Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype

Jenny Sandström Von Tobel, Paola Antinori, Marie Gabrielle Zurich, Robin Rosset, Michael Aschner, Florent Glück, Alexander Scherl, Florianne Monnet-Tschudi

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Neurotoxic effects of the environmentally abundant mycotoxin Ochratoxin A (OTA) were studied in histotypic 3D rat brain cell cultures, comprising all brain cell types. Cultures were exposed to nanomolar OTA concentrations and samples were collected 48. h after a single exposure, or after 10 days of repeated administration. OTA-induced changes in gene- and protein expression, as well as alterations in cell morphology were assessed.Forty-eight-hour OTA exposure resulted in a disruption of the neuronal cytoskeleton and reduced expression of several oligodendrocyte-specific markers indicative of demyelination. Astrocyte disturbances were revealed by a decrease in two astrocytic proteins involved in regulation of inflammatory responses, metallothioneins I and II. Repeated OTA administration induced a neuroinflammatory response, as visualized by an increase of isolectin B4 labelled cells, increased expression of pro-inflammatory cytokines, and detection of macrophagic ED1/CD68 positive cells, as well as an upregulation of neurodegenerative M1 microglial phenotype markers.Partial recovery from OTA-induced deleterious effects on oligodendrocytes and astrocytes was achieved by co-treatment with sonic hedgehog (SHH). In addition, metallothionein I and II co-treatment partially restored OTA-induced effects on oligodendrocytes after 48. h, and modulated microglial reactivity after 10 days. These results suggest that OTA-exposure affects Shh-signalling, which in turn may influence both oligodendrocytes and astrocytes. Furthermore, the primarily astrocytic proteins MTI/MTII may affect microglial activation. Thus the neuroinflammatory response appears to be downstream of OTA-induced effects on demyelination, axonal instabilities and astrocytes disturbances. In conclusion, repeated OTA-exposure induced a secondary neuroinflammatory response characterized by neurodegenerative M1 microglial activation and pro-inflammatory response that could exacerbate the neurodegenerative process.

Original languageEnglish (US)
Pages (from-to)61-70
Number of pages10
JournalNeuroToxicology
Volume44
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Phenotype
Oligodendroglia
Astrocytes
Metallothionein
Demyelinating Diseases
Cell culture
Brain
Chemical activation
ochratoxin A
Proteins
Hedgehogs
Mycotoxins
Cytoskeleton
Lectins
Rats
Up-Regulation
Cell Culture Techniques
Cells
Cytokines
Gene Expression

Keywords

  • 3D brain cell cultures
  • Demyelination
  • M1/M2 microglial phenotypes
  • Metallothionein I and II
  • Neuroinflammation
  • Ochratoxin A

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology
  • Medicine(all)

Cite this

Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype. / Von Tobel, Jenny Sandström; Antinori, Paola; Zurich, Marie Gabrielle; Rosset, Robin; Aschner, Michael; Glück, Florent; Scherl, Alexander; Monnet-Tschudi, Florianne.

In: NeuroToxicology, Vol. 44, 2014, p. 61-70.

Research output: Contribution to journalArticle

Von Tobel, Jenny Sandström ; Antinori, Paola ; Zurich, Marie Gabrielle ; Rosset, Robin ; Aschner, Michael ; Glück, Florent ; Scherl, Alexander ; Monnet-Tschudi, Florianne. / Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype. In: NeuroToxicology. 2014 ; Vol. 44. pp. 61-70.
@article{f17ee3a7c54248b58ca5590967db7abe,
title = "Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype",
abstract = "Neurotoxic effects of the environmentally abundant mycotoxin Ochratoxin A (OTA) were studied in histotypic 3D rat brain cell cultures, comprising all brain cell types. Cultures were exposed to nanomolar OTA concentrations and samples were collected 48. h after a single exposure, or after 10 days of repeated administration. OTA-induced changes in gene- and protein expression, as well as alterations in cell morphology were assessed.Forty-eight-hour OTA exposure resulted in a disruption of the neuronal cytoskeleton and reduced expression of several oligodendrocyte-specific markers indicative of demyelination. Astrocyte disturbances were revealed by a decrease in two astrocytic proteins involved in regulation of inflammatory responses, metallothioneins I and II. Repeated OTA administration induced a neuroinflammatory response, as visualized by an increase of isolectin B4 labelled cells, increased expression of pro-inflammatory cytokines, and detection of macrophagic ED1/CD68 positive cells, as well as an upregulation of neurodegenerative M1 microglial phenotype markers.Partial recovery from OTA-induced deleterious effects on oligodendrocytes and astrocytes was achieved by co-treatment with sonic hedgehog (SHH). In addition, metallothionein I and II co-treatment partially restored OTA-induced effects on oligodendrocytes after 48. h, and modulated microglial reactivity after 10 days. These results suggest that OTA-exposure affects Shh-signalling, which in turn may influence both oligodendrocytes and astrocytes. Furthermore, the primarily astrocytic proteins MTI/MTII may affect microglial activation. Thus the neuroinflammatory response appears to be downstream of OTA-induced effects on demyelination, axonal instabilities and astrocytes disturbances. In conclusion, repeated OTA-exposure induced a secondary neuroinflammatory response characterized by neurodegenerative M1 microglial activation and pro-inflammatory response that could exacerbate the neurodegenerative process.",
keywords = "3D brain cell cultures, Demyelination, M1/M2 microglial phenotypes, Metallothionein I and II, Neuroinflammation, Ochratoxin A",
author = "{Von Tobel}, {Jenny Sandstr{\"o}m} and Paola Antinori and Zurich, {Marie Gabrielle} and Robin Rosset and Michael Aschner and Florent Gl{\"u}ck and Alexander Scherl and Florianne Monnet-Tschudi",
year = "2014",
doi = "10.1016/j.neuro.2014.04.005",
language = "English (US)",
volume = "44",
pages = "61--70",
journal = "NeuroToxicology",
issn = "0161-813X",
publisher = "Elsevier",

