Fluoride Action Network

Mechanisms by Which Fluoride Causes Dental Fluorosis Remain Unknown

By Michael Connett | July 2012

When it comes to how fluoride impacts human health, no tissue in the body has been studied more than the teeth. Yet, despite over 50 years of research, the mechanism by which fluoride causes dental fluorosis (a hypo-mineralization of the enamel that results in significant staining of the teeth) is not yet fully understood. Several mechanisms, however, have been proposed, and it is generally believed that the mechanism involves a toxic effect on the cells (ameloblasts) involved in enamel formation.


“Currently the molecular mechanism responsible for dental fluorosis remains unclear, but it is known that fluorotic enamel has higher protein content and is therefore soften than nonfluorosed enamel.”
SOURCE:  Sierant ML, Bartlett JD. (2011). A Potential Mechanism for the Development of Dental Fluorosis. In: Interface Oral Health Science (K Sasaki, et al., eds).

“Both collagenous and noncollagenous components appear to undergo structural alterations during fluorosis, although the precise mechanisms are unclear.”
SOURCE: Moseley R, et al. (2003). The influence of fluoride exposure on dentin mineralization using an in vitro organ culture model. Calcified Tissue International 73:470-5.

“While it is well-accepted that fluoride interacts with mineralized tissues and, at elevated concentrations, disturbs the mineralization process, the molecular mechanisms that underlie the pathogenesis of dental fluorosis are not known.”
SOURCE: Everett ET, et al. (2002). Dental fluorosis: variability among different inbred mouse strains. Journal of Dental Research 81: 794-8.

“In the past, several explanations or hypotheses have been proposed for the fluoride-induced retention of amelogenin-derived fragments (as well as the degraded products of other matrix proteins) in the matured enamel. The postulated fluoride effects are categorized into two groups: (i) on intracellular events, including gene expression, synthesis, trafficking and secretion of proteins, resorption and degradation of the once-secreted products; and (ii) on extracellular events constituting multivarious interactions between and among matrix proteins, proteases, crystals, and other fluid constituents, particularly fluoride and calcium ions.”
SOURCE: Aoba T, Fejerskov O. (2002). Dental fluorosis: chemistry and biology. Critical Reviews of Oral Biology and Medicine 13: 155-70.

“Considering the complexity of the biological mineralization process, the exact mechanism leading to dental fluorosis is not fully understood.”
SOURCE: Susheela AK, Bhatnagar M. (1999). Structural aberrations in fluorosed human teeth: Biochemical and scanning electron microscopic studies. Current Science 77: 1677-1680.

“The fact that human dentin also exhibits hypomineralization in human fluorotic teeth indicates that fluoride exerts its effects on very basic processes involved in biomineralization in general, irrespective of whether crystal formation and growth occurs in mesenchymally or ectodermally derived mineralized tissues. However, relatively little work has been done to identify the mechanisms by which low serum levels of fluoride which result in dental fluorosis affect the development of mineralizing tissues.”
SOURCE: Fejerskov O, Richards A, DenBesten P. (1996). The effect of fluoride on tooth mineralization. In: Fejerskov O, Ekstrand J, Burt B, Eds. Fluoride in Dentistry, 2nd Edition. Munksgaard, Copenhagen. pp. 112-152.

“Fluoride (F-) that reaches developing teeth induces defects in the hard tissues, particularly in the enamel. This is broadly the mechanism of dental fluorosis but many details of the mechanism, including the exact minimal threshold doses are not clear.”
SOURCE: Bronckers AL, Woltgens JH. (1985). Short-term effects of fluoride on biosynthesis of enamel-matrix proteins and dentine collagens and on mineralization during hamster tooth-germ development in organ culture. Archives of Oral Biology 30: 181-91.

“The mechanism underlying the development of dental fluorosis remains unknown.”
SOURCE: Angmar-Mansson B, Whitford GM. (1984). Enamel fluorosis related to plasma F levels in the rat. Caries Research 18:25-32.

POSSIBLE MECHANISMS by which fluoride causes fluorosis:

“In addition to effects on mineral structure and extracellular processes, NaF affects intracellular pathways leading to alterations in the actin cytoskeleton. These alterations in ‘functional morphology’’ correlate with interference with the Rho pathway, and are expected to affect ameloblast cyclic morphologic changes known to be disturbed in fluoride-treated animals. The Rho pathway in ameloblasts may provide a target for fluoride, potentially leading also to Rho-linked changes in gene expression. ”
SOURCE: LI Y, et al. (2005). Effects of sodium fluoride on the actin cytoskeleton of murine ameloblasts. Archives of Oral Biology (in press)

“we have been able to more accurately localise the pathological effects of fluoride in altering mineralisation patterns within fluorotic teeth… In summary, the present study has demonstrated important structural and quantitative changes in different PG species (decorin, biglycan and versican) within the individual tissue compartments of the dentine–pulp complex, following fluoride exposure. Such changes probably reflect the effects of fluoride on both the synthesis and extracellular processing of these molecules, the consequences of which will be to influence the mineralisation process, thereby providing a pathogenic basis for the altered mineralisation patterns observed during fluorosis.”
SOURCE: Waddington RJ, et al. (2004). Fluoride-induced changes to proteoglycan structure synthesised within the dentine–pulp complex in vitro. Biochimica et Biophysica Acta 1689:142-51.

