryotoxic effects of four legacy PFAS using a 3D human induced pluripotent stem cell (hiPSC) model.
- To determine the bioaccumulation and gene expression changes induced by these PFAS in early human development.
- To evaluate whether mixture effects align with concentration addition principles.
Main Methods:
- Utilized the PluriLum assay, a 3D hiPSC-based model, for embryotoxicity testing of PFOS, PFOA, PFNA, and PFHxS.
- Established individual PFAS potencies and evaluated them in equipotent and real-life concentration mixtures.
- Conducted uptake studies in 3D embryoid bodies and performed RNA sequencing to analyze gene expression changes.
Main Results:
- PFNA exhibited the highest individual embryotoxic potency, followed by PFOS, PFOA, and PFHxS.
- Mixture responses were consistent with concentration additivity across tested concentrations.
- PFOS showed the highest bioaccumulation, while RNA sequencing revealed significant changes in pathways related to cardiac and muscle tissue development, particularly with PFOS exposure.
Conclusions:
- The four tested legacy PFAS induce significant embryotoxicity, primarily by impairing cardiomyocyte differentiation.
- The combined toxicological effects of PFAS mixtures are predictable using the concentration addition principle.
- Shared functional pathways and common molecular sites of action underlie the observed PFAS-induced developmental toxicity.
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