title: Impairment of glutamate signaling in mouse central nervous system neurons in vitro by tri-ortho-cresyl phosphate at noncytotoxic concentrations.
abstract: Occupational and environmental exposure to tri-cresyl phosphates (TCPs) may cause various types of neurotoxicity. Among the TCP isomers, tri-ortho-cresyl phosphate is a well-studied organophosphate (OP) known to cause OP-induced delayed neuropathy (OPIDN). Clinically, OPIDN is characterized by limb paralysis caused by the inhibition of neuropathy target esterase. Like other OPs, TOCP may also trigger acute toxicity by yet unknown mechanisms. Neurotoxic effects of TCPs, including TOCP, on central nervous system functions have not been studied in depth, and such non-OPIDN mechanisms might be related to the aerotoxic syndrome. To identify alternative mechanisms of TOCP neurotoxicity, we conducted an in vitro study using primary cortical neurons isolated from mouse embryos (E 16.5). After 24 h or 6 days in vitro (DIV), cell cultures were treated with different TOCP concentrations for 24 h. On DIV 2 and 7, we investigated three different endpoints--general cytotoxicity, neurite outgrowth, and glutamatergic signaling. At both time points, the EC50 for TOCP-induced cell death was 90 μM, however, neurite outgrowth was already significantly affected at TOCP concentrations of 10 μM. The number of cells responding to glutamate, as well as the corresponding mean response amplitudes were reduced with TOCP concentrations as low as 100 nM. For the first time, functional neurotoxicity is observed with very low TOCP concentrations, and in the absence of structural damages. Our proposed mechanism is that TOCP exposure may lead to cognitive deficits relevant in aerotoxic syndrome by inhibiting the signaling of glutamate, the most abundant excitatory neurotransmitter in the brain.
authors.affiliation: IfADo - Leibniz Research Center for Working Environment and Human Factors, 44139 Dortmund, Germany hausherr@ifado.de.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hausherr
authors.affiliation: IfADo - Leibniz Research Center for Working Environment and Human Factors, 44139 Dortmund, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: van Thriel
authors.affiliation: Doerenkamp-Zbinden Chair for in vitro toxicology and biomedicine, University of Konstanz, 78462 Konstanz, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Krug
authors.affiliation: Doerenkamp-Zbinden Chair for in vitro toxicology and biomedicine, University of Konstanz, 78462 Konstanz, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
authors.affiliation: IfADo - Leibniz Research Center for Working Environment and Human Factors, 44139 Dortmund, Germany Department of Animal Physiology, Ruhr-University Bochum, 44801 Bochum, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schöbel
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D018698:Glutamic Acid / Q000378:metabolism*; D007150:Immunohistochemistry; D008815:Mice, Inbred Strains; D016501:Neurites / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000187:drug effects*; D014317:Tritolyl Phosphates / Q000633:toxicity*
chemical_list: D004785:Environmental Pollutants; D014317:Tritolyl Phosphates; D018698:Glutamic Acid; C025541:tri-o-cresyl phosphate
keywords: aerotoxic syndrome; glutamate signaling; neurite outgrowth inhibition; neurotoxicity; tri-ortho-cresyl phosphate