PFOS-induced excitotoxicity is dependent on Ca2+ influx via NMDA receptors in rat cerebellar granule neurons

Berntsen, Hanne Friis; Bjørklund, Cesilie Granum; Strandabø, Rønnaug A.U.; Haug, Trude M.; Moldes-Anaya, Angel; Fuentes-Lazaro, Judit; Verhaegen, Steven; Paulsen, Ragnhild E.; Tasker, R. Andrew; Ropstad, Erik

doi:10.1016/j.taap.2018.08.015

Cited by 29 publications

(21 citation statements)

References 61 publications

(87 reference statements)

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“…In our unpublished studies (manuscript under review) we found that the POP mixture at 500x fold human blood levels and PFOS at 20 mM, in a corresponding concentration, induced excitotoxicity via the involvement of N-methyl-D-aspartate receptor (NMDA-R) in cultures of chicken cerebellar granule neurons (CGNs). A similar result has been observed by our group using the same POP mixture at concentrations from 500x, and PFOS in rat as well as in chicken CGNs (Berntsen et al, 2018(Berntsen et al, , 2020. PFOS-induced neurotoxicity has also previously been studied in PC12 cells (Li et al, 2017;Slotkin et al, 2008).…”

Section: Introductionsupporting

confidence: 86%

Differential effects of some novel synthetic oestrogen analogs on oxidative PC12 cell death caused by serum deprivation

Sørvik

Solum

Labba

et al. 2018

Free Radical Research

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Oestrogens with no or reduced oestrogen receptor (ER) binding properties are reported to have neuroprotective functions. However, we have previously shown that the hormonally inactive isomer of 17β-estradiol (17β-E), 17α-estradiol (17α-E), down-regulates glutathione (GSH) synthesis, and fails to rescue serum deprivation-induced cell death in the rat pheochromocytoma cell line PC12 in micromolar concentration. The present study examined cellular protective effects of new 17β-E analogs and 2-methoxyestradiol (2-ME) analogs with no or little oestrogen activity. 17β-E, 17α-E, 2-ME, and an antagonist of the G protein-coupled oestrogen receptor (GPER), G36, were also included. Both 17α-E and 2-ME protected against deprivation-induced cell death in PC12 cells at 1 nM, but they enhanced the deprivation-induced cell death accompanied by caspase 3 activity and decreased intracellular GSH levels during deprivation at 10 µM. In addition, 10 μM 17α-E activated the p38 mitogen activated protein kinase pathway, which was linked to the enhanced death and reduced GSH levels. Analogs of 2-ME modified with a 6-isoquinoline moiety (6iq) protected against deprivation-induced cell death at 1 nM and did not interfere with the GSH levels nor increase p38 protein levels at 10 µM. The promoter activity of the catalytic subunit of the rate-limiting enzyme, glutamate cysteine ligase (GCLC) in GSH synthesis as well as protein levels of GCLC and Nrf2, increased with the 2-ME analogs at 10 µM. In conclusion, the steroids have differential protective effects, and modifying 2-ME may give the steroid more favourable properties than 17α-E, 2-ME, and G36 in regard to GSH regulation.

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Section: Introductionsupporting

confidence: 86%

Differential effects of some novel synthetic oestrogen analogs on oxidative PC12 cell death caused by serum deprivation

Sørvik

Solum

Labba

et al. 2018

Free Radical Research

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“…For example, PFAS could act on different neurotransmitter receptors, such as glutamate receptors, thereby masking the inhibition of the GABA A receptor. This idea is supported by research that showed that PFOS induces NMDA receptor mediated excitotoxicity 59 . Toxicity results of a high influx of extracellular Ca 2+ , which in its turn over-activates the NMDA receptor.…”

Section: Discussionmentioning

confidence: 87%

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) acutely affect human α1β2γ2L GABAA receptor and spontaneous neuronal network function in vitro

