Perfluorooctane sulfonate-induced apoptosis of cerebellar granule cells is mediated by ERK 1/2 pathway

Lee, Youn Ju; Lee, Hyun-Gyo; Yang, Jae‐Ho

doi:10.1016/j.chemosphere.2012.08.033

Cited by 39 publications

(10 citation statements)

References 41 publications

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“…In Lee et al (2016) PFHxS-induced increases in [Ca 2+ ]i was found to be linked to the induction of apoptosis via the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK) 1/2 pathway. Apoptosis induction in CGNs through ERK 1/2 activation was also observed in the studies by Lee et al (2013) and Lee et al (2014) in CGNs after exposure to PFOS and PFHxS, respectively. Whereas the activation of ERK after PFOS exposure was found to occur through a ROS-dependent activation of protein kinase C (PKC) (Lee et al, 2012;Lee et al, 2013), experiments using PFHxS indicated that ROS production here was rather a downstream target and not an upstream regulator of ERK 1/2 activation (Lee et al, 2014).…”

Section: Discussionsupporting

confidence: 73%

“…Apoptosis induction in CGNs through ERK 1/2 activation was also observed in the studies by Lee et al (2013) and Lee et al (2014) in CGNs after exposure to PFOS and PFHxS, respectively. Whereas the activation of ERK after PFOS exposure was found to occur through a ROS-dependent activation of protein kinase C (PKC) (Lee et al, 2012;Lee et al, 2013), experiments using PFHxS indicated that ROS production here was rather a downstream target and not an upstream regulator of ERK 1/2 activation (Lee et al, 2014). Despite these previous reports and mechanisms discussed, chelation of [Ca 2+ ] i in the present study did not affect toxicity, indicating that any contribution via other Ca 2+ channels is secondary to that of the NMDA-R.…”

Section: Discussionsupporting

confidence: 73%

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

Berntsen

Bjørklund

Strandabø

et al. 2018

Toxicology and Applied Pharmacology

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Perfluoroalkyl acids (PFAAs) are persistent compounds used in many industrial as well as consumer products. Despite restrictions, these compounds are found at measurable concentrations in samples of human and animal origin. In the present study we examined whether the effects on cell viability of two sulfonated and four carboxylated PFAAs in cultures of cerebellar granule neurons (CGNs), could be associated with deleterious activation of the N-methyl-d-aspartate receptor (NMDA-R). PFAA-induced effects on viability in rat CGNs and unstimulated PC12 cells were examined using the MTT assay. Cells from the PC12 rat pheochromocytoma cell line lack the expression of functional NMDA-Rs and were used to verify lower toxicity of perfluorooctanesulfonic acid (PFOS) in cells not expressing NMDA-Rs. Protective effects of NMDA-R antagonists, and extracellular as well as intracellular Ca chelators were investigated. Cytosolic Ca ([Ca]) was measured using Fura-2. In rat CGNs the effects of the NMDA-R antagonists MK-801, memantine and CPP indicated involvement of the NMDA-R in the decreased viability induced by PFOS and perfluorohexanesulfonic acid (PFHxS). No effects were associated with the four carboxylated PFAAs studied. Further, EGTA and CPP protected against PFOS-induced decreases in cell viability, whereas no protection was afforded by BAPTA-AM. [Ca] significantly increased after exposure to PFOS, and this increase was completely blocked by MK-801. In PC12 cells a higher concentration of PFOS was required to induce equivalent levels of toxicity as compared to in rat CGNs. PFOS-induced toxicity in PC12 cells was not affected by CPP. In conclusion, PFOS at the tested concentrations induces excitotoxicity in rat CGNs, which likely involves influx of extracellular Ca via the NMDA-R. This effect can be blocked by specific NMDA-R antagonists.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionsupporting

confidence: 73%

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

Berntsen

Bjørklund

Strandabø

et al. 2018

Toxicology and Applied Pharmacology

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“…Research has revealed the potential of ERK signalling cascades to regulate diverse neuronal processes, such as cell death, differentiation, and synaptic plasticity [ 25 ]. Research by Lee et al suggested that PFOS induced apoptosis of cerebellar granule cells by increasing pERK levels [ 42 ]. In the present study, ERK phosphorylation was reduced significantly in all the experimental groups compared with the controls, and the pERK/ERK ratio was significantly lower in all the experimental groups.…”

