1. Academic Validation
  2. ERK1/2-mediated disruption of BDNF-TrkB signaling causes synaptic impairment contributing to fluoride-induced developmental neurotoxicity

ERK1/2-mediated disruption of BDNF-TrkB signaling causes synaptic impairment contributing to fluoride-induced developmental neurotoxicity

  • Toxicology. 2018 Dec 1;410:222-230. doi: 10.1016/j.tox.2018.08.009.
Jingwen Chen 1 Qiang Niu 1 Tao Xia 1 Guoyu Zhou 1 Pei Li 1 Qian Zhao 1 Chunyan Xu 1 Lixin Dong 1 Shun Zhang 2 Aiguo Wang 3
Affiliations

Affiliations

  • 1 Department of Environmental Health, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, Hubei, People's Republic of China.
  • 2 Department of Environmental Health, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, Hubei, People's Republic of China. Electronic address: shunzhang@hust.edu.cn.
  • 3 Department of Environmental Health, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, Hubei, People's Republic of China. Electronic address: wangaiguo@mails.tjmu.edu.cn.
Abstract

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.

Keywords

BDNF–TrkB signaling; Developmental neurotoxicity; Fluoride; Phospho–ERK1/2; Synaptic impairment.

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