Abstract
Highlights
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- Pregnant mice were exposed to environmentally relevant doses of sodium fluoride from GD1 to GD20.
- Exposure to sodium fluoride resulted in structural and functional impairments in male offspring mouse hippocampus.
- The activation of P-Creb1 signaling pathway played a role in sodium fluoride-induced cognitive impairment.
- We provided new insight into the mechanisms of sodium fluoride-induced developmental toxicity.
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.
Graphical abstract
Synaptic damage contributes to prenatal fluoride exposure induced cognitive dysfunction via disruption of the BDNF-TrkB axis, which is mediated by p-Creb1 signaling. Prenatal NaF exposure activated p-Creb1 and disrupted the BDNF-TrkB axis, leading to increased pro-BDNF accumulation and reduced TrkB protein abundance, as well as synaptogenesis failure and cognitive impairment. By reducing p-Creb1 with 66615, prenatal fluoride exposure induced BDNF-TrkB signaling was considerably inhibited.
Extras
*Full-text study online at https://www.sciencedirect.com/science/article/pii/S014765132200522X?via%3Dihub
Excerpt:
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