Long-term high fluoride exposure during adolescence causes hippocampal impairments

By Shanet Susan AlexJul 13 2023Reviewed by Benedette Cuffari, M.Sc.

In a recent study published in Scientific Reports, researchers evaluated the impacts of prolonged fluoride exposure during adolescence and adulthood on cognition and associated hippocampal alterations.

Study: Prolonged exposure to high fluoride levels during adolescence to adulthood elicits molecular, morphological, and functional impairments in the hippocampus. Image Credit: SedovaY / Shutterstock.com

Background

Fluoride, a naturally occurring chemical element with high electronegativity, is used in various industries. Water is also treated with fluoride to strengthen teeth and reduce tooth decay rates. Nevertheless, considering its presence in reservoirs and soils at high concentrations, fluoride may be considered an environmental toxicant.

Previous studies indicate that fluoride exposure might impact cognitive functions in developing organisms. However, recent evidence suggests that the World Health Organization (WHO)' recommended levels of fluoride in drinking water are not linked with neurological illnesses, whereas higher levels potentially lower intelligence quotient.

About the study

In the present study, researchers assessed whether long-term fluoride exposure at concentrations typically observed in fluorosis endemic areas and artificially fluoridated water during adolescence and adulthood is related to learning and memory problems in mice. The morphological aspects and hippocampal proteomic profile associated with hippocampal fluoride neurotoxicity were also evaluated through a dose-response comparison of the study subjects.

To this end, 21-day-old male mice with a body mass of about 10 g were used in the investigation. The mice were randomly divided into three groups, each of which comprised 14 animals.

Mice consumed drinking water with 50 or 10 mg/L of fluoride for 60 days. A fluoride ion-specific electrode was used to measure the plasma fluoride bioavailability.

While the Morris water maze test was used to evaluate spatial memory, the step-down inhibitory avoidance test was used to assess short- and long-term memory. The hippocampal proteomic profile was determined through mass spectrometry. 

Low fluoride exposure is safe

Long-term exposure to high fluoride levels was found to cause morphological and molecular alterations in the hippocampus, as well as learning and memory deficits in mice. While low fluoride concentration exposure did not result in cognitive impairments, exposure to high fluoride concentrations may provoke cognitive impairments. 

The onset of short- and long-term memory deficits following high fluoride concentrations was related to the raised plasma fluoride bioavailability. These alterations were linked to a neurodegenerative trend in the hippocampal CA3 and dentate gyrus (DG) regions, as well as a hippocampal proteomic profile, particularly of proteins involved in synaptic communication. 

The step-down inhibitory avoidance test revealed that both short-and long-term memory were impaired following 50 mg/L fluoride exposure, whereas no impairment was observed among the 10 mg/L group. Mice in the 50 mg/L group also exhibited poor spatial memory relative to the 10 mg/L and control groups. 

Bioinformatic analysis of biological processes involving proteins revealed both high and low fluoride concentration exposure significantly affected the proteomic profile. Processes connected to energy metabolism and morphological aspects were the most affected. 

Chronic exposure to high fluoride levels was linked to a significant modification of proteins involved in synaptic transmission. Moreover, these alterations may be responsible for the functional deficits observed in the behavioral evaluation, as well as the morphological and molecular assays. Hippocampal neurodegeneration also reflects how long-term high fluoride concentration exposure may harm cognitive function. 

Overall, the study results support the safety of exposure to low fluoride concentrations and offer evidence of possible fluoride neurotoxicity molecular targets in the hippocampus at levels considerably higher than those in artificially fluoridated water.                                                                                                 

Conclusions

While long-term exposure to artificially fluoridated water at the recommended fluoride level was not linked to cognitive impairments, a higher concentration linked to fluorosis caused learning and memory problems and decreased hippocampal neuronal density. 

The study findings are important for future public health regulations regarding the fluoridation of drinking water. To this end, the researchers of the current study emphasize the importance of monitoring fluoride levels in drinking water to confirm that they remain within safe ranges.

Although these findings indicate that chronic exposure to high fluoride levels may negatively impact cognitive function, a better understanding of possible risks involved with long-term fluoride exposure requires additional investigation. Further research at various ages and with longer exposure times is also needed to determine whether the molecular changes observed ad 10 mg/L are innocuous to cognitive function.