Mini-review
Molecular mechanisms of fluoride toxicity

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Abstract

Halfway through the twentieth century, fluoride piqued the interest of toxicologists due to its deleterious effects at high concentrations in human populations suffering from fluorosis and in in vivo experimental models. Until the 1990s, the toxicity of fluoride was largely ignored due to its “good reputation” for preventing caries via topical application and in dental toothpastes. However, in the last decade, interest in its undesirable effects has resurfaced due to the awareness that this element interacts with cellular systems even at low doses. In recent years, several investigations demonstrated that fluoride can induce oxidative stress and modulate intracellular redox homeostasis, lipid peroxidation and protein carbonyl content, as well as alter gene expression and cause apoptosis. Genes modulated by fluoride include those related to the stress response, metabolic enzymes, the cell cycle, cell–cell communications and signal transduction.

The primary purpose of this review is to examine recent findings from our group and others that focus on the molecular mechanisms of the action of inorganic fluoride in several cellular processes with respect to potential physiological and toxicological implications. This review presents an overview of the current research on the molecular aspects of fluoride exposure with emphasis on biological targets and their possible mechanisms of involvement in fluoride cytotoxicity. The goal of this review is to enhance understanding of the mechanisms by which fluoride affects cells, with an emphasis on tissue-specific events in humans.

Introduction

The fluoride ion is derived from the element fluorine, a gas that never occurs in a free state in nature. Fluoride is abundant in the environment and exists only in combination with other elements as fluoride compounds, which are constituents of minerals in rocks and soil. Therefore, fluoride is commonly associated with volcanic activity.

Sources of fluoride include natural fluoride in foodstuffs and water, i.e., fluoridated water (usually at 1.0 mg/l), fluoride supplements (such as fluoride tablets), fluoride dentifrices (containing on average 1000 mg/kg), and professionally applied fluoride gel (containing on average 5000 mg/kg). The main source of fluoride for humans is the intake of groundwater contaminated by geological sources (maximum concentrations reaching 30–50 mg/l). The level of fluoride contamination is dependent on the nature of the rocks and the occurrence of fluoride-bearing minerals in groundwater. Fluoride concentrations in water are limited by fluorite solubility, so that in the absence of dissolved calcium, higher fluoride solubility should be expected in the groundwater of areas where fluoride-bearing minerals are common and vice versa [1].

Excessive fluoride intake over a long period of time may result in a serious public health problem called fluorosis, which is characterized by dental mottling and skeletal manifestations such as crippling deformities, osteoporosis, and osteosclerosis. Endemic fluorosis is now known to be global in scope, occurring on all continents and affecting many millions of people [2].

In some regions, artificial fluorides used to fluoridate community water supplies (mostly at around 1 mg/l) include silicofluoride compounds (sodium silicofluoride and hydrofluosilicic acid) and sodium fluoride (NaF). At neutral pH, silicofluoride is dissociated to silic acid, fluoride ion, and hydrogen fluoride (HF) [3]. The primary benefit associated with fluoride supplementation is linked to the potential to reduce the risk of dental caries due to the cariostatic effects of fluoride. Even in the past, fluoride was considered an essential element. In actuality, there is a lack of consensus as to the role of fluoride in human nutrition and optimal development and growth [4].

Additional risks of increased fluoride exposure are known; the most significant are effects on bone cells (both osteoblasts and osteoclasts) that can lead to the development of skeletal fluorosis. It is now recognized that fluoride also affects cells from soft tissues, i.e., renal, endothelial, gonadal, and neurological cells [5].

The minimal risk level for daily oral fluoride uptake was determined to be 0.05 mg/kg/day [6], based on a non-observable adverse effect level (NOAEL) of 0.15 mg fluoride/kg/day for an increased fracture rate. Estimations of human lethal fluoride doses showed a wide range of values, from 16 to 64 mg/kg in adults and 3 to 16 mg/kg in children [6].

Organofluoride compounds (carbon–fluoride bond) are increasingly used. These compounds have a wide range of functions and can serve as agrochemicals, pharmaceuticals, refrigerants, pesticides, surfactants, fire extinguishing agents, fibers, membranes, ozone depletors, and insulating materials [7]. An estimated 20% of pharmaceuticals and 30–40% of agrochemicals are organofluorines [8]. However, environmental and health issues are still a problem for many organofluorines. Because of the strength of the carbon–fluoride bond, many synthetic fluorocarbons and fluorocarbon-based compounds are persistent global contaminants and may be harming the health of wildlife [7]. Their effects on human health are unknown. However, the toxicity of fluorinated organic chemicals is usually related to their molecular characteristics rather than to the fluoride ions that are metabolically displaced.

