The mechanisms leading to Dental Fluorosis remain unknown...

Mechanisms Unknown?
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The mechanisms leading to Dental Fluorosis remain unknown...

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"Excessive fluoride intake during enamel development can affect enamel mineralization, leading to dental fluorosis. However, its potential mechanisms remain largely unexplored."
Bi R, Sun Y, Xiang L, Xu Z, Ye X, Tian Y, Lin Y, Yang C, Gao Y - "TGF-β1/Smad3 Signaling Is Required to Alleviate Fluoride-Induced Enamel Hypomineralization" Biol Trace Elem Res 202(2):569-579 (2024). doi: 10.1007/s12011-023-03688-y

"The precise mechanism via which fluoride induces the alterations that result in enamel fluorosis remains unclear..."
Sidhu S, Kathuria N, Mahajan B, Sidhu GK, Ramalingam K - "Prevalence and Distribution of Developmental Defects of Enamel in Children Aged 12–15 Years in Fazilka District, Punjab, India, and Their Correlation With Drinking Water Fluoride Level" Cureus 15(12): e51238 (2023) doi:10.7759/cureus.51238

"The underlying mechanism of fluorosis has not been fully elucidated."
Yu FF, Yu SY, Duan LZ, Yang S, Hou XB, Du YH, Gao MH, Zuo J, Sun L, Fu XL, Li ZY, Huang H, Zhou GY, Jia DL, Chen RQ, Ba Y - "Proteomics Sequencing Reveals the Role of TGF-β Signaling Pathway in the Peripheral Blood of Offspring Rats Exposed to Fluoride" Biol Trace Elem Res (2023 Aug 16) doi:10.1007/s12011-023-03805-x

"Presently, the pathogenesis of DF remains unclear."
Zhang K, Lu Z, Guo X - "Advances in epidemiological status and pathogenesis of dental fluorosis" Front Cell Dev Biol 11:1168215 (2023) doi: 10.3389/fcell.2023.1168215

"...the mechanisms underlying fluoride-induced enamel damage are still not fully elucidated."
Yao S, Weng Q, Zhu Y, Liu J, Luo Y, Da D, Zhang Y - "Excessive fluoride impairs autophagy flux in ameloblasts which is prevented by the autophagy activator rapamycin" Environ Toxicol 38(1):193-204 (2023)

"However, the pathogenesis mechanism underlying dental fluorosis has not been fully clarified."
Gong QM, Ling JQ, Wei X - "Research progress in the pathogenesis mechanism of dental fluorosis" Chinese Journal of Stomatology 58(3):217-223 (2023)

"Excess consumption of fluoride during the development of tooth enamel will cause dental fluorosis, but the exact molecular mechanisms remain to be elucidated."
Zou T, Ma L, Gu L, Xi S, Zhang K, Guo X - "Role of Wnt/β-catenin signaling pathway in ameloblast differentiation in relevance to dental fluorosis" Chem Biol Interact 367:110145 (2022)

"Clearly, dental fluorosis remains a world health issue, and despite decades of research, the proximate causes remain unclear."
Costiniti V, Bomfim GH, Mitaishvili E, Son GY, Li Y, Lacruz RS - "Calcium transport in specialized dental epithelia and its modulation by fluoride" Front Endocrinol (Lausanne) 12:730913 (2021)

"...the pathogenesis of dentin fluorosis and its mechanisms are poorly understood."
Kao YH, Igarashi N, Abduweli Uyghurturk D, Li Z, Zhang Y, Ohshima H, MacDougall M, Takano Y, Den Besten P, Nakano Y - "Fluoride Alters Signaling Pathways Associated with the Initiation of Dentin Mineralization in Enamel Fluorosis Susceptible Mice" Biol Trace Elem Res 199(8):3021-3034 (2021)

"Although there are multiple causes of dental fluorosis, the precise mechanism remains controversial."
Ji M, Duan X, Han X, Sun J, Zhang D - "Exogenous transforming growth factor-β1 prevents the inflow of fluoride to ameleoblasts through regulation of voltage-gated chloride channels 5 and 7" Exp Ther Med 21(6):615 (2021)

"Despite decades of research on DF, the cellular mechanisms directly responsible for this disease remain poorly understood."
Aulestia FJ, Groeling J, Bomfim GHS, Costiniti V, Manikandan V, Chaloemtoem A, Concepcion AR, Li Y, Wagner LE 2nd, Idaghdour Y, Yule DI, Lacruz RS - "Fluoride exposure alters Ca2+ signaling and mitochondrial function in enamel cells" Sci Signal 13(619):eaay0086 (2020)

