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Cited by 35Heavy Metal Exposure and ToxicityNeuroinflammation and Neurodegeneration MechanismsArsenic contamination and mitigation

Hijacking microglial glutathione by inorganic arsenic impels bystander death of immature neurons through extracellular cystine/glutamate imbalance

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Singh, Vikas, Gera, Ruchi, Kushwaha, Rajesh, Sharma, Anuj Kumar, Patnaik, Satyakam, Ghosh, Debabrata·2016·Scientific Reports
DOI 10.1038/srep30601PMC PMC4967897
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Abstract

Arsenic-induced altered microglial activity leads to neuronal death, but the causative mechanism remains unclear. The present study showed, arsenic-exposed (10 μM) microglial (N9) culture supernatant induced bystander death of neuro-2a (N2a), which was further validated with primary microglia and immature neuronal cultures. Results indicated that arsenic-induced GSH synthesis by N9 unfavorably modified the extracellular milieu for N2a by lowering cystine and increasing glutamate concentration. Similar result was observed in N9-N2a co-culture. Co-exposure of arsenic and 250 μM glutamate, less than the level (265 μM) detected in arsenic-exposed N9 culture supernatant, compromised N2a viability which was rescued by cystine supplementation. Therefore, microglia executes bystander N2a death by competitive inhibition of system Xc- (xCT) through extracellular cystine/glutamate imbalance. We confirmed the role of xCT in mediating bystander N2a death by siRNA inhibition studies. Ex-vivo primary microglia culture supernatant from gestationally exposed mice measured to contain lower cystine and higher glutamate compared to control and N-acetyl cysteine co-treated group. Immunofluorescence staining of brain cryosections from treated group showed more dead immature neurons with no such effect on microglia. Collectively, we showed, in presence of arsenic microglia alters cystine/glutamate balance through xCT in extracellular milieu leading to bystander death of immature neurons.

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  • Arsenic increases extracellular glutamate and disrupts cystine/glutamate transport, thereby promoting excitotoxicity and neuronal injury.

    “It also increases extracellular glutamate and disrupts cystine/glutamate transport, thereby promoting excitotoxicity and neuronal injury (Nelson-Mora et al., 2018; Singh et al., 2016).”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Singh et al., 2016

    The Discussion (page unavailable) reports that arsenic-exposed microglia increase extracellular glutamate, which inhibits neuronal xCT-mediated cystine uptake and contributes to immature-neuron death. The Abstract says extracellular glutamate can cause excitotoxicity in differentiated neurons, but the study does not establish excitotoxicity as the mechanism of the arsenic-induced immature-neuron injury it reports. (LLM, conf=0.82)

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Cited by

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Authors
Singh, V., Gera, R., Kushwaha, R., Sharma, A. K., Patnaik, S., & Ghosh, D.
Affiliations
Indian Institute of Toxicology Research (IN)
Corresponding author
Ghosh, Debabrata
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2016-08-01
Volume
6
Issue
1
Pages
30601-30601
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep30601
PMC
PMC4967897
OpenAlex
W2478989392
Cited by
35
References
2
Citations by year
2026: 3 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 6 · 2018: 5 · 2017: 3
FWCI
2.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Indian Institute of Technology Roorkee (BSC0111)
  • Science and Engineering Research Board (BSC-0111)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Physical Sciences › Environmental Science › Environmental Chemistry › Arsenic contamination and mitigation
Keywords
inorganic arsenic, microglia, immature neurons, glutathione, cystine, glutamate, neurotoxicity, N-acetylcysteine, N2a cells
MeSH terms
Animals, Arsenic, Cell Line, Cell Survival, Cells, Cultured, Cystine, Female, Glutathione, Male, Neurons, Gene Expression Regulation, Neoplastic, Reactive Oxygen Species, Microglia, Glutamic Acid, Coculture Techniques, Amino Acid Transport System y+, Mice

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