Impairment of glutamate signaling in mouse central nervous system neurons in vitro by tri-ortho-cresyl phosphate at noncytotoxic concentrations

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2014
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Hausherr, Vanessa
van Thriel, Christoph
Krug, Anne
Schobel, Nicole
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Toxicological sciences : an official journal of the Society of Toxicology. 2014, 142(1), pp. 274-284. ISSN 1096-6080. eISSN 1096-0929. Available under: doi: 10.1093/toxsci/kfu174
Zusammenfassung

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.

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570 Biowissenschaften, Biologie
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aerotoxic syndrome; glutamate signaling; neurite outgrowth inhibition; neurotoxicity; tri-ortho-cresyl phosphate
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ISO 690HAUSHERR, Vanessa, Christoph VAN THRIEL, Anne KRUG, Marcel LEIST, Nicole SCHOBEL, 2014. Impairment of glutamate signaling in mouse central nervous system neurons in vitro by tri-ortho-cresyl phosphate at noncytotoxic concentrations. In: Toxicological sciences : an official journal of the Society of Toxicology. 2014, 142(1), pp. 274-284. ISSN 1096-6080. eISSN 1096-0929. Available under: doi: 10.1093/toxsci/kfu174
BibTex
@article{Hausherr2014Impai-30048,
  year={2014},
  doi={10.1093/toxsci/kfu174},
  title={Impairment of glutamate signaling in mouse central nervous system neurons in vitro by tri-ortho-cresyl phosphate at noncytotoxic concentrations},
  number={1},
  volume={142},
  issn={1096-6080},
  journal={Toxicological sciences : an official journal of the Society of Toxicology},
  pages={274--284},
  author={Hausherr, Vanessa and van Thriel, Christoph and Krug, Anne and Leist, Marcel and Schobel, Nicole}
}
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