"There are multiple potential causes of dental fluorosis; however, the precise mechanism by which dental fluorosis occurs remain controversial."
Ji M, Xiao L, Xu L, Huang S, Zhang D - "How pH is regulated during amelogenesis in dental fluorosis" Exp Ther Med 16(5):3759-3765 (2018)

"Treatments to prevent fluorosis and the molecular pathways responsive to fluoride exposure remain to be elucidated."
Suzuki M, Ikeda A, Bartlett JD - "Sirt1 overexpression suppresses fluoride-induced p53 acetylation to alleviate fluoride toxicity in ameloblasts responsible for enamel formation" Arch Toxicol 92(3):1283-1293 (2018)

"Fluoride excess of 0.05-0.07 mgF/kgbw/day in water or food additives like salt is the principal cause of endemic dental fluorosis. How fluoride causes these defects is not clear yet."
Jalali R, Guy F, Ghazanfari S, Lyaruu D, van Ruijven L, DenBesten P, Martignon S, Castiblanco G, Bronckers ALJJ - "Mineralization-defects are comparable in fluorotic impacted human teeth and fluorotic mouse incisors" Arch Oral Biol 83:214-221 (2017)

"The mechanism of dental fluorosis is very complex and not fully understood."
Ullah R, Zafar MS, Shahani N - "Potential fluoride toxicity from oral medicaments: A review" Iran J Basic Med Sci 20(8):841-848 (2017)

"The mechanisms by which excessive ingestion of fluoride (F) during amelogenesis leads to fluorosis are still not precisely known."
Charone S, De Lima Leite A, Peres-Buzalaf C, Silva Fernandes M, Ferreira de Almeida L, Zardin Graeff MS, Cardoso de Oliveira R, Campanelli AP, Groisman S, Whitford GM, Everett ET, Buzalaf MA - "Proteomics of Secretory-Stage and Maturation-Stage Enamel of Genetically Distinct Mice" Caries Res 50(1):24-31 (2016)

"...the mechanism of dental fluorosis remains unclear."
Lei S, Zhang Y, Zhang K, Li J, Liu L - "Effects of Fluoride on the Expression of Beclin1 and mTOR in Ameloblasts" Cells Tissues Organs 200(6):405-12 (2015)

"...the underlying mechanism is unclear."
Wei W, Gao Y, Wang C, Zhao L, Sun D "Excessive fluoride induces endoplasmic reticulum stress and interferes enamel proteinases secretion" Environ Toxicol. 28(6):332-41 (2013)

"Currently the molecular mechanism responsible for dental fluorosis remains unknown..."
Sierant ML, Bartlett JD -"Stress Response Pathways in Ameloblasts: Implications for Amelogenesis and Dental Fluorosis" Cells 1(3):631-645 (2012)

"Despite extensive investigation, the developmental mechanism or mechanisms resulting in dental fluorosis are unknown."
Chaturvedi R, Kaur M, Gauba K, Bhalla S - "Dental Fluorosis: An update" Indian J Dent Ed 4(1/2):23 (2011)

"The molecular mechanisms that underlie dental fluorosis are poorly understood."
Sharma R, Tye CE, Arun A, MacDonald D, Chatterjee A, Abrazinski T, Everett ET, Whitford GM, Bartlett JD - "Assessment of dental fluorosis in Mmp20 +/- mice" J Dent Res 90(6):788-92 (2011)

"The exact mechanism through which dental fluorosis develops is not fully understood."
Wong MC, Glenny AM, Tsang BW, Lo EC, Worthington HV, Marinho VC - "Topical fluoride as a cause of dental fluorosis in children" Cochrane Database Syst Rev 2010(1):CD007693 (2010)

"The mechanisms by which fluoride affects enamel formation to result in fluorosis are not fully understood."
Tanimoto K, Le T, Zhu L, Chen J, Featherstone JD, Li W, DenBesten P - "Effects of fluoride on the interactions between amelogenin and apatite crystals" J Dent Res 87(1):39-44 (2008)

"...the mechanism of F(-)-induced toxicity is unclear."
Sharma R, Tsuchiya M, Bartlett JD - "Fluoride induces endoplasmic reticulum stress and inhibits protein synthesis and secretion" Environ Health Perspect 116(9):1142-6 (2008)

"...the precise mechanisms are unclear.”
Moseley R, Waddington RJ, Sloan AJ, Smith AJ, Hall RC, Embery G - "The influence of fluoride exposure on dentin mineralization using an in vitro organ culture model" Calcified Tissue International 73:470-5 (2003)

