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Cell-based in vitro screening methods for developmental neurotoxicity

AuthorsSuñol, Cristina CSIC ORCID
Issue DateJul-2010
CitationXII International Congress of Toxicology (2010)
AbstractMore than 200 chemicals have been reported to produce neurotoxicity in humans. Pesticides account for 45% of them, and metals like lead and mercury have been proved to produce developmental neurotoxicity. The organochlorine pesticide dieldrin and the organometallic methylmercury are examples of these chemicals, both being permanent organic pollutants. Neurotoxicity is usually manifested as alterations of behavior, and cognitive motor and learning-memory processes, which are often a consequence of alterations in GABAergic and glutamatergic neurotransmission, and of neurodegenerative processes. Primary rodent neuronal cultures, from different brain areas, are useful for the study of specific and general neural functions (voltage- and receptor-operated ion-channels, like GABAA and NMDA-glutamate receptors, GABAAR and NMDAR; synthesis, release and uptake of neurotransmitters; cell and mitochondrial membranepotential, intracellular calcium homeostasis, red-ox status). Cultured cortical and cerebellar granule neurons are mainly constituted by GABAergic and glutamatergic neurons, respectively, and express functional GABAAR and NMDAR. Prolonged exposure to dieldrin during neuronal differentiation in vitro reduced both GABAAR and NMDAR function due to (i) inhibition of the GABAAR and (ii) subsequent internalization of NMDARs. The latest may be attributable to a mechanism of synaptic scaling after permanent inhibition of the GABAAR. Neurodegenerative processes are generally a consequence of glutamate-mediated excitotoxicity and/or of cellular red-ox imbalance. Acute exposure to methylmercury inhibits neural glutamate uptake, increases extracellular glutamate, intracellular calcium and production of reactive oxygen species, eventually leading to cell death. Prolonged exposure to methylmercury during neuronal differentiation in vitro resulted in reduced glutathione peroxydase (GPx) activity before methylmercury-induced neuronal death, which was related to enhanced susceptibility to hydrogen-peroxide. A proteomic study revealed that methylmercury impaired the phosphorylation of the cytoskeleton protein cofilin. Primary cultured neurons allow for testing of chemicals acting on general (red-ox homeostasis, cytoskeleton) and specific (receptor-operated ion channels, neurotransmitter transport) neural endpoints during development.
DescriptionTrabajo presentado en el XII International Congress of Toxicology, celebrado en Barcelona, España, del 19 al 23 de julio de 2010
Appears in Collections:(IIBB) Comunicaciones congresos

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