Sodium fluoride exposure induced cognitive impairment via disorders synaptic protein expression and neuronal development in mice brain.

Fluoride (F), as an active nonmetal element, primarily exists in the form of different compounds in nature (Zhang et al., 2019). Fluoride is a trace element needed by the human body, which can prevent the occurrence and prevalence of dental caries (Indermitte et al., 2009, Wang et al., 2019) when the concentration of fluoride is low. In general, fluoride concentrations in surface water are below 1.0 mg/L, but the concentrations tend to increase because of groundwater having contact with large amounts of fluorite (Ferreira et al., 2010). Drinking water is the biggest source of fluoride exposure in patients with fluorosis (Flores-Méndez et al., 2014). Long-term and excessive fluoride exposure can lead to severe endemic fluorosis in humans and animals (Wang et al., 2017, Wei et al., 2019). Studies have shown that other diseases gradually worsen with the increase in fluoride concentration in drinking water (Indermitte et al., 2009). The structure and function of the central nervous system are damaged because of the accumulation of toxic fluoride in human and animals (Flores-Méndez et al., 2014, Zhou et al., 2020), such as permanent injury of all brain structures, abnormal behavior, and cognitive dysfunction (Dec et al., 2017). Data suggested that fluoride deposits in the brain may lead to learning impairment, and the mass accumulation of fluoride can cause a decline in memory (Niu et al., 2018). Therefore, people who dwell at high-fluoride areas have lower IQ scores than those who live in areas with low fluoride concentration (Razdan et al., 2017, Choi et al., 2012). Thus, fluoride-induced neurotoxicity on the central nervous system draws considerable attention.

Normal neural synaptic function and related behavioral performance rely on the coordinated expression of key synaptic structural and functional proteins, including the Drebrin (DBN), the postsynaptic density protein 95 (PSD95) and the axonal growth-associated protein 43 (GAP43) —core markers for synaptic development, plasticity and functional integrity that we focused on in this study. DBN is a cytoskeleton-associated protein found in many brain neurons. This developmentally regulated brain protein is involved in the regulation of synaptic plasticity (Liu et al., 2017, Willmes et al., 2017) and memory formation (Takizawa et al., 2012, Ketschek et al., 2016). Some studies have shown that DBN contributes to the coordination of the actin and microtubule cytoskeleton during the initial stages of axon branching (Ketschek et al., 2016). The expression level of DBN is decreased in the brain tissues of patients with chronic neurodegenerative diseases, such as Alzheimer’s disease and Down syndrome (Chimura et al., 2015). The nerve cell damage model showed that decreasing the expression level of DBN in primary hippocampal neurons reduces the density and width of the dendritic spine, thereby reducing information transmission efficiency (Chimura et al., 2015). PSD95 is a pivotal postsynaptic scaffold protein, which is essential for synaptic development, information transmission, and synaptic remodeling (Mardones et al., 2019, Kneussel and Hausrat, 2016). PSD95 plays an crucial role in the maturation of newborn neurons in the hippocampus of adult mice (Mardones et al., 2019). Numerous studies showed that the decreased expression of PSD95 protein is positively correlated with the extent of damage to the central nervous system (Hyun et al., 2022). In a mouse model, the mRNA expression of PSD95 decreases in the brain tissue accompanied with a cognitive decline (Liu et al., 2022). GAP43 is usually associated with axon plasticity and regeneration (Hung et al., 2016), and this protein is a good indicator of neural growth and development. The expression level of the GAP43 protein is elevated in neural cell repair models (Pattarachotanant et al., 2022), and mRNA levels are reduced in injury mouse models (Chen et al., 2022). Therefore, PSD95 and GAP43 can be used as indicators of normal growth and development of nerve cells, which play an essential role in improving cognitive ability.

The present study aimed to investigate the effects of fluoride exposure on neural function in vivo and in vitro. This study revealed that fluoride exposure could damage synaptic and cytoskeleton-associated proteins, thereby providing a new direction for fluoride-induced neurotoxicity.