"The molecular mechanisms that underlie the pathogenesis of dental fluorosis are not known.”
Everett ET, McHenry MA, Reynolds N, Eggertsson H, Sullivan J, Kantmann C, Martinez-Mier EA, Warrick JM, Stookey GK - "Dental fluorosis: variability among different inbred mouse strains" J Dent Res. 81(11):794-8 (2002)

"....the exact mechanism leading to dental fluorosis is not fully understood.”
Susheela AK, Bhatnagar M. - "Structural aberrations in fluorosed human teeth: Biochemical and scanning electron microscopic studies"
Current Science 77:1677-80 (1999)

"The specific mechanisms by which fluoride causes the changes leading to enamel fluorosis are not well defined."
DenBesten PK - "Biological mechanisms of dental fluorosis relevant to the use of fluoride supplements." Community Dent.Oral Epidemiol 27:41–47 (1999)

"How the fluoride disturbs the intracellular transport of the cell in forming the mottled enamel is still unknown."
Matsuo S, Kiyomiya K, Kurebe M - "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" Arch Toxicol 72(12):798-806 (1998)

"Despite extensive investigation, the developmental mechanism or mechanisms resulting in dental fluorosis are unknown."
Wright JT, Chen SC, Hal KI, Yamauchi M, Bawden JW - "Protein Characterization of Fluorosed Human Enamel." Dent Res 75(12):1936 (1996)

"The action of fluoride on tooth development and the observed side-effects of fluorosis are not yet fully understood."
Veron MH, Couble ML - "The biological effects of fluoride on tooth development: possible use of cell culture systems" Int Dent J 42(2):108-12 (1992)

"The mechanism underlying the development of dental fluorosis remains unknown."
Angmar-Månsson B, Whitford GM -"Enamel Fluorosis Related to Plasma F Levels in the Rat" Caries Research 18(1):25–32 (1984) doi:10.1159/000260743

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But...the mechanisms leading to Dental Fluorosis have been known for a long time, perhaps?

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UPDATE: December 2023: We have recently found information on experiments conducted in the early 1910s, showing that enamel defects then known as "mottled teeth" would not occur without a thyroid gland. This evidence was presented in 1917 by Prof. William John Gies, the so-called "father of modern dental education". It preceded the research by Hammett by 5 years.

In 1922 it was first shown by Hammett that the thyroid was essential for the dental defects later described as "dental fluorosis" to occur, therefore providing confirmation from animals studies for the observations made earlier by Greves on goiter and mottled teeth, described in McKay's 1918 paper (Schuld, 2005).
"We shall sooner or later discover that mottled enamel and other similar conditions of this tissue are due to a disturbance of balance in the functioning of the endocrine glands." (Williams et al., 1923)

Schuld A - "Is dental fluorosis causes by thyroid hormone disturbances?" Fluoride 38(2):91–94 (2005)

McKay, FS - "Progress of the year in the investigation of mottled enamel with special reference to its association with artesian water" J Natl Dental Assn 5:721 (1918)

Gies W - "Investigations on the Influence of Internal Secretions on the Development and Status of Teeth" Experimental Biology and Medicine 15(1)5–8 (1917)

For many more recent papers documenting thyroid involvement in dental fluorosis, please see:
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Floyd DeEds - Early evidence that DF is caused by fluoride effects on thyroid hormones...

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A few historic notes...

Floyd DeEds was Assistant Professor of Pharmacology at Stanford until 1927, when he left to take the position of pharmacologist at the US Hygienic Laboratory, Washington D.C. [Science 64:422 (Nov. 4, 1927), courtesy P. Meiers]

In 1931, he was appointed Senior Toxicologist for the U. S. Department of Agriculture, stationed in the department of pharmacology at Stanford's School of Medicine to carry on the investigation of chronic intoxications for the bureau of chemistry and soils. [Science 74:335 (Oct. 2, 1931), courtesy P. Meiers]
"The first problem assigned to the new laboratory was the determination of the chronic toxicity of inorganic fluorine compounds, which were finding increasing use as substitutes and supplements to lead and arsenic compounds as insecticides." (De Eds et al., 1951)
In 1932, DeEds warned dentists about the use of fluoride in dental materials, including ammonium fluoride (NH4F) - "used sometimes in dental office for whitening teeth". (NOTE: Ammonium fluoride was also used by Goldemberg as an antithyroid medication at this time.)
"Dentists submit themselves also to possibilities of chronic intoxication in the mixing of F compounds with mild abrasives or pastes; they should also avoid swallowing or inhalation of F in dust."
In 1933, DeEds authored the very first review of chronic fluoride poisoning.

