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dc.contributor.authorSöderström, Sofie Karin
dc.contributor.authorLille-Langøy, Roger
dc.contributor.authorYadetie, Fekadu
dc.contributor.authorRauch, Mateusz
dc.contributor.authorMilinski, Ana
dc.contributor.authorDejaegere, Annick
dc.contributor.authorStote, Roland H.
dc.contributor.authorGoksøyr, Anders
dc.contributor.authorKarlsen, Odd André
dc.date.accessioned2022-08-12T10:36:50Z
dc.date.available2022-08-12T10:36:50Z
dc.date.created2022-04-26T15:31:03Z
dc.date.issued2022
dc.identifier.citationEnvironment International. 2022, 163 .en_US
dc.identifier.issn0160-4120
dc.identifier.urihttps://hdl.handle.net/11250/3011580
dc.description.abstractToxicity mediated by per- and polyfluoroalkyl substances (PFAS), and especially perfluoroalkyl acids (PFAAs), has been linked to activation of peroxisome proliferator-activated receptors (Ppar) in many vertebrates. Here, we present the primary structures, phylogeny, and tissue-specific distributions of the Atlantic cod (Gadus morhua) gmPpara1, gmPpara2, gmPparb, and gmPparg, and demonstrate that the carboxylic acids PFHxA, PFOA, PFNA, as well as the sulfonic acid PFHxS, activate gmPpara1 in vitro, which was also supported by in silico analyses. Intriguingly, a binary mixture of PFOA and the non-activating PFOS produced a higher activation of gmPpara1 compared to PFOA alone, suggesting that PFOS has a potentiating effect on receptor activation. Supporting the experimental data, docking and molecular dynamics simulations of single and double-ligand complexes led to the identification of a putative allosteric binding site, which upon binding of PFOS stabilizes an active conformation of gmPpara1. Notably, binary exposures of gmPpara1, gmPpara2, and gmPparb to model-agonists and PFAAs produced similar potentiating effects. This study provides novel mechanistic insights into how PFAAs may modulate the Ppar signaling pathway by either binding the canonical ligand-binding pocket or by interacting with an allosteric binding site. Thus, individual PFAAs, or mixtures, could potentially modulate the Ppar-signaling pathway in Atlantic cod by interfering with at least one gmPpar subtype.en_US
dc.language.isoengen_US
dc.titleAgonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars)en_US
dc.title.alternativeAgonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars)en_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US
dc.description.versionpublishedVersionen_US
dc.source.pagenumber15en_US
dc.source.volume163en_US
dc.source.journalEnvironment Internationalen_US
dc.identifier.doi10.1016/j.envint.2022.107203
dc.identifier.cristin2019260
dc.relation.projectNorges forskningsråd: 244564en_US
dc.relation.projectNorges forskningsråd: 248840en_US
dc.relation.projectNorges forskningsråd: 323092en_US
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1


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