ERK1/2-mediated disruption of BDNF–TrkB signaling causes synaptic impairment contributing to fluoride–induced developmental neurotoxicity
Autor: | Jingwen Chen, Shun Zhang, Pei Li, Chunyan Xu, Tao Xia, Guoyu Zhou, Qian Zhao, Qiang Niu, Lixin Dong, Aiguo Wang |
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Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine medicine.medical_specialty Dendritic spine MAP Kinase Signaling System Dendritic Spines Synaptophysin Synaptogenesis Tropomyosin receptor kinase B Toxicology Cell Line Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Cognition 0302 clinical medicine Pregnancy Neurotrophic factors Internal medicine Sodium fluoride medicine Animals Humans Receptor trkB Maze Learning biology Brain-Derived Neurotrophic Factor Rats 030104 developmental biology Endocrinology nervous system chemistry Synapses biology.protein Sodium Fluoride Female Neurotoxicity Syndromes Fluoride Postsynaptic density 030217 neurology & neurosurgery Signal Transduction |
Zdroj: | Toxicology. 410:222-230 |
ISSN: | 0300-483X |
Popis: | Excessive exposure to fluoride has adverse effects on neurodevelopment, but the mechanisms remain unclear. This study aimed to investigate the effects of fluoride exposure on synaptogenesis, and focused on the role of brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling in these effects. Using Sprague-Dawley rats developmentally exposed to sodium fluoride (NaF) from pregnancy until 6 months of delivery as in vivo model, we showed that fluoride impaired the cognitive abilities of offspring rats, decreased the density of dendritic spines and the expression of synapse proteins synaptophysin (SYN) and postsynaptic density protein-95 (PSD-95) in hippocampus, suggesting fluoride-induced cognitive deficit associates with synaptic impairment. Consistently, NaF treatment reduced dendritic outgrowth and expression of SYN and PSD-95 in human neuroblastoma SH-SY5Y cells. Further studies demonstrated that the BDNF-TrkB axis was disrupted in vivo and in vitro, as manifested by BDNF accumulation and TrkB reduction. Importantly, fluoride treatment increased phospho-extracellular signal-regulated kinases 1 and 2 (p-ERK1/2) expression, while inhibition of p-ERK1/2 significantly attenuated the effects of NaF, indicating a regulating role of p-ERK1/2 in BDNF-TrkB signaling disruption. Collectively, these data suggest that the developmental neurotoxicity of fluoride is associated with the impairment of synaptogenesis, which is caused by ERK1/2-mediated BDNF-TrkB signaling disruption. |
Databáze: | OpenAIRE |
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