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Involvement of TLR4 in diazinon-induced neurotoxicity in mice
Tin-Tin Win-Shwe1, Daisuke Nakajima, Hidekazu Fujimaki
1Center for Environmental Health Sciences, National Institute for Environmental Studies, Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
Abstract:
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.
Insights
Toll-like receptor 4 (TLR4) plays a key role in how the brain responds to toxins. Diazinon exposure suppressed neurotrophin expression in mice with defective TLR4 signaling, but not in those with intact TLR4.
Area of Science:
- Neuroscience
- Toxicology
- Immunology
Background:
- Toll-like receptor (TLR) 4 is implicated in neurotoxic effects from environmental chemicals.
- Investigating TLR4's role in hippocampal neurotrophin expression is crucial for understanding neurotoxicity.
Purpose of the Study:
- To examine the role of TLR4 in hippocampal neurotrophin (NGF, BDNF) expression following diazinon exposure.
- To compare the effects of diazinon on neurotrophin levels in mice with intact versus defective TLR4 signaling.
Main Methods:
- Adult male C3H/HeN (TLR4 intact) and C3H/HeJ (TLR4 defective) mice were administered varying doses of diazinon weekly for three weeks.
- Hippocampal mRNA expression of NGF, BDNF, CCL3, and Bax was analyzed using real-time RT-PCR 24 hours after the final injection.
Main Results:
- No significant differences in neurotrophin expression were observed in TLR4-intact mice (C3H/HeN).
- Diazinon administration significantly suppressed NGF and BDNF mRNA expression in TLR4-defective mice (C3H/HeJ).
- TLR4-defective mice showed increased pro-inflammatory chemokine CCL3 and pro-apoptotic Bax mRNA levels after diazinon exposure.
Conclusions:
- Diazinon affects hippocampal neurotrophin expression in a TLR4-dependent manner.
- A defective TLR4 signaling pathway exacerbates the impact of diazinon on neurotrophin expression and promotes inflammatory and apoptotic gene expression in the hippocampus.