2026: Sodium fluoride exposure induced cognitive impairment via disorders synaptic protein expression

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Chen L, Wang R, Jia P, Jiang Q, An S, Yin Z, Hu D, Ning H, Ge Y - "Sodium fluoride exposure induced cognitive impairment via disorders synaptic protein expression and neuronal development in mice brain" Brain Res 1881:150262 (2026)
https://doi.org/10.1016/j.brainres.2026.150262

Abstract

As an environmental pollutant, fluoride is widespread in the natural environment in different forms, and drinking water is the primary way of exposure in human and animals. Structural damage to the central nervous system may occur in human and animals after fluoride exposure, which can lead to cognitive dysfunction. However, the mechanism of cognitive impairment caused by fluoride remains unclear. In this research, a fluoride-exposed model of mice and HT-22 cells was established to explore the neurotoxic mechanisms of fluoride. In vitro, CCK-8 results showed that HT-22 cells decreased with the increase in fluoride concentrations, and the morphology appeared abnormal. Similarly, laser confocal microscopy revealed that the number of axons and dendrites decreased with the increase in fluoride concentrations. Western blot results showed that the expression level of synaptic and cytoskeleton-associated proteins decreased in fluoride groups. In vivo, the mice exhibited losses in body and brain weights in the fluoride groups compared with the control group. The step-down test demonstrated that the cognitive ability of mice in the fluoride groups significantly decreased compared with that in the control group. Western blot results showed that the expression of synaptic and cytoskeleton-associated proteins decreased in the low-fluoride group compared with the control group, and qRT-PCR results showed that PSD95 expression decreased significantly compared with the control group. These results indicated that cognitive impairment induced by fluoride is involved in the morphological damage of synapse and the abnormal expression of synaptic proteins.

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PFPC Commentary

Fluoride-induced impairment of PSD95 protein expression has already been reported in numerous studies - in vivo and in vitro (Zhu et al., 2011; Chen et al., 2018; Zeng et al., 2025, Qi et al., 2025; Yang et al., 2018).

PSD95 expression is regulated by thyroid hormone (T3) (Huang et al., 2022; Suo et al., 2018; Dong et al. 2013).

Fluoride has been shown to reduce PSD95 in hippocampus (Chen et al., 2018; Yang et al., 2018), while T3 increases it (Huang et al., 2022).

Maternal hypothyroxinemia, commonly observed in iodine-excess scenarios, has shown to dysregulate PSD95 expression in offspring (Opazo et al., 2008).

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SEE also: BDNF, ERK1/2

Other studies of interest

Wang F, Cai YJ, Ma X, Wang N, Wu ZB, Sun Y, Xu YX, Yang H, Liu TT, Xia Q, Yu Z, Zhu DF - "Synaptic loss in a mouse model of euthyroid Hashimoto's thyroiditis: possible involvement of the microglia" BMC Neurosci 23:25 (2022)
https://doi.org/10.1186/s12868-022-00710-2

Cortés C, Eugenin E, Aliaga E, Carreño LJ, Bueno SM, Gonzalez PA, Gayol S, Naranjo D, Noches V, Marassi MP, Rosenthal D, Jadue C, Ibarra P, Keitel C, Wohllk N, Court F, Kalergis AM, Riedel CA - "Hypothyroidism in the adult rat causes incremental changes in brain-derived neurotrophic factor, neuronal and astrocyte apoptosis, gliosis, and deterioration of postsynaptic density" Thyroid 22(9):951-63 (2012) doi: 10.1089/thy.2010.0400
https://pmc.ncbi.nlm.nih.gov/articles/PMC3429274/