In 1934, DeEds presented first evidence that much higher doses of fluoride are required to produce similar signs of toxicity in rats when compared to humans. [In the same year, Phillips, English and Hart (US Dept. of Agriculture) also showed that nontoxic dosages of desiccated thyroid become toxic when sodium fluoride was fed or injected, and nontoxic doses of fluoride became toxic when desiccated thyroid was fed.]

In 1940, DeEds and Robert Wilson reported dental fluorosis in rats as a result of the synergistic action of fluoride and thyroid hormones. Results were described as "strikingly clearcut".

In the same year, DeEds et al. investigated fluoride and the thyroid-stimulating hormone (TSH) and reported that TSH also increased bleaching of the incisors (dental fluorosis) in rats.

In 1941, he summarized his findings in the journal of the American Dental Association (JADA).

Incredibly, in 1975, in a public press release denying that fluoride causes the delayed eruption of teeth, the US Public Health Service (Division of Dentistry) claimed that none of the published work of DeEds refers to fluoride as affecting thyroid function. [Misrepresentation of scientific findings --> scientific misconduct?]


DeEds F - "Dental significance of fluoride in dietary and therapeutic products" JADA 19:861-862 (1932)

DeEds F - "Factors in the Etiology of Mottled Enamel" The Journal of the American Dental Association 28(11):1804–1814 (1941) doi:10.14219/jada.archive.1941.0297
"Administration of thyroid greatly enhances the susceptibility to fluorine poisoning....Administration of the thyrotropic hormone secreted by the anterior pituitary gland increases susceptibility to fluorine toxicity...Variations in the activity of the thyroid and pituitary glands may be factors in the individual variation in susceptibility to fluorine toxicity."

De Eds F, Wilson RH, Cutting WC - "Thyrotropic hormone and fluorine activity" Endocrinology 26(6):1053-1056 (1940) ... m=fulltext

Gabovich RD, Ovrutskiy GD - "Fluorine in Stomatology and Hygiene" Kazan State Medical Institute (1969)
Translated by: U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health (1977)

Wilson RH, DeEds F - "The Synergistic Action Of Thyroid On Fluoride Toxicity" Endocrinology 26:851 (1940) ... edFrom=PDF

DeEds F, Wilson RH, Ambrose A - "Hazards and potential drugs" in: Crops in Peace and War, The Yearbook of Agriculture 1950-1951, US Department of Agriculture, Washington, D.C. (1951)

DeEds F - "Chronic fluorine intoxication. A review" Medicine 12:1-60 (1933)

DeEds F - "Comparative toxicities with special reference to arsenical and fluorine-containing insecticides" (Sci Note) Jour Econ Ent. 26:301-304 (1933)

DeEds F, Thomas JO - "Comparative chronic toxicities of fluorine compounds" Soc. Expt. Biol. and Med. Proc. 31:824-825 (1934)

Phillips PH, English H, Hart EB - "The augmentation of the toxicity of fluorosis in the chick by feeding desiccated thyroid" Jour Nutr 10:399-407 (1934) (Wisconsin Agricultural Experiment Station) ... 99/4726460

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, Public Health Service, Health Resources Administration,
Division of Dentistry ... denial.pdf
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Re: The mechanisms leading to Dental Fluorosis remain unknown...

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Repost from the "Apple a Day" forum:


Since 1935 has it been known that fluoride and desiccated thyroid have synergistic effects.

In 1935 Phillips et al. found that the toxicity of NaF to chicks was much increased when desiccated thyroid was fed. They observed that non-toxic doses of thyroid became toxic when NaF was fed, and non-toxic doses of NaF became toxic when fed together with desiccated thyroid.

When fed sodium fluoride the "relatively harmless level" of 0.2 percent, desiccated thyroid produced results similar as if fluoride levels had been at the highly toxic 9.6 percent level (Phillips et al., 1935a, 1935b, 1936a, 1936b).

Wilson & DeEds made similar observations during repeated experiments with rats (1940), reporting that effects of fluoride and desiccated thyroid on dental fluorosis were "strikingly clear-cut".

Dental fluorosis was induced either by feeding desiccated thyroid or by injecting TSH (Wilson et al., 1940; DeEds et al., 1940).

In 1969, Russian researchers Gabovich and Ovrutskiy reported:

"In rats receiving fluorine with the diet, changes in tooth enamel increased with simultaneous administration of dry substance of thyroid gland. This agrees completely with our observations: with the use of tap water containing 2 mg fluorine, there was more severe damage ("mottled enamel") to the teeth of children with signs of goiter than in others."
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