Exposure to high levels of sodium fluoride can alter how brain cells grow and communicate, impairing cognitive abilities. A new small-scale study in mice and tissue grown in the lab shows that excess amounts of the chemical destroy structural proteins needed for healthy nerve connections. The results of this study were recently published in the journal Brain Research.
Fluoride is an active non-metallic element that is widely found in nature. Although in small amounts, it has benefits for human health. Dental professionals often recommend lower concentrations to harden enamel and prevent cavities.
However, excessive exposure over long periods poses systemic health risks. In many regions, surface water and groundwater naturally contain high concentrations of minerals. This occurs when groundwater flows through surrounding rock formations that contain large deposits of fluorite. Chronic fluoride toxicity can occur in communities that rely on these untreated water sources.
Over time, toxic amounts of minerals can accumulate in the body. In addition to physical diseases that affect the skeleton, exposure to large amounts of chemicals alters the central nervous system. Previous observations in human populations suggest that people living in high-fluoride areas often have lower scores on intelligence tests compared to people living in low-fluoride areas.
The biological mechanisms behind this cognitive decline remain largely a mystery to the scientific community, but the subject is receiving increasing academic scrutiny. Another paper published in early 2024 showed a link between maternal fluoride levels and infant behavior problems, pointing to early developmental vulnerabilities. To find out exactly how chemicals damage nerve tissue, lead author Linli Chen and a team of researchers from China’s Henan University of Science and Technology conducted laboratory experiments.
The researchers decided to focus on specific proteins that govern the development and structural stability of brain networks. For the brain to process information and form memories, its neurons must communicate effectively. They do this by sending chemical signals across tiny gaps known as synapses.
The receiving and transmitting ends of these neural connections constantly grow, shrink, and adapt based on the organism’s learning experiences. This adaptive cell behavior relies on a fine internal scaffold called the cytoskeleton. Several specialized proteins maintain this internal framework and guide the precise formation of new nerve branches.
The researchers tracked three prominent structural markers: drebrin, postsynaptic density protein 95, and growth-related protein 43. Drebrin stabilizes the internal skeleton and helps form the receiving antennae of neurons. Postsynaptic density protein 95 anchors the receiving end of the synapse so that the signal is caught properly. Growth-associated protein 43 guides the tips of growing nerve fibers toward their desired targets.
To test how fluoride affects these proteins, the research team designed a small study using 30 female mice. After an initial adaptation period, they divided the animals into three equal experimental groups. One group drank pure deionized water, the second group drank water containing 50 milligrams of sodium fluoride per liter, and the third group drank water containing 100 milligrams of sodium fluoride per liter.
Exposure lasted for 5 months. The team then assessed the animals’ learning and memory abilities using a behavioral technique known as a step-down test. The researchers temporarily placed the mice on an insulated elevated platform in a designated test room.
The metal grid floor surrounding the platform caused a mild electric shock. Natural instinct will cause a placed mouse to jump off a high stage, but it should quickly learn how to stay in place to avoid the uncomfortable floor. The scientists recorded how many times the animals jumped incorrectly and counted each jump as an error in avoidance memory.
Behavioral results showed a clear decline in cognitive performance in the experimental group. Mice that drank contaminated water experienced weight loss and decreased overall brain weight. During the test phase, animals exposed to moderate doses of fluoride made more errors than animals that drank pure water. The highest dose group also made more errors, but the results for that particular comparison were not statistically significant.
The team then examined the animals’ brain tissue using molecular analysis techniques. They measured messenger RNA, which acts as genetic instructions that are copied from DNA to build structural proteins. They also measured the final assembled proteins using laboratory methods that identify specific cellular molecules.
Genetic instructions for building postsynaptic density protein 95 were reduced in animals exposed to the highest levels of fluoride. Drebrin protein levels also showed a decreasing trend after sustained exposure, but the measured changes were not statistically significant.
As the dose of the chemical increased, the blueprint for growth-related protein 43 also decreased. Curiously, physical protein levels of this particular marker actually increased in the low-dose group. The researchers believe this may represent an early body compensatory mechanism, in which the organism attempts to repair initial nerve damage by rapidly producing more growth proteins.
To isolate the cellular machinery without interfering with the animal’s entire body, the researchers conducted a secondary experiment. They used a common line of lab-grown cells originally derived from the mouse hippocampus. The hippocampus is a specialized brain region essential for spatial learning and memory consolidation.
The scientists exposed these cultured cells to varying concentrations of sodium fluoride, from zero to 50 millimolar, for 24 hours. They observed the samples using a scanning laser microscope. To visualize the microscopic anatomy, they treated the cells with a specific fluorescent dye that binds to the cytoskeleton and glows under a laser device.
To ensure the cell counts were accurate, the researchers recorded the optical density of the tissue layers. They found that doses as low as 0.5 mmol had little effect on cells. However, a rapid increase to a concentration of 2 mmol prompted rapid death in the artificial environment and stopped the cells from proliferating.
Surviving units exhibited severe physical deformation when viewed under laser microscopy. The branch-like extensions known as dendrites began to atrophy. In some samples, the extension disappeared completely. The number of connection points between adjacent cells has been reduced. The protein’s internal network, especially a structural component called F-actin, has completely lost its dense matrix.
Molecular tests on cultured cells mirrored the results of early animal studies. After 1 day of exposure, cells showed a sharp decline in the production of drebrin, postsynaptic density protein 95, and growth-related protein 43. Without these components, neurons cannot maintain their intended structural shape.
Results obtained from both live animals and isolated cells demonstrate disruption of basic synaptic structures. Excess fluoride appears to physically degrade the brain’s memory networks by stopping the normal production of structural scaffolding materials. The scientists noted that the specific biological effects largely depend on the severity of exposure.
There are several caveats to consider regarding this particular research approach. The concentrations of chemicals used in laboratory experiments were very high. In this setting, natural drinking water is unlikely to reach the extreme levels applied to mice or tissues.
Furthermore, although the results demonstrate a strong physiological correlation between toxic exposure and protein degradation, they do not establish an absolute sequence of events. The researchers noted that further genetic experiments are needed to prove a causal relationship. In the future, the research team plans to use larger numbers of samples and environmental concentrations closer to natural human exposure.
The research paper, “Sodium fluoride exposure induces cognitive impairment through impaired synaptic protein expression and neuronal development in mouse brain,” was authored by Lingli Chen, Rui Wang, Penghuan Jia, Qian Jiang, Siyuan An, Zhihong ying, Dongfang Hu, Hongmei Ning, and Yaming Ge.
