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 48h 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 48h, 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.
authors.affiliation: Swiss Centre for Applied Human Toxicology (SCAHT), Switzerland; Department of Physiology, University of Lausanne, CH-1005 Lausanne, Switzerland. Electronic address: jenny.sandstrom@unil.ch.
authors.forename: Jenny Sandström
authors.initials: JS
authors.lastname: von Tobel
authors.affiliation: Swiss Centre for Applied Human Toxicology (SCAHT), Switzerland; Department of Human Protein Sciences, University of Geneva, CH-1200 Geneva, Switzerland.
authors.forename: Paola
authors.initials: P
authors.lastname: Antinori
authors.affiliation: Swiss Centre for Applied Human Toxicology (SCAHT), Switzerland; Department of Physiology, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors.forename: Marie-Gabrielle
authors.initials: MG
authors.lastname: Zurich
authors.affiliation: Department of Physiology, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors.forename: Robin
authors.initials: R
authors.lastname: Rosset
authors.affiliation: Vanderbilt University Medical Center, Nashville, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.affiliation: Swiss Centre for Applied Human Toxicology (SCAHT), Switzerland; Department of Human Protein Sciences, University of Geneva, CH-1200 Geneva, Switzerland.
authors.forename: Florent
authors.initials: F
authors.lastname: Glück
authors.affiliation: Swiss Centre for Applied Human Toxicology (SCAHT), Switzerland; Department of Human Protein Sciences, University of Geneva, CH-1200 Geneva, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Scherl
authors.affiliation: Swiss Centre for Applied Human Toxicology (SCAHT), Switzerland; Department of Physiology, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors.forename: Florianne
authors.initials: F
authors.lastname: Monnet-Tschudi
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D004660:Encephalitis / Q000139:chemically induced* / Q000378:metabolism*; D008668:Metallothionein / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009793:Ochratoxins / Q000633:toxicity*; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C491055:Mt2A protein, rat; D009793:Ochratoxins; C025589:ochratoxin A; D008668:Metallothionein
keywords: 3D brain cell cultures; Demyelination; M1/M2 microglial phenotypes; Metallothionein I and II; Neuroinflammation; Ochratoxin A