Tukker

Bouwman

Kleef

et al. 2020

Sci Rep

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Concerns about the neurotoxic potential of polyfluoroalkyl substances (PFAS) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) increase, although their neurotoxic mechanisms of action remain debated. Considering the importance of the GABA A receptor in neuronal function, we investigated acute effects of PFAS on this receptor and on spontaneous neuronal network activity. PFOS (Lowest Observed Effect Concentration (LOEC) 0.1 µM) and PFOA (LOEC 1 µM) inhibited the GABA-evoked current and acted as non-competitive human GABA A receptor antagonists. Network activity of rat primary cortical cultures increased following exposure to PFOS (LOEC 100 µM). However, exposure of networks of human induced pluripotent stem cell (hiPSC)-derived neurons decreased neuronal activity. The higher sensitivity of the α 1 β 2 γ 2L GABA A receptor for PFAS as compared to neuronal networks suggests that PFAS have additional mechanisms of action, or that compensatory mechanisms are at play. Differences between rodent and hiPSC-derived neuronal networks highlight the importance of proper model composition. LOECs for PFAS on GABA A receptor and neuronal activity reported here are within or below the range found in blood levels of occupationally exposed humans. For PFOS, LOECs are even within the range found in human serum and plasma of the general population, suggesting a clear neurotoxic risk. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are well-known perfluoroalkyl substances (PFAS) consisting of an eight-carbon chain in which hydrogen atoms have been substituted with fluorine. Their combined hydrophobic, hydrophilic, oleophobic and lipophobic properties make them ideal industrial surfactants for the manufacturing of consumer products, including paint, stain repellents, fire-fighting foams, and non-stick cookware coatings. The strong carbon-fluorine bond renders PFOS and PFOA highly persistent and studies have shown their presence in the environment, wildlife and even human blood (for reviews see 1,2). By 2002, production of PFOS was phased out and production phase out of PFOA followed in 2006 3. Recent studies indicate that these efforts may be responsible for a reduction in human blood levels in some areas, but the long half-lives of PFOS and PFOA result in slow elimination from environment and humans 4,5. Research has demonstrated that the (developing) nervous system is one of the most sensitive targets for PFOS and PFOA. In mice and rats exposed pre-and/or neonatally to PFOS or PFOA, increased motor activity, decreased habituation and deficits in spatial learning and memory abilities have been observed 6-11. Developmental neurotoxicity has also been observed in other species, including chicken 12 and zebrafish larvae 13,14. However, epidemiological studies have been inconclusive on the risks of PFAS exposure on neurodevelopment. Some studies indicate an association between prenatal PFOS and/or PFOA exposure and an increased risk on congenital cerebral palsy 15 , neuro-behavioural developmen...

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“…In a follow-up study, Berntsen et al (2018) showed that excitotoxicity induction by PFOS in CGNs is likely due to over-activation of the N-methyl-D-aspartate receptor (NMDA-R) and excess influx of Ca 2+ . Channel blockers (memantine and MK-801) also showed some effects against PFHxS-induced reductions in viability.…”

Section: In Vitro Studiesmentioning

confidence: 99%

Risk to human health related to the presence of perfluoroalkyl substances in food

Schrenk¹,

Bignami²,

Bodin³

et al. 2020

EFS2

304

265

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The European Commission asked EFSA for a scientific evaluation on the risks to human health related to the presence of perfluoroalkyl substances ( PFAS s) in food. Based on several similar effects in animals, toxicokinetics and observed concentrations in human blood, the CONTAM Panel decided to perform the assessment for the sum of four PFAS s: PFOA , PFNA , PFH xS and PFOS . These made up half of the lower bound ( LB ) exposure to those PFAS s with available occurrence data, the remaining contribution being primarily from PFAS s with short half‐lives. Equal potencies were assumed for the four PFAS s included in the assessment. The mean LB exposure in adolescents and adult age groups ranged from 3 to 22, the 95th percentile from 9 to 70 ng/kg body weight (bw) per week. Toddlers and ‘other children’ showed a twofold higher exposure. Upper bound exposure was 4‐ to 49‐fold higher than LB levels, but the latter were considered more reliable. ‘Fish meat’, ‘Fruit and fruit products’ and ‘Eggs and egg products’ contributed most to the exposure. Based on available studies in animals and humans, effects on the immune system were considered the most critical for the risk assessment. From a human study, a lowest BMDL 10 of 17.5 ng/ mL for the sum of the four PFAS s in serum was identified for 1‐year‐old children. Using PBPK modelling, this serum level of 17.5 ng/ mL in children was estimated to correspond to long‐term maternal exposure of 0.63 ng/kg bw per day. Since accumulation over time is important, a tolerable weekly intake ( TWI ) of 4.4 ng/kg bw per week was established. This TWI also protects against other potential adverse effects observed in humans. Based on the estimated LB exposure, but also reported serum levels, the CONTAM Panel concluded that parts of the European population exceed this TWI , which is of concern.

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PFOS-induced excitotoxicity is dependent on Ca2+ influx via NMDA receptors in rat cerebellar granule neurons

Cited by 29 publications

References 61 publications

Differential effects of some novel synthetic oestrogen analogs on oxidative PC12 cell death caused by serum deprivation

Differential effects of some novel synthetic oestrogen analogs on oxidative PC12 cell death caused by serum deprivation

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) acutely affect human α1β2γ2L GABAA receptor and spontaneous neuronal network function in vitro

Risk to human health related to the presence of perfluoroalkyl substances in food

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