Systemic PFOS and PFOA exposure and disturbed lipid homeostasis in humans: what do we know and what not?

Styliani Fragki*, Hubert Dirven, Tony Fletcher, Bettina Grasl-Kraupp, Kristine Bjerve Gützkow, Ron Hoogenboom, Sander Kersten, Birgitte Lindeman, Jochem Louisse, Ad Peijnenburg, Aldert H. Piersma, Hans M.G. Princen, Maria Uhl, Joost Westerhout, Marco J. Zeilmaker, Mirjam Luijten

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

11 Citations (Scopus)


Associations between per- and polyfluoroalkyl substances (PFASs) and increased blood lipids have been repeatedly observed in humans, but a causal relation has been debated. Rodent studies show reverse effects, i.e. decreased blood cholesterol and triglycerides, occurring however at PFAS serum levels at least 100-fold higher than those in humans. This paper aims to present the main issues regarding the modulation of lipid homeostasis by the two most common PFASs, PFOS and PFOA, with emphasis on the underlying mechanisms relevant for humans. Overall, the apparent contrast between human and animal data may be an artifact of dose, with different molecular pathways coming into play upon exposure to PFASs at very low versus high levels. Altogether, the interpretation of existing rodent data on PFOS/PFOA-induced lipid perturbations with respect to the human situation is complex. From a mechanistic perspective, research on human liver cells shows that PFOS/PFOA activate the PPARα pathway, whereas studies on the involvement of other nuclear receptors, like PXR, are less conclusive. Other data indicate that suppression of the nuclear receptor HNF4α signaling pathway, as well as perturbations of bile acid metabolism and transport might be important cellular events that require further investigation. Future studies with human-relevant test systems would help to obtain more insight into the mechanistic pathways pertinent for humans. These studies shall be designed with a careful consideration of appropriate dosing and toxicokinetics, so as to enable biologically plausible quantitative extrapolations. Such research will increase the understanding of possible perturbed lipid homeostasis related to PFOS/ PFOA exposure and the potential implications for human health.

Original languageEnglish
Pages (from-to)141-164
Number of pages24
JournalCritical Reviews in Toxicology
Issue number2
Publication statusPublished - 2021

Bibliographical note

Funding Information:
This work was supported by the European Union?s Horizon 2020 research and innovation programme under Grant agreement No 733032 HBM4EU ( Additional funding sources are the TNO research program ?Biomedical Health?. This work is conducted within the HBM4EU project. HBM4EU represents a joint effort of 28 countries, the European Environment Agency and the European Commission, co-funded by Horizon 2020. The main aim of the initiative is to coordinate and advance human biomonitoring in Europe. HBM4EU provides evidence of the actual exposure of citizens to chemicals and the possible health effects to support policy making. The project involves collaboration between several Commission services, EU agencies, national representatives, stakeholders and scientists, demonstrating how research funding can build bridges between the research and policy worlds. The authors acknowledge Shalenie den Braver-Sewradj and Wieneke Bil, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands, for their critical reading of the paper and valuable comments. The authors cordially thank the reviewers the Editor selected, whose identity was anonymous, for their thoughtful insight and comments towards the improvement of the manuscript.

Publisher Copyright:
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.


  • HBM4EU
  • LDL
  • PFOA
  • PFOS
  • cholesterol
  • hepatocytes
  • lipid perturbation
  • lipoprotein metabolism
  • serum levels
  • triglycerides


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