PMID- 30130557 OWN - NLM STAT- MEDLINE DCOM- 20190501 LR - 20200930 IS - 1879-3185 (Electronic) IS - 0300-483X (Linking) VI - 410 DP - 2018 Dec 1 TI - ERK1/2-mediated disruption of BDNF-TrkB signaling causes synaptic impairment contributing to fluoride-induced developmental neurotoxicity. PG - 222-230 LID - S0300-483X(18)30253-1 [pii] LID - 10.1016/j.tox.2018.08.009 [doi] AB - 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. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Chen, Jingwen AU - Chen J AD - 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. FAU - Niu, Qiang AU - Niu Q AD - 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. FAU - Xia, Tao AU - Xia T AD - 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. FAU - Zhou, Guoyu AU - Zhou G AD - 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. FAU - Li, Pei AU - Li P AD - 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. FAU - Zhao, Qian AU - Zhao Q AD - 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. FAU - Xu, Chunyan AU - Xu C AD - 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. FAU - Dong, Lixin AU - Dong L AD - 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. FAU - Zhang, Shun AU - Zhang S AD - 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. FAU - Wang, Aiguo AU - Wang A AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180818 PL - Ireland TA - Toxicology JT - Toxicology JID - 0361055 RN - 0 (Bdnf protein, rat) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Synaptophysin) RN - 0 (Syp protein, rat) RN - 8ZYQ1474W7 (Sodium Fluoride) RN - EC 2.7.10.1 (Ntrk2 protein, rat) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*drug effects MH - Cell Line MH - Cognition/drug effects MH - Dendritic Spines/drug effects MH - Female MH - Humans MH - MAP Kinase Signaling System/*drug effects MH - Male MH - Maze Learning/drug effects MH - Neurotoxicity Syndromes/*physiopathology/psychology MH - Pregnancy MH - Rats MH - Rats, Sprague-Dawley MH - Receptor, trkB/*drug effects MH - Signal Transduction/*drug effects MH - Sodium Fluoride/*toxicity MH - Synapses/drug effects MH - Synaptophysin/biosynthesis/genetics OTO - NOTNLM OT - BDNF-TrkB signaling OT - Developmental neurotoxicity OT - Fluoride OT - Phospho-ERK1/2 OT - Synaptic impairment EDAT- 2018/08/22 06:00 MHDA- 2019/05/02 06:00 CRDT- 2018/08/22 06:00 PHST- 2018/05/31 00:00 [received] PHST- 2018/08/13 00:00 [revised] PHST- 2018/08/17 00:00 [accepted] PHST- 2018/08/22 06:00 [pubmed] PHST- 2019/05/02 06:00 [medline] PHST- 2018/08/22 06:00 [entrez] AID - S0300-483X(18)30253-1 [pii] AID - 10.1016/j.tox.2018.08.009 [doi] PST - ppublish SO - Toxicology. 2018 Dec 1;410:222-230. doi: 10.1016/j.tox.2018.08.009. Epub 2018 Aug 18.