Section: Discussionmentioning

confidence: 99%

PFOS Disturbs BDNF-ERK-CREB Signalling in Association with Increased MicroRNA-22 in SH-SY5Y Cells

He²,

Cui-zhen

et al. 2015

BioMed Research International

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Perfluorooctane sulfonate (PFOS), a ubiquitous environmental pollutant, is neurotoxic to mammalian species. However, the underlying mechanism of its neurotoxicity was unclear. We hypothesized that PFOS suppresses BDNF expression to produce its neurotoxic effects by inhibiting the ERK-CREB pathway. SH-SY5Y human neuroblastoma cells were exposed to various concentrations of PFOS to examine the role of the BDNF-ERK-CREB signalling pathway in PFOS-induced apoptosis and cytotoxicity. Furthermore, to ascertain the mechanism by which PFOS reduces BDNF signalling, we examined the expression levels of miR-16 and miR-22, which potentially regulate BDNF mRNA translation at the posttranscriptional level. Results indicated that PFOS significantly decreased cell viability and induced apoptosis in SH-SY5Y cells. In addition, BDNF and pERK protein levels decreased after PFOS treatment; however, pCREB protein levels were significantly elevated in PFOS treated groups. TrkB protein expression increased in the 10 μM and 50 μM PFOS groups and significantly decreased in the 100 μM PFOS group. Our results demonstrated that PFOS exposure decreased miR-16 expression and increased miR-22 expression, which may represent a possible mechanism by which PFOS decreases BDNF protein levels. PFOS may inhibit BDNF-ERK-CREB signalling by increasing miR-22 levels, which may, in part, explain the mechanism of PFOS neurotoxicity.

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“…As members of the MAPK family, ERK is stimulated primarily by growth factors and tumor promoters, and JNK is activated in response to inflammatory agents and environmental stress (Cargnello & Roux, ). One study indicated that in cerebellar granule cells, PFOS increased ERK1/2 phosphorylation within 5–30 min with simultaneous neural apoptosis (Lee et al ., ). Consistent with the results, our data showed that ERK1/2 and JNK pathways were rapidly activated in 30 min, and both signal pathways displayed a dose‐dependent manner.…”

Section: Discussionmentioning

confidence: 97%

Involvement of mitogen‐activated protein kinase and NF‐κB signaling pathways in perfluorooctane sulfonic acid‐induced inflammatory reaction in BV2 microglial cells

Zhu

Qian

Wang

et al. 2015

J of Applied Toxicology

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Microglial activation is closely related to the pathogenesis of neurodegenerative diseases by producing proinflammatory cytokines. Perfluorooctane sulfonic acid (PFOS), known as an emerging persistent organic pollutant, is reported to disturb human immune homeostasis; however, whether it affects cytokine production or the immune response in the central nervous system remains unclear. The present study was aimed to explore whether PFOS contributed to inflammatory action and to investigate the corresponding mechanisms in BV2 microglia. PFOS-mediated morphologic changes, cytokine responses and signaling events were examined by light microscopy, real-time polymerase chain reaction, enzyme-linked immunosorbent assay and Western blot assays. Our results indicated that PFOS increased BV2 cells activation and simultaneously increased tumor necrosis factor alpha and interleukin-6 expression. In addition, the c-Jun N-terminal protein kinase inhibitor (SP600125), as well as ERK1/2 blocker (PD98059), transcriptionally at least, displayed anti-inflammatory properties on PFOS-elicited cytokine responses. Moreover, the inflammatory transcription factor NF-κB was specifically activated by PFOS as well. These results, taken together, suggested that PFOS exerts its functional effects on the response of microglial cell activation via, in part, the c-Jun N-terminal protein kinase, ERK and NF-κB signaling pathways with its subsequent influence on proinflammatory action.

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Perfluorooctane sulfonate-induced apoptosis of cerebellar granule cells is mediated by ERK 1/2 pathway

Cited by 39 publications

References 41 publications

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

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

PFOS Disturbs BDNF-ERK-CREB Signalling in Association with Increased MicroRNA-22 in SH-SY5Y Cells

Involvement of mitogen‐activated protein kinase and NF‐κB signaling pathways in perfluorooctane sulfonic acid‐induced inflammatory reaction in BV2 microglial cells

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