The present review is focused on the molecular effects of inorganic fluoride with respect to potential physiological and toxicological implications. It addresses the current understanding of the signal transduction pathways and mechanisms underlying the sensitivity of various organs and tissues to fluoride. This review provides information on the cellular and molecular aspects of the interactions between fluoride and cells, with an emphasis on tissue-specific events in humans.

Section snippets

Uptake and accumulation

Fluoride is very electronegative, which means that it has a strong tendency to acquire a negative charge and forms fluoride ions in solution. In aqueous solutions of fluoride in acidic conditions such as those of the stomach, fluoride is converted into HF, and up to about 40% of ingested fluoride is absorbed from the stomach as HF [9].

Fluoride transport through biological membranes occurs primarily through the non-ionic diffusion of HF. Classic studies with artificial lipid bilayers and pH

Cellular effects of fluoride

Fluoride exerts diverse cellular effects in a time-, concentration-, and cell-type-dependent manner. The main toxic effect of fluoride in cells consists of its interaction with enzymes. In most cases, fluoride acts as an enzyme inhibitor, but fluoride ions can occasionally stimulate enzyme activity. The mechanisms depend on the type of enzyme that is affected [20]. Fluoride at micromolar levels is considered an effective anabolic agent because it promotes cell proliferation, whereas millimolar

Consequences of co-exposure to fluoride and other substances

Drinking water is the primary source of fluoride exposure in humans. In this route of exposure, fluoride coexists with several other xenobiotics, frequently metals. Fluoride consumption within these mixtures could modify its kinetic and toxicity properties. Here, we present some mixtures that should be mentioned given their frequency and biological relevance.

Conclusions

In this work, we focused on showing the effects of inorganic fluoride compounds on the cellular function of several biological systems. The studies described above demonstrated that fluoride can interact with a wide range of cellular processes such as gene expression, cell cycle, proliferation and migration, respiration, metabolism, ion transport, secretion, endocytosis, apoptosis/necrosis, and oxidative stress, and that these mechanism are involved in a wide variety of signaling pathways (Fig.

Conflicts of interest

None.

Acknowledgement

This review was made possible by the Mexican Council for Science and Technology supported (Conacyt, grants 56785 and 104316).

References (170)

  • H.A. Hassan et al.

    Mitigating effects of antioxidant properties of black berry juice on sodium fluoride induced hepatotoxicity and oxidative stress in rats

    Food Chem. Toxicol.

    (2009)
  • E.A. García-Montalvo et al.

    Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress

    Toxicology

    (2009)
  • J.A. Izquierdo-Vega et al.

    Decreased in vitro fertility in male rats exposed to fluoride-induced oxidative stress damage and mitochondrial transmembrane potential loss

    Toxicol. Appl. Pharmacol.

    (2008)
  • C.D. Nobes et al.

    Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia

    Cell

    (1995)
  • M. Zhang et al.

    Effects of fluoride on the expression of NCAM, oxidative stress, and apoptosis in primary cultured hippocampal neurons

    Toxicology

    (2007)
  • J. Ghosh et al.

    Cytoprotective effect of arjunolic acid in response to sodium fluoride mediated oxidative stress and cell death via necrotic pathway

    Toxicol. In Vitro

    (2008)
  • M. Mittal et al.

    Effects of individual and combined exposure to sodium arsenite and sodium fluoride on tissue oxidative stress, arsenic and fluoride levels in male mice

    Chem. Biol. Interact.

    (2006)
  • W. Ridley et al.

    Fluoride-induced cyclooxygenase-2 expression and prostaglandin E2 production in A549 human pulmonary epithelial cells

    Toxicol. Lett.

    (2009)
  • A. Paul et al.

    Stress-activated protein kinases: activation, regulation and function

    Cell Signal.

    (1997)
  • X.A. Zhan et al.

    Effects of fluoride on hepatic antioxidant system and transcription of Cu/Zn SOD gene in young pigs

    J. Trace Elem. Med. Biol.

    (2006)
  • H. Matsui et al.

    Some characteristics of fluoride-induced cell death in rat thymocytes: cytotoxicity of sodium fluoride

    Toxicol. In Vitro

    (2007)
  • S.J. Flora et al.

    Co-exposure to arsenic and fluoride on oxidative stress, glutathione linked enzymes, biogenic amines and DNA damage in mouse brain

    J. Neurol. Sci.

    (2009)
  • D. Chlubek et al.

