title: 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.
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.
authors.affiliation: Bioengineering Institute, Miguel Hernández University, Elche 03202, Alicante, Spain. dpamies@jhsph.edu.
authors.forename: David
authors.initials: D
authors.lastname: Pamies
authors.affiliation: Bioengineering Institute, Miguel Hernández University, Elche 03202, Alicante, Spain. msogorb@umh.es.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Sogorb
authors.affiliation: Bioengineering Institute, Miguel Hernández University, Elche 03202, Alicante, Spain. marco.fabbri@gmail.com.
authors.forename: Marco
authors.initials: M
authors.lastname: Fabbri
authors.affiliation: Bioengineering Institute, Miguel Hernández University, Elche 03202, Alicante, Spain. laura.gribaldo@ec.europa.eu.
authors.forename: Laura
authors.initials: L
authors.lastname: Gribaldo
authors.affiliation: Bioengineering Institute, Miguel Hernández University, Elche 03202, Alicante, Spain. angelo.collotta@jrc.ec.europa.eu.
authors.forename: Angelo
authors.initials: A
authors.lastname: Collotta
authors.affiliation: Bioengineering Institute, Miguel Hernández University, Elche 03202, Alicante, Spain. bibiana.scelfo@gmail.com.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Scelfo
authors.affiliation: Bioengineering Institute, Miguel Hernández University, Elche 03202, Alicante, Spain. evilanova@umh.es.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Vilanova
authors.affiliation: Bioengineering Institute, Miguel Hernández University, Elche 03202, Alicante, Spain. georgina.hlopez@gmail.com.
authors.forename: Georgina
authors.initials: G
authors.lastname: Harris
authors.affiliation: Bioengineering Institute, Miguel Hernández University, Elche 03202, Alicante, Spain. anna.price@jrc.ec.europa.eu.
authors.forename: Anna
authors.initials: A
authors.lastname: Bal-Price
mesh_terms: D042002:Chromatin Assembly and Disassembly; D054278:Embryonal Carcinoma Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015894:Genome, Human / Q000187:drug effects; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D007531:Isoflurophate / Q000031:analogs & derivatives* / Q000633:toxicity; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D010261:Paraoxon / Q000633:toxicity*; D010641:Phenotype; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D006657:Histones; D007306:Insecticides; D009707:Nucleosomes; D007531:Isoflurophate; C005238:mipafox; D014212:Tretinoin; D010261:Paraoxon