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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"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 Fluorid" Front Endocrinol (Lausanne) 12:730913 (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)

"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. doi: 10.1159/000442301(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 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)

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

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Williams JL - "Mottled enamel, and other studies of normal and pathological conditions of this tissue" J Dent Res 5:117 (1923) ... 0050030101
"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".
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)

For many more 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 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). (NOTE: Ammonium fluoride was 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) - see below.

Incredibly, in 1975, in a public release denying that fluoride causes the delayed eruption of teeth, the US PHS Division of Dentistry claimed that none of the published work of DeEds refers to fluoride as affecting thyroid function. [This denial should be classified as scientific misconduct, as this is simply a false representation of scientific findings!]

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

1. In the experimental production of defective enamel in rats, the toxic action of fluorine may be associated with its inhibitory effect on the enzyme phosphatase.
2. Administration of thyroid greatly enhances the susceptibility to fluorine poisoning.
3. Administration of the thyrotropic hormone secreted by the anterior pituitary gland increases susceptibility to fluorine toxicity.
4. Variations in the activity of the thyroid and pituitary glands may be factors in the individual variation in susceptibility to fluorine toxicity.
5. Cadmium ingestion causes defects of the enamel in rats and in man.
De Eds F, Wilson RH, Cutting WC - "Thyrotropic hormone and fluorine activity" Endocrinology 26(6):1053-1056 (1940)

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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