    Activity of pancreatic antioxidative enzymes and malondialdehyde concentrations in rats with hyperglycemia caused by fluoride intoxication

    J. Trace Elem. Med. Biol.

    (2003)
  • K. Kubota et al.

    Fluoride induces endoplasmic reticulum stress in ameloblasts responsible for dental enamel formation

    J. Biol. Chem.

    (2005)
  • J.L. Borke et al.

    Chronic fluoride ingestion decreases 45Ca uptake by rat kidney membranes

    J. Nutr.

    (1999)
  • I.C. Park et al.

    Tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis is dependent on activation of cysteine and serine proteases

    Cytokine

    (2001)
  • M. Salgado-Bustamante et al.

    Pattern of expression of apoptosis and inflammatory genes in humans exposed to arsenic and/or fluoride

    Sci. Total Environ.

    (2010)
  • I. Mellman et al.

    The road taken: past and future foundations of membrane traffic

    Cell

    (2000)
  • P.G. Borasio et al.

    Low concentrations of sodium fluoride inhibit neurotransmitter release from the guinea-pig superior cervical ganglion

    Neurosci. Lett.

    (2004)
  • G. Decorti et al.

    Endocytosis of gentamicin in a proximal tubular renal cell line

    Life Sci.

    (1999)
  • D.E. Clapham

    Calcium signalling

    Cell

    (1995)
  • T.K. Das et al.

    Effect of long-term administration of sodium fluoride on plasma calcium level in relation to intestinal absorption and urinary excretion in rabbits

    Environ. Res.

    (1993)
  • T. Kawase et al.

    The calcium mobilizing action of low concentrations of sodium fluoride in single fibroblasts

    Life Sci.

    (1988)
  • N. Narayanan et al.

    Inhibitory and stimulatory effects of fluoride on the calcium pump of cardiac sarcoplasmic reticulum

    Biochim. Biophys. Acta

    (1991)
  • J. Caverzasio et al.

    Characteristics and regulation of Pi transport in osteogenic cells for bone metabolism

    Kidney Int.

    (1996)
  • B.E. Peerce

    Effect of substrates and pH on the intestinal Na+/phosphate cotransporter: evidence for an intervesicular divalent phosphate allosteric regulatory site

    Biochim Biophys. Acta

    (1995)
  • A. Rigalli et al.

    Bone mass increase and glucose tolerance in rats chronically treated with sodium fluoride

    Bone Miner.

    (1992)
  • S. L’hoste et al.

    CFTR mediates cadmium-induced apoptosis through modulation of ROS level in mouse proximal tubule cells

    Free Radic. Biol. Med.

    (2009)
  • W.M. Edmunds, P.L. Smedley, Groundwater geochemistry and health: an overview, in: Appleton, Fuge, McCall (Eds.),...
  • World Health Organization (WHO), in: K. Bailey, J. Chilton, E. Dahi, M. Lennon, P. Jackson, J. Fawell (Eds.), Fluoride...
  • E.T. Urbansky

    Fate of fluorosilicate drinking water additives

    Chem. Rev.

    (2002)
  • F.H. Nielsen

    Micronutrients in parenteral nutrition: boron, silicon, and fluoride

    Gastroenterology

    (2009)
  • National Research Council (NRC), Fluoride in drinking-water, A scientific review of EPA's standards, Washington DC,...
  • ATSDR (Agency for Toxic Substances and Disease Registry), Toxicological Profile for Fluorides, Hydrogen Fluoride, and...
  • L.H. Weinstein et al.

    Fluorides in the Environment. Effects on Plants and Animals

    (2004)
  • W.K. Hagmann

    The many roles for fluorine in medicinal chemistry

    J. Med. Chem.

    (2008)
  • G.M. Whitford et al.

    Report for Working Group I: strategies for improving the assessment of fluoride accumulation in body fluids and tissues

    Adv. Dent. Res.

    (1994)
  • A. Gofa et al.

    NaF potentiates a K(+)-selective ion channel in G292 osteoblastic cells

    J. Membr. Biol.

    (1996)
  • G.M. Whitford et al.

    Effects of fluoride on structure and function of canine gastric mucosa

    Dig. Dis. Sci.

    (1997)
  • M. Sireli et al.

    The effect of acute fluoride poisoning on nitric oxide and methemoglobin formation in the Guinea pig

    Turk. J. Vet. Anim. Sci.

    (2004)
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