Perfluoroalkyl acids potentiate glutamate excitotoxicity in rat cerebellar granule neurons

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  • Hanne Friis Berntsen, Department of Production Animal Clinical Sciences NMBU-School of Veterinary Science, National Institute of Occupational Health
  • ,
  • Angel Moldes-Anaya, University Hospital of North Norway, UiT The Arctic University of Norway
  • ,
  • Cesilie Granum Bjørklund, Department of Production Animal Clinical Sciences NMBU-School of Veterinary Science
  • ,
  • Lorenzo Ragazzi, UiT The Arctic University of Norway
  • ,
  • Trude Marie Haug, University of Oslo
  • ,
  • Rønnaug A.U. Strandabø, University of Oslo
  • ,
  • Steven Verhaegen, Department of Production Animal Clinical Sciences NMBU-School of Veterinary Science
  • ,
  • Ragnhild Elisabeth Paulsen, University of Oslo
  • ,
  • Erik Ropstad, Department of Production Animal Clinical Sciences NMBU-School of Veterinary Science
  • ,
  • R. Andrew Tasker

Perfluoroalkyl 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.

Original languageEnglish
Article number152610
JournalToxicology
Volume445
ISSN0300-483X
DOIs
Publication statusPublished - Dec 2020

    Research areas

  • Glutamate excitotoxicity, N-methyl-D-aspartate (NMDA) receptor, Perfluorooctane sulfonic acid (PFOS), Perfluorooctanoic acid (PFOA), Rat cerebellar granule neurons

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