To investigate the molecular bases of dental fluorosis, the researchers analyzed the effects of exposing tooth enamel cells to fluoride—levels on the higher end of what you would find in drinking water and consistent with what is found in areas where people commonly have fluorosis. They then 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 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.

“This gives us a very promising mechanistic view of how fluorosis arises,” Lacruz said. “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.”

The researchers then 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.

“You would think that if you expose the enamel cells and kidney cells to the same stressor—treating them with the same amount of fluoride for the same period of time—that you’d have more or less similar responses. But that was not the case,” said Lacruz. “Under the same circumstances, enamel cells react to coping with stress in vastly different ways than kidney cells. We are unraveling a mechanism that highlights the uniqueness of enamel cells and explains why fluorosis is more of a problem in the teeth than anywhere else in the body.”

In addition to Lacruz, study authors include Francisco J. Aulestia, Johnny Groeling, Guilherme H.S. Bomfim, Veronica Costiniti, and Yi Li of NYU College of Dentistry; Vinu Manikandan, Ariya Chaloemtoem, and Youssef Idaghdour of NYU Abu Dhabi; Axel R. Concepcion of NYU Grossman School of Medicine; and Larry E. Wagner II and David I. Yule of the University of Rochester. This work was funded by the National Institute of Dental and Craniofacial Research (R01DE025639, R01DE027679, and R01DE014756), NYU Abu Dhabi (AD105), and a support grant to NYU Langone’s Laura and Isaac Perlmutter Cancer Center from the National Cancer Institute (P30CA016087).

About NYU College of Dentistry

Founded in 1865, New York University College of Dentistry (NYU Dentistry) is the third oldest and the largest dental school in the US, educating 9 percent of the nation’s dentists. NYU Dentistry has a significant global reach with a highly diverse student body. Visit http://dental.nyu.edu for more.