Involvement of TLR4 in diazinon-induced neurotoxicity in mice

Our laboratory recently reported that Toll-like receptor (TLR) 4 may play a role in the neurotoxic effects in mice exposed to the environmental toxic chemical toluene. To investigate the role of TLR4 in hippocampal neurotrophin expression, C3H/HeN (TLR4 intact) and C3H/HeJ (TLR4 defective) male adult mice were administered diazinon (0, 0.05, 0.5 or 5 mg/kg) intraperitoneally once a week for three weeks. Twenty-four hours after the final diazinon injection, the hippocampus was collected from each mouse to detect mRNA expression of neurotrophins (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) by the real-time RT-PCR method. There was no difference between groups in neurotrophin expression in the C3H/HeN mice. However, the expression of NGF and BDNF mRNAs was suppressed significantly in the diazinon-injected C3H/HeJ mice compared with their control group. We also found an increased tendency of proinflammatory chemokine CCL3 mRNA and a marked increase in the proapoptotic gene Bax mRNA in the diazinon-injected C3H/HeJ mice. Our findings indicate that diazinon injection affects neurotrophin expression in the hippocampus in TLR4-defective mice but not in TLR4 intact mice. These results suggest that a defective TLR4 signaling pathway in the mouse hippocampus can be easily affected by diazinon administration.