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Evaluation of neurotoxic properties of gliotoxin
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
2006 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

The occurrence of mould in food and animal feed is a severe problem due to the secondary metabolites, called mycotoxins, which can possess toxic activity. Aspergillus fumigatus is a common fungus found in improperly stored animal feed and the abundance of spores of the fungus is frequently spread into the air. Gliotoxin has been identified as one of the most toxic second metabolites produced by A. fumigatus. Although A. fumigatus is known to produce mycotoxins that induce neurological syndromes, the neurotoxic properties of gliotoxin have not previously been studied. In this thesis a neurotoxic activity of gliotoxin was demonstrated by using differentiated human neuroblastoma SH-SY5Y cells as a surrogate for the nervous system. The major findings were as follows:

i. Gliotoxin is highly toxic to SH-SY5Y cells and there is a correlation between the toxicity and the cellular redox status.

ii. Gliotoxin reduces the number of neurites, but does not affect the cell bodies morphologically, at non-cytotoxic concentrations. This indicates that the toxin may induce peripheral axonopathy in vivo.

iii. The intracellular free Ca2+ concentration is increased after exposure to gliotoxin, an effect that is the most ubiquitous feature of neuronal cell death. Simultaneously, calpains and caspases, proteases known to be involved in neuronal death and axonal degeneration, are activated.

iv. The observed irreversible neurite degenerative effects of gliotoxin are mainly dependent on caspase activation, whereas calpains are involved in the gliotoxin-induced cytotoxicity.

v. Gliotoxin induces a decreased rate of protein synthesis at non-cytotoxic concentration, which may contribute to the degeneration of neurites.

vi. We did also succeed in developing an in vitro method for determination of toxic activity in animal feed. This study was done in collaboration with National Veterinary Institute (SVA) in Uppsala, and the method is today established and in use at Department of Animal Feed, SVA.

sted, utgiver, år, opplag, sider
Stockholm: Institutionen för neurokemi , 2006. , s. 80
Emneord [en]
mycotoxin, gliotoxin, A. fumigatus, cytotoxicity, neurotoxicity
HSV kategori
Identifikatorer
URN: urn:nbn:se:su:diva-1312ISBN: 91-7155-286-3 (tryckt)OAI: oai:DiVA.org:su-1312DiVA, id: diva2:189848
Disputas
2006-11-17, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2006-10-06 Laget: 2006-10-06 Sist oppdatert: 2018-01-13bibliografisk kontrollert
Delarbeid
1. Glutathione intensifies gliotoxin-induced cytotoxicity in human neuroblastoma SH-SY5Y cells
Åpne denne publikasjonen i ny fane eller vindu >>Glutathione intensifies gliotoxin-induced cytotoxicity in human neuroblastoma SH-SY5Y cells
2006 Inngår i: Cell Biology and Toxicology, Vol. 22, s. 127-136Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:su:diva-22977 (URN)
Merknad
Part of urn:nbn:se:su:diva-1312Tilgjengelig fra: 2006-10-06 Laget: 2006-10-06bibliografisk kontrollert
2. Gliotoxin induces caspase-dependent neurite degeneration and calpain-mediated general cytotoxicity in differentiated human neuroblastoma SH-SY5Y cells.
Åpne denne publikasjonen i ny fane eller vindu >>Gliotoxin induces caspase-dependent neurite degeneration and calpain-mediated general cytotoxicity in differentiated human neuroblastoma SH-SY5Y cells.
Vise andre…
2006 (engelsk)Inngår i: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 345, nr 3, s. 1068-74Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

In this study, a significant increase by 50% in intracellular free calcium concentration ([Ca(2+)](i)) was observed in differentiated human neuroblastoma (SH-SY5Y) cells after exposure to 0.25microM of the fungal metabolite gliotoxin for 72h. Further, the involvement of caspases and calpains was demonstrated to underlie the gliotoxin-induced cytotoxic and neurite degenerative effects. The caspase inhibitor Z-VAD-fmk almost completely reduced the neurite degeneration from 40% degeneration of neurites to 5% as compared to control. Inhibition of calpains with calpeptin significantly attenuated gliotoxin-induced cytotoxicity, determined as reduction in total cellular protein content, from 43% to 14% as compared to control cells. Western blot analyses of alphaII-spectrin breakdown fragments confirmed activity of the proteases, and that alphaII-spectrin was cleaved by caspases in gliotoxin-exposed cells. These results show that calpains and caspases have a role in the toxicity of gliotoxin in differentiated SH-SY5Y cells and that the process may be Ca(2+)-mediated.

Emneord
Calcium/metabolism, Calpain/*metabolism, Caspases/*metabolism, Cell Differentiation, Cell Line;/pharmacology, Gliotoxin/*pharmacology, Humans, Immunosuppressive Agents/*pharmacology, Neurites/*metabolism, Neuroblastoma/*metabolism, Spectrin/metabolism
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-20495 (URN)16712786 (PubMedID)
Tilgjengelig fra: 2007-11-26 Laget: 2007-11-26 Sist oppdatert: 2018-01-13bibliografisk kontrollert
3. Effects of gliotoxin on mitochondrial function and protein synthesis
Åpne denne publikasjonen i ny fane eller vindu >>Effects of gliotoxin on mitochondrial function and protein synthesis
(engelsk)Manuskript (Annet vitenskapelig)
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-22979 (URN)
Merknad
Part of urn:nbn:se:su:diva-1312Tilgjengelig fra: 2006-10-06 Laget: 2006-10-06 Sist oppdatert: 2012-04-26bibliografisk kontrollert
4. Cytotoxic response of Aspergillus fumigatus-produced mycotoxins on growth medium, maize and commercial animal feed substrates
Åpne denne publikasjonen i ny fane eller vindu >>Cytotoxic response of Aspergillus fumigatus-produced mycotoxins on growth medium, maize and commercial animal feed substrates
Vise andre…
2003 Inngår i: Food and Chemical Toxicology, Vol. 41, s. 395-403Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:su:diva-22980 (URN)
Merknad
Part of urn:nbn:se:su:diva-1312Tilgjengelig fra: 2006-10-06 Laget: 2006-10-06bibliografisk kontrollert

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