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dc.contributor.authorFragki, Styliani
dc.contributor.authorDirven, Hubert
dc.contributor.authorFletcher, Tony
dc.contributor.authorGrasl-Kraupp, Bettina
dc.contributor.authorBjerve Gützkow, Kristine
dc.contributor.authorHoogenboom, Ron
dc.contributor.authorKersten, Sander
dc.contributor.authorLindeman, Birgitte
dc.contributor.authorLouisse, Jochem
dc.contributor.authorPeijnenburg, Ad
dc.contributor.authorPiersma, Aldert H
dc.contributor.authorPrincen, Hans M G
dc.contributor.authorUhl, Maria
dc.contributor.authorWesterhout, Joost
dc.contributor.authorZeilmaker, Marco J
dc.contributor.authorLuijten, Mirjam
dc.date.accessioned2021-04-26T13:02:08Z
dc.date.available2021-04-26T13:02:08Z
dc.date.issued2021-04-15
dc.identifier.pmid33853480
dc.identifier.doi10.1080/10408444.2021.1888073
dc.identifier.urihttp://hdl.handle.net/10029/624898
dc.description.abstractAssociations 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.en_US
dc.language.isoenen_US
dc.subjectHBM4EUen_US
dc.subjectLDLen_US
dc.subjectPFOAen_US
dc.subjectPFOSen_US
dc.subjectcholesterolen_US
dc.subjecthepatocytesen_US
dc.subjectlipid perturbationen_US
dc.subjectlipoprotein metabolismen_US
dc.subjectserum levelsen_US
dc.subjecttriglyceridesen_US
dc.titleSystemic PFOS and PFOA exposure and disturbed lipid homeostasis in humans: what do we know and what not?en_US
dc.typeArticleen_US
dc.identifier.eissn1547-6898
dc.identifier.journalCrit Rev Toxicol 2021; 51(2):141-64en_US
dc.source.journaltitleCritical reviews in toxicology
dc.source.beginpage1
dc.source.endpage24
dc.source.countryEngland


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