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

Styliani S. 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 journalArticleAcademicpeer-review

2 Citations (Scopus)

Abstract

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
JournalCritical Reviews in Toxicology
DOIs
Publication statusE-pub ahead of print - 15 Apr 2021

Keywords

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

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