Gestational exposure to fluoride impairs cognition in C57 BL/6 J male offspring mice via the p-Creb1-BDNF-TrkB signaling pathway.

Abstract

Fluoride exposure has a detrimental effect on neurodevelopment, while the underlying processes remain unknown. The goal of this study was to investigate how fluoride impacts synaptogenesis, with a focus on the phosphorylation of Creb1 (p-Creb1)-brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) pathway. We generated a sodium fluoride (NaF) model using C57 BL/6 J mice exposed to 100 mg/L NaF from gestation day 1 (GD1) to GD20. It was identified that NaF treatment impaired the learning and memory abilities of the male offspring, reduced dendritic spine density, lowered postsynaptic density protein-95 (PSD95) and synaptophysin (SYN) expression in the male offspring's hippocampus, indicating that synaptic dysfunction may contribute to the cognitive impairment in the NaF model. In addition, in vivo experiment demonstrated that the protein abundance of BDNF and the ratio of p-Creb1 to Creb1 were increased in the hippocampus of NaF offspring, while the level of TrkB was reduced. Similarly, PC12 cells treated with NaF also showed increased expression of BDNF and decreased levels of TrkB. Notably, fluoride treatment increased p-Creb1 in vitro, while inhibiting p-Creb1 by 66615 significantly alleviated the effects of NaF exposure, indicating that p-Creb1 exerts a regulatory function in the BDNF-TrkB pathway. Altogether, these results demonstrated prenatal fluoride exposure triggered neurotoxicity in the male offspring hippocampus was linked to synaptogenesis damage caused by activating p-Creb1, which disrupted the BDNF-TrkB pathway.

• Authors: Weisheng Li, Likui Lu, Dan Zhu, Jingliu Liu, Yajun Shi, Hongtao Zeng, Xi Yu, Jun Guo, Bin Wei, Yongle Cai, Miao Sun
• Journal: Ecotoxicology and environmental safety (Ecotoxicol Environ Saf) Vol. 239 Pg. 113682 (Jul 01 2022) ISSN: 1090-2414 [Electronic] Netherlands
• PMID: 35643027 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Brain-Derived Neurotrophic Factor
• CREB1 protein, rat
• Cyclic AMP Response Element-Binding Protein
• Protein-Tyrosine Kinases
• Receptor, trkB
• Fluorides

Topics

• Animals
• Brain-Derived Neurotrophic Factor (metabolism)
• Cognition
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Female
• Fluorides (toxicity)
• Hippocampus (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Phosphorylation
• Pregnancy
• Prenatal Exposure Delayed Effects (physiopathology)
• Protein-Tyrosine Kinases (metabolism)
• Rats
• Receptor, trkB (metabolism)
• Signal Transduction