Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Interference with thyroid hormone (T3) action as a possible mechanism for ochratoxin A toxicity

In aggregating brain cell cultures, 2-20 nM OTA elicited cell type-specific effects, while at higher concentrations general cytotoxicity was observed. Measurements at the mRNA level using real-time RT-PCR showed that 10nM OTA rapidly and significantly upregulated the inducible nitric oxide synthase, heme oxygenase-1, and peroxisome proliferator-activated receptor-g, while it downregulated two macroglia-specific markers, glial fibrillary acidic protein and myelin basic protein.

These findings were confirmed by microarray analysis. In addition, this analysis confirmed the results obtained during the first two years indicating that ochratoxin A does not interfere systematically with T3-regulated genes in aggregating brain cell cultures, and showed that 24 h after exposure to 10nM OTA, alterations in the expression (up- or down-regulation) at a two-fold or greater level (p ≤ 0.0001) occurred for several hundred genes related to different CNS cell types and to a variety of functional classes.

Overall, the altered gene expression suggests a predominantly anti-oxidant and anti-apoptotic reaction pattern, and impairments in ras-like GTPase functions, in the cytoskeleton, and in vesicle biosynthesis and trafficking.

Our results show that brain cells are highly susceptible to OTA, and suggest that the profound alterations in gene expression caused by nanomolar concentrations of OTA reflect alternative (non-genotoxic) pathways of OTA toxicity.

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