}

TY - JOUR

T1 - Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype

AU - Von Tobel, Jenny Sandström

AU - Antinori, Paola

AU - Zurich, Marie Gabrielle

AU - Rosset, Robin

AU - Aschner, Michael

AU - Glück, Florent

AU - Scherl, Alexander

AU - Monnet-Tschudi, Florianne

PY - 2014

Y1 - 2014

N2 - Neurotoxic effects of the environmentally abundant mycotoxin Ochratoxin A (OTA) were studied in histotypic 3D rat brain cell cultures, comprising all brain cell types. Cultures were exposed to nanomolar OTA concentrations and samples were collected 48. h after a single exposure, or after 10 days of repeated administration. OTA-induced changes in gene- and protein expression, as well as alterations in cell morphology were assessed.Forty-eight-hour OTA exposure resulted in a disruption of the neuronal cytoskeleton and reduced expression of several oligodendrocyte-specific markers indicative of demyelination. Astrocyte disturbances were revealed by a decrease in two astrocytic proteins involved in regulation of inflammatory responses, metallothioneins I and II. Repeated OTA administration induced a neuroinflammatory response, as visualized by an increase of isolectin B4 labelled cells, increased expression of pro-inflammatory cytokines, and detection of macrophagic ED1/CD68 positive cells, as well as an upregulation of neurodegenerative M1 microglial phenotype markers.Partial recovery from OTA-induced deleterious effects on oligodendrocytes and astrocytes was achieved by co-treatment with sonic hedgehog (SHH). In addition, metallothionein I and II co-treatment partially restored OTA-induced effects on oligodendrocytes after 48. h, and modulated microglial reactivity after 10 days. These results suggest that OTA-exposure affects Shh-signalling, which in turn may influence both oligodendrocytes and astrocytes. Furthermore, the primarily astrocytic proteins MTI/MTII may affect microglial activation. Thus the neuroinflammatory response appears to be downstream of OTA-induced effects on demyelination, axonal instabilities and astrocytes disturbances. In conclusion, repeated OTA-exposure induced a secondary neuroinflammatory response characterized by neurodegenerative M1 microglial activation and pro-inflammatory response that could exacerbate the neurodegenerative process.

AB - Neurotoxic effects of the environmentally abundant mycotoxin Ochratoxin A (OTA) were studied in histotypic 3D rat brain cell cultures, comprising all brain cell types. Cultures were exposed to nanomolar OTA concentrations and samples were collected 48. h after a single exposure, or after 10 days of repeated administration. OTA-induced changes in gene- and protein expression, as well as alterations in cell morphology were assessed.Forty-eight-hour OTA exposure resulted in a disruption of the neuronal cytoskeleton and reduced expression of several oligodendrocyte-specific markers indicative of demyelination. Astrocyte disturbances were revealed by a decrease in two astrocytic proteins involved in regulation of inflammatory responses, metallothioneins I and II. Repeated OTA administration induced a neuroinflammatory response, as visualized by an increase of isolectin B4 labelled cells, increased expression of pro-inflammatory cytokines, and detection of macrophagic ED1/CD68 positive cells, as well as an upregulation of neurodegenerative M1 microglial phenotype markers.Partial recovery from OTA-induced deleterious effects on oligodendrocytes and astrocytes was achieved by co-treatment with sonic hedgehog (SHH). In addition, metallothionein I and II co-treatment partially restored OTA-induced effects on oligodendrocytes after 48. h, and modulated microglial reactivity after 10 days. These results suggest that OTA-exposure affects Shh-signalling, which in turn may influence both oligodendrocytes and astrocytes. Furthermore, the primarily astrocytic proteins MTI/MTII may affect microglial activation. Thus the neuroinflammatory response appears to be downstream of OTA-induced effects on demyelination, axonal instabilities and astrocytes disturbances. In conclusion, repeated OTA-exposure induced a secondary neuroinflammatory response characterized by neurodegenerative M1 microglial activation and pro-inflammatory response that could exacerbate the neurodegenerative process.

KW - 3D brain cell cultures

KW - Demyelination

KW - M1/M2 microglial phenotypes

KW - Metallothionein I and II

KW - Neuroinflammation

KW - Ochratoxin A

UR - http://www.scopus.com/inward/record.url?scp=84902310550&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902310550&partnerID=8YFLogxK

U2 - 10.1016/j.neuro.2014.04.005

DO - 10.1016/j.neuro.2014.04.005

M3 - Article

C2 - 24792326

AN - SCOPUS:84902310550

VL - 44

SP - 61

EP - 70

JO - NeuroToxicology

JF - NeuroToxicology

SN - 0161-813X

ER -