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Int. J. Mol. Sci. 2014, 15(1), 905-926; doi:10.3390/ijms15010905
Article

Genomic and Phenotypic Alterations of the Neuronal-Like Cells Derived from Human Embryonal Carcinoma Stem Cells (NT2) Caused by Exposure to Organophosphorus Compounds Paraoxon and Mipafox

1,2,3,* , 1
, 2,4
, 2
, 2
, 2
, 1
, 2,3
 and 2
1 Bioengineering Institute, Miguel Hernández University, Elche 03202, Alicante, Spain 2 Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra, Varese 21027, Italy 3 Bloomberg School of Public Health, Johns Hopkins University, CAAT, Baltimore, MD 21205, USA 4 Department of Experimental and Clinical Medicine, University of Insubria, Varese 21100, Italy
* Author to whom correspondence should be addressed.
Received: 14 October 2013 / Revised: 8 December 2013 / Accepted: 17 December 2013 / Published: 9 January 2014
(This article belongs to the collection Molecular Research in Neurotoxicology)
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Abstract

Historically, only few chemicals have been identified as neurodevelopmental toxicants, however, concern remains, and has recently increased, based upon the association between chemical exposures and increased developmental disorders. Diminution in motor speed and latency has been reported in preschool children from agricultural communities. Organophosphorus compounds (OPs) are pesticides due to their acute insecticidal effects mediated by the inhibition of acetylcholinesterase, although other esterases as neuropathy target esterase (NTE) can also be inhibited. Other neurological and neurodevelopmental toxic effects with unknown targets have been reported after chronic exposure to OPs in vivo. We studied the initial stages of retinoic acid acid-triggered differentiation of pluripotent cells towards neural progenitors derived from human embryonal carcinoma stem cells to determine if neuropathic OP, mipafox, and non-neuropathic OP, paraoxon, are able to alter differentiation of neural precursor cells in vitro. Exposure to 1 µM paraoxon (non-cytotoxic concentrations) altered the expression of different genes involved in signaling pathways related to chromatin assembly and nucleosome integrity. Conversely, exposure to 5 µM mipafox, a known inhibitor of NTE activity, showed no significant changes on gene expression. We conclude that 1 µM paraoxon could affect the initial stage of in vitro neurodifferentiation possibly due to a teratogenic effect, while the absence of transcriptional alterations by mipafox exposure did not allow us to conclude a possible effect on neurodifferentiation pathways at the tested concentration.
Keywords: neurodifferentiation; neurodevelopmental toxicity; NT2; organophosphorus pesticides; NTE; human embryonal carcinoma stem cells neurodifferentiation; neurodevelopmental toxicity; NT2; organophosphorus pesticides; NTE; human embryonal carcinoma stem cells
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Pamies, D.; Sogorb, M.A.; Fabbri, M.; Gribaldo, L.; Collotta, A.; Scelfo, B.; Vilanova, E.; Harris, G.; Bal-Price, A. Genomic and Phenotypic Alterations of the Neuronal-Like Cells Derived from Human Embryonal Carcinoma Stem Cells (NT2) Caused by Exposure to Organophosphorus Compounds Paraoxon and Mipafox. Int. J. Mol. Sci. 2014, 15, 905-926.

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