Chlorpyrifos Induces Delayed Cytotoxicity after Withdrawal in Primary Hippocampal Neurons through Extracellular Signal-Regulated Kinase Inhibition

  • Tan De-Hong
    Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences Department of Pharmacology, College of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University
  • Peng Shuang-Qing
    Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences
  • Wu Ying-Liang
    Department of Pharmacology, College of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University
  • Wang Yi-Mei
    Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences
  • Lu Chun-Feng
    Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences Department of Pharmacology, College of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University
  • Ding Wei
    Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences
  • Wang Qiao-Xu
    Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences
  • Yan Chang-Hui
    Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences

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In this study, the delayed effect and related mechanism after chlorpyrifos (CPF) withdrawal was studied in primary rat hippocampal neurons. The results showed that 10 μM CPF induced no detectable cytotoxicity during 96 h continuous exposure while its withdrawal after 48 h exposure induced evident cytotoxicity, as indexed by decreased methyl thiazolyl tetrazolium (MTT) metabolism, increased loss of neurons immunostained by neuron-specific enolase (NSE) antibody, and the increased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) positive cell rate in the following 24 h and 48 h incubation in the absence of CPF. Extracellular signal-related kinase (ERK)1/2 activation by phosphorylation was observed and persisted during CPF exposure. However, CPF withdrawal after 48 h exposure led to inhibition of ERK1/2 phosphorylation. Carbacol and nerve growth factor (NGF), which are ERK1/2 activators, protected the neurons after CPF withdrawal, while atropine and PD98059, which are ERK1/2 inhibitors, exacerbated the cytotoxicity, indicating the involvement of inhibition of ERK1/2 phosphorylation in CPF-induced delayed cytotoxicity. In conclusion, CPF withdrawal after exposure induced delayed cytotoxicity in cultured neurons. Inhibition of ERK1/2 phosphorylation was found to be related to the delayed cytotoxicity. This finding may provide a new insight into the toxicological mechanism of organophosphorus pesticides, especially chronic organophosphate-induced neuropsychiatric disorder characterized by delayed occurrence.

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