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dc.contributor.authorBerntsen, Hanne Friis
dc.contributor.authorMoldes-Anaya, Angel
dc.contributor.authorBjørklund, Cesilie Granum
dc.contributor.authorRagazzi, Lorenzo
dc.contributor.authorHaug, Trude M
dc.contributor.authorStrandabø, Rønnaug
dc.contributor.authorVerhaegen, Steven
dc.contributor.authorPaulsen, Ragnhild Elisabeth
dc.contributor.authorRopstad, Erik
dc.contributor.authorTasker, Andrew
dc.date.accessioned2020-10-27T15:57:19Z
dc.date.available2020-10-27T15:57:19Z
dc.date.issued2020-10-04
dc.description.abstractPerfluoroalkyl acids (PFAAs) are persistent man-made chemicals, ubiquitous in nature and present in human samples. Although restrictions are being introduced, they are still used in industrial processes as well as in consumer products. PFAAs cross the blood-brain-barrier and have been observed to induce adverse neurobehavioural effects in humans and animals as well as adverse effects in neuronal in vitro studies. The sulfonated PFAA perfluorooctane sulfonic acid (PFOS), has been shown to induce excitotoxicity via the N-methyl-D-aspartate receptor (NMDA-R) in cultures of rat cerebellar granule neurons (CGNs). In the present study the aim was to further characterise PFOS-induced toxicity (1–60 μM) in rat CGNs, by examining interactions between PFOS and elements of glutamatergic signalling and excitotoxicity. Effects of the carboxylated PFAA, perfluorooctanoic acid (PFOA, 300–500 μM) on the same endpoints were also examined. During experiments in immature cultures at days in vitro (DIV) 8, PFOS increased both the potency and efficacy of glutamate, whereas in mature cultures at DIV 14 only increased potency was observed. PFOA also increased potency at DIV 14. PFOS-enhanced glutamate toxicity was further antagonised by the competitive NMDA-R antagonist 3-((R)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) at DIV 8. At DIV 8, PFOS also induced glutamate release (9–13 fold increase vs DMSO control) after 1−3 and 24 h exposure, whereas for PFOA a large (80 fold) increase was observed, but only after 24 h. PFOS and PFOA both also increased alanine and decreased serine levels after 24 h exposure. In conclusion, our results indicate that PFOS at concentrations relevant in an occupational setting, may be inducing excitotoxicity, and potentiation of glutamate signalling, via an allosteric action on the NMDA-R or by actions on other elements regulating glutamate release or NMDA-R function. Our results further support our previous findings that PFOS and PFOA at equipotent concentrations induce toxicity via different mechanisms of action.en_US
dc.identifier.citationBerntsen, Moldes-Anaya, Bjørklund, Ragazzi, Haug, Strandabø, Verhaegen, Paulsen, Ropstad, Tasker. Perfluoroalkyl acids potentiate glutamate excitotoxicity in rat cerebellar granule neurons. Toxicology. 2020;445:1-10en_US
dc.identifier.cristinIDFRIDAID 1838963
dc.identifier.doi10.1016/j.tox.2020.152610
dc.identifier.issn0300-483X
dc.identifier.issn1879-3185
dc.identifier.urihttps://hdl.handle.net/10037/19681
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.journalToxicology
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/BEDREHELSE/204361/Norway/Persistent organic pollutants (POPs), development, and cancer - a multi-tiered approach/MultiPOP/en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/BEDREHELSE/213076/Norway/Do environmental pollutants interact with stress responses?//en_US
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2020 The Author(s)en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Pharmacology: 728en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Farmakologi: 728en_US
dc.titlePerfluoroalkyl acids potentiate glutamate excitotoxicity in rat cerebellar granule neuronsen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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