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

Declan Timothy Waugh

doi:10.3390/ijerph16081427

Abstract

In this study, several lines of evidence are provided to show that , -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 , -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 , -ATPase enzyme activity. Taken together, the findings of this study provide unprecedented insights into the molecular mechanisms and biological pathways by which F inhibits , -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 , -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.

Highlights

Sodium, potassium-activated adenosine triphosphatase (Na+, K+-ATPase) is an integral protein in the plasma membrane that transports Na+-ions to the outside and K+-ions to the inside of the cell at the expense of ATP, and maintains sodium and potassium homeostasis in animal cells [1,2]
In animal studies, loss of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been found to result in early-onset motor deficits, hyperactivity, cognitive defects, behavioural seizures and sleep disorders [105]. These findings suggest a possible causal link between loss of NKA activity and childhood neurodevelopmental disorders that present with motor deficits, hyperactivity and cognitive defects including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD)
Karademir et al demonstrated that serum calcium levels were 0.075 mmol/L and 0.1 mmol/L lower among subjects with urinary F− levels of 0.70 mg/L and 0.90 mg/L respectively, compared to controls with urinary F− levels of 0.20 mg/L [260]. These findings provide a basis for the hypothesis that F−- induced parathyroid hormone (PTH) release contributes to NKA inhibition by a mechanistic pathway that involves protein kinase C (PKC), cyclic adenosine monophosphate (cAMP) and phospholipase A2 (PLA2)

Summary

Introduction

Potassium-activated adenosine triphosphatase (Na+, K+-ATPase) is an integral protein in the plasma membrane that transports Na+-ions to the outside and K+-ions to the inside of the cell at the expense of ATP, and maintains sodium and potassium homeostasis in animal cells [1,2]. Na+, K+-ATPase (NKA) is responsible for the electrochemical gradient across the plasma membrane, a prerequisite for electrical excitability and secondary transport in neurons, as well as for the transport of other ions and metabolites necessary for the regulation of the cellular ionic homeostasis [3]. By using the energy from ATP to establish asymmetric distributions of ions across the cell membrane, NKA couples metabolic energy to cellular functions and to signaling events both between and within cells [5]. Public Health 2019, 16, 1427; doi:10.3390/ijerph16081427 www.mdpi.com/journal/ijerph

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