“We conclude that the ingestion of fluoride resulting in a serum fluoride of 5-10 uM (95-190 ppb) can affect the amount of active proteinase (enzyme) present in maturation-stage enamel in the rat. In addition, fluoride at concentrations as low as 2 uM (38 ppb) can reduce metalloproteinase activity at low pH. These combined effects of fluoride on enamel might contribute to a mechanism by which high concentrations of systemic fluoride can affect the hydrolysis of enamel matrix protein and subsequent biomineralization, resulting in fluorosis.”
SOURCE: DenBesten PK, et al. (2002). Effects of fluoride on rat dental enamel matrix proteinases. Archives of Oral Biology 47: 763-770.

“Overall these results provide further verification that fluoride may alter post-translational events during fluorosis through enzyme activity, and they may aid in the elucidation of a mechanism for fluorosis.”
SOURCE: Milan AM, et al. (2001). Fluoride alters casein kinase II and alkaline phosphatase activity in vitro with potential implications for dentine mineralization. Archives of Oral Biology 46:343-51.

“Of the several mechanisms proposed for the adverse effect on tooth development, the most likely is that fluoride has an effect on cell function, either through interactions with the developing ameloblasts or the intracellular matrix.”
SOURCE: Fomon SJ, et al. (2000). Fluoride intake and prevalence of dental fluorosis: trends in fluoride intake with special attention to infants. Journal of Public Health Dentistry 60: 131-9.

“In our previous studies on the enamel fuorosis model rat, morphological observation of the secretory ameloblast shows accumulation of transport vesicles, disorganization of Golgi stacks and accumulation of abnormal large granules; pertussis toxin-induced adenosine diphosphate (ADP)-ribosylation of the membrane fraction reveals activation of trimeric G proteins bound to rough endoplasmic reticulum (rER) and Golgi membranes with fluoride treatment. These findings suggest that fluoride results in aberrant intracellular transport in the ameloblast through the G proteins.”
SOURCE: Matsuo S, et al. (2000). Fluoride-induced ultrastructural changes in exocrine pancreas cells of rats: fluoride disrupts the export of zymogens from the rough endoplasmic reticulum (rER). Archives of Toxicology 73:611-7.

“Such a major change in the biochemical structure of DPP, together with those previously reported for other macromolecules such as proteoglycans, are likely to be important in considering the hypomineralization associated with fluorosis.”
SOURCE: Milan AM, et al. (1999). Altered phosphorylation of rat dentine phosphoproteins by fluoride in vivo. Calcified Tissue International 64:234-8.

“An increase in fluoride content and decrease in calcium content in fluorosed human teeth were observed when compared to the control.”
SOURCE: Susheela AK, Bhatnagar M. (1999). Structural aberrations in fluorosed human teeth: Biochemical and scanning electron microscopic studies. Current Science 77: 1677-1680.

“[S]tructural alterations of ameloblastic layer result in the retardation of enamel matrix formation and its mineralization. Calcium deficiency and generalized malnutrition disturb the physiological conditions that affect amelogenesis in humans and can lead to variations in clinical appearance of dental fluorosis at similar levels of fluoride intake.”
SOURCE: Susheela AK, Bhatnagar M. (1999). Structural aberrations in fluorosed human teeth: Biochemical and scanning electron microscopic studies. Current Science 77: 1677-1680.

“The secretory ameloblast exposed to fluoride showed accumulations of black globules and large clear vacuoles in distal cytoplasm. In our previous study on the enamel fluorosis rat model, the secretory ameloblast showed accumulation of transport vesicles, disorganization of the Golgi stack, and accumulation of abnormal large granules, suggesting that fluoride resulted in aberrant intracellular transport in the ameloblast. How the fluoride disturbs the intracellular transport of the cell in forming the mottled enamel is still unknown… We wished to clarify the participation of the heterotrimeric G proteins in the toxic action of fluoride on forming enamel fluorosis… It is suggested that these heterotrimeric G proteins are activated by fluoride, resulting in disruption of organelles and abberrant intracellular transport in the secretory ameloblast of enamel fluorosis model rats.”
SOURCE: Matsuo S, et al. (1998). Mechanism of toxic action of fluoride in dental fluorosis: whether trimeric G proteins participate in the disturbance of intracellular transport of secretory ameloblast exposed to fluoride. Archives of Toxicology 72: 798-806.

“It can be speculated that fluoride may affect the maturation of ameloblasts by influencing their ability to remove protein and water from maturing enamel and/or may interfere with the ameloblast’s capacity to produce proteolytic enzymes necessary to initiate amelogenin breakdown.”
SOURCE: Fejerskov O, et al. (1990). The nature and mechanisms of dental fluorosis in man. Journal of Dental Research 69(Spec Iss): 692-700.

“some of the reported changes in cell morphology, such as increased vacuolation, might be due to an accumulation of unsecreted matrix and could produce changes in the lysosomal system.”
SOURCE: Robinson C, Kirkham J. (1990). The effect of fluoride on the developing mineralized tissues. Journal of Dental Research 69(Spec Issue): 685-91.

“a significant increase in the dermatan sulphate content may be an important detrimental factor in dental fluorosis.”
SOURCE: Susheela AK, et al. (1988). The status of sulphated isomers of glycosaminoglycans in fluorosed human teeth. Archives of Oral Biology 33: 765-7.

“Fluorosed enamel has a reduced amount of mineral when compared with control enamel.”
SOURCE: Denbesten PK, et al. (1985). Changes in the fluoride-induced modulation of maturation stage ameloblasts of rats. Journal of Dental Research 64: 1365-70.