Fluoride Exposure Induces Inhibition of Sodium-and Potassium-Activated Adenosine Triphosphatase (Na+, K+-ATPase) Enzyme Activity: Molecular Mechanisms and Implications for Public Health

Abstract

In this study, several lines of evidence are provided to show that Na + , K + -ATPase activity exerts vital roles in normal brain development and function and that loss of enzyme activity is implicated in neurodevelopmental, neuropsychiatric and neurodegenerative disorders, as well as increased risk of cancer, metabolic, pulmonary and cardiovascular disease. Evidence is presented to show that fluoride (F) inhibits Na + , K + -ATPase activity by altering biological pathways through modifying the expression of genes and the activity of glycolytic enzymes, metalloenzymes, hormones, proteins, neuropeptides and cytokines, as well as biological interface interactions that rely on the bioavailability of chemical elements magnesium and manganese to modulate ATP and Na + , K + -ATPase enzyme activity. Taken together, the findings of this study provide unprecedented insights into the molecular mechanisms and biological pathways by which F inhibits Na + , K + -ATPase activity and contributes to the etiology and pathophysiology of diseases associated with impairment of this essential enzyme. Moreover, the findings of this study further suggest that there are windows of susceptibility over the life course where chronic F exposure in pregnancy and early infancy may impair Na + , K + -ATPase activity with both short- and long-term implications for disease and inequalities in health. These findings would warrant considerable attention and potential intervention, not to mention additional research on the potential effects of F intake in contributing to chronic disease.

Effects of Fluoride Long-Term Exposure over the Cerebellum: Global Proteomic Profile, Oxidative Biochemistry, Cell Density, and Motor Behavior Evaluation

“…As an example, there is the interaction of fluoride ions with amino acid chains of enzymes associated with mitochondrial function such as glycolytic enzymes in the Krebs’ cycle, which leads to a functional inhibition, hence contributing to the generation of ROS [ 40 ]. In addition, the Na + /K + -ATPases enzymes that are responsible for maintaining the membrane potential in mitochondria, are also sensitive to the action of fluorine and may suffer functional inhibition resulting in the reduction of ATP [ 41 ] and alteration in cell permeability, consequently causing the inhibition of cell respiration [ 42 ]. These mitochondrial changes lead to a higher generation of ROS that induces the action of cellular antioxidant compounds, however if this level of ROS is too high, cells tend not to be able to intercept these compounds resulting in oxidative damage [ 43 ].…”

Mechanisms of Fluoride Toxicity: From Enzymes to Underlying Integrative Networks

“…Na + , K + -ATPase (NKA) is an integral protein in the plasma membrane that transports Na + ions to the outside and K + ions to the inside of the cell [25]. By using the energy from ATP to establish asymmetric distributions of ions across the cell membrane, NKA links metabolic energy to cellular functions and to signaling events both between and within cells.…”

“…More than 60 papers describe the effects of fluoride on the NKA activity, for example, in erythrocytes, hepatocytes and the liver, neurons and the brain, kidney, cardiac muscle and the heart, and adipocytes in both laboratory animals as well as humans. Declan T. Waugh explains the molecular mechanisms by which fluoride inhibits NKA [25]. He suggests that fluoride can inhibit NKA activity by lowering serum Mg 2+ .…”

“…Animal studies have also shown that fluoride exposure results in decreased serum Mg 2+ due to the decreased Mg 2+ absorption in the gastrointestinal tract. NKA activity is also downregulated by the activity of adenylyl cyclase, various hormones, cytokines, and neuropeptides [25]. NKA is a member Intracellular PPi is a by-product of more than 200 different enzyme reactions and its hydrolysis plays a major role in driving fundamental biochemical reactions [23].…”

“…Animal studies have also shown that fluoride exposure results in decreased serum Mg 2+ due to the decreased Mg 2+ absorption in the gastrointestinal tract. NKA activity is also downregulated by the activity of adenylyl cyclase, various hormones, cytokines, and neuropeptides [25]. NKA is a member of the P-type family of active cation transport proteins, such as the Ca 2+ -ATPase or the gastric H + , K + -ATPase [26].…”