Changes within enamel cells point to mechanism by which excessive fluoride leads to Fluorosis

Abu Dhabi, UAE – April 7, 2020:  A team of researchers from NYU Abu Dhabi (NYUAD) and NYU College of Dentistry discovered a novel explanation for how dental fluorosis, a condition caused by overexposure to fluoride during childhood, arises. The researchers found that exposing teeth to excessive fluoride alters calcium signaling, mitochondrial function, and gene expression in the cells, forming tooth enamel.

The study, published in Science Signaling, was led by Associate Professor of Basic Science and Craniofacial Biology at NYU College of Dentistry Rodrigo Lacruz in collaboration with other researchers including NYUAD Assistant Professor of Biology Youssef Idaghdour, NYUAD Bioinformatician Vinu Manikandan, and NYUAD undergraduate student Ariya Chaloemtoem, among others.

To investigate the molecular bases of dental fluorosis, the researchers analyzed the effects of exposing tooth enamel cells to high levels of fluoride. Then, they assessed fluoride’s impact on calcium signaling within the cells, given calcium’s role in mineralizing tooth enamel. 

The researchers found that exposing enamel cells from rodents to fluoride resulted in calcium dysregulation, with decreases in calcium entering and stored in the endoplasmic reticulum, a compartment within cells with many functions, including storing calcium. In addition, fluoride disrupted the function of mitochondria (the cells’ power generators), and therefore energy production was altered. Finally, RNA sequencing—which queries the functional output of genomes of cells—revealed that, in enamel cells exposed to fluoride, there was an increased expression of genes encoding endoplasmic reticulum stress response proteins and those encoding mitochondrial proteins, which are involved in producing the cell’s energy. 

'Despite significant efforts in dental health education in the UAE, dental disease still remains a public health concern. Integrating physiology, genomics, and computational methods was instrumental in helping us demonstrate how too much fluoride alters enamel cell function and teeth development. NYUAD undergraduate student Ariya Chaloemtoem, who participated in computational analysis of the data, is currently pursuing this work to understand the effect of fluoride on other cell types,' Idaghdour said.

'Our research highlights how overexposure to fluoride can be detrimental to the teeth, especially in children when they are developing. Children should get the right amount of fluoride through a combination of fluoridated toothpaste and fluoridated water or supplements,' he added.
 
Lacruz commented: “The benefits of fluoride for oral health considerably outweigh the risks. But given how common dental fluorosis is and how poorly understood the cellular mechanisms responsible for this disease are, it is important to study this problem.” 

“If your cells have to make enamel, which is heavily calcified, and due to exposure to too much fluoride the cells undergo continued stress in their capacity to handle calcium, that will be reflected in the enamel crystals as they are formed and will impact mineralization,” Lacruz added.

The researchers repeated the experiment using early-stage kidney cells from humans, but they did not observe the same effects when the kidney cells were exposed to fluoride—suggesting that enamel cells are different from cells forming tissue in other parts of the body.

Fluoride is a naturally occurring mineral that helps to prevent cavities by promoting mineralization and making tooth enamel more resistant to acid. The Centers for Disease Control and Prevention (CDC) named water fluoridation one of 10 great public health achievements of the 20th century for its role in reducing tooth decay. 

While low levels of fluoride help strengthen and protect tooth enamel, too much fluoride can cause dental fluorosis—a discoloration of teeth, usually with opaque white marks, lines, or mottled enamel. Dental fluorosis occurs when children between birth and around nine years of age are exposed to high levels fluoride during this critical window when their teeth are forming, and can actually increase their risk of tooth decay.