Fluoride’s Epigenetic Effect on Bone Development

When it comes to dental health, fluoride is considered a champion against tooth decay. It’s in just about every brand of toothpaste, even added to our drinking water here in the US. But fluoride is a chemical and too much of it can be toxic. Excessive exposure to fluoride has been shown to cause adverse health effects, many of which cannot be corrected.  While several studies have examined chronic fluoride exposure and its link to certain conditions, little is known about the epigenetic mechanisms involved.

In a study published in Environmental Toxicology and Pharmacology, scientists set out to learn more about the epigenetic effects of excessive fluoride exposure. In particular, they focused on the role of histone modification in the development of skeletal fluorosis, a crippling and painful bone disease that affects millions of people worldwide.

Found naturally in soil, water, and food, fluoride is safe in small amounts and necessary to ensure proper bone and tooth development. However, overexposure to the chemical can cause skeletal and dental deformities. Known collectively as fluorosis, this condition results in bone deterioration and/or mottling and discoloration of tooth enamel. Ranging in severity, the condition is dependent upon the amount, duration, and age of the individual during fluoride exposure.

Dental fluorosis is a mild condition that affects the tooth enamel and is often seen in young children who ingest fluoride. It appears as faint white lines or streaks on the teeth and is more a cosmetic issue than damaging. Skeletal fluorosis, on the other hand, is more severe and caused by prolonged, excessive exposure to fluoride. Often misdiagnosed for other types of bone and joint diseases, this condition has no known cure.  Although few cases are reported in the US, skeletal fluorosis is becoming a major health issue in countries like India due to fluoride contaminated groundwater.

Even though certain populations may be more susceptible to skeletal fluorosis, the only practical way to reduce the occurrence of the disease right now is to keep fluoride intake within safe limits (below 1 mg/L). For those already afflicted with the disease, treatment of the side effects can be challenging and recovery, if possible, can take a very long time. Therapies being considered might include reducing the toxicity of fluoride in the body and repairing damaged tissue and bone loss. To do this, it’s important to first understand the pathogenic mechanisms of skeletal fluorosis, including any epigenetic factors implicated in the process.

Epigenetics refers to changes in gene expression arising from chemical modification of DNA or histone proteins. Histone modification is a key epigenetic mechanism and is involved in many various biological processes including gene regulation, DNA repair, and chromosome condensation. Methylation, acetylation, and phosphorylation are just a few covalent histone modifications that have been shown to alter gene expression. For instance, H3K9 acetylation and H3K4 trimethylation are associated with gene activation, whereas trimethylation of H3K9 and H3K27 are associated with gene repression. Environmental toxin exposure can alter histone protein, and research has shown that histone modification plays an essential role in epigenetic activation or repression of genes associated with specific diseases.

Previous studies have reported that fluoride exposure increased H3K9 and H3K4 dimethylation levels in early mouse embryos with impaired oocyte maturation and development. In the current study, the researchers investigated fluoride-induced histone alterations present in the bone development pathway (TGFβ signaling) using human osteosarcoma cell line.

The results showed that fluoride exposure increased histone methyltransferases expression and global histone H3K9 and H3K27 trimethylation which subsequently led to silencing two critical genes in the pathway: TGFBR2 and SMAD3. Decreased expression of these two genes disrupted the extracellular matrix (ECM) which regulates tissue organization and cell behavior. During bone development, proper formation of ECM is critical for providing structural strength to bone tissue. According to this study, chronic fluoride exposure appears to alter ECM formation, as well as bone mineralization and skeletal growth, thus leading to the development of fluorosis.

As the researchers reported, “The repressive epigenetic markers of H3K9 trimethylation can alter secretion and formation of extracellular matrix, mineralization of bone, angiogenesis, bone porosity, and connective tissue formation and may lead to the brittle bone formation, a hallmark of skeletal fluorosis.“

While further research is needed to validate the results from this study, the overall findings indicate that an epigenetic modification, H3K9 trimethylation, may be involved in skeletal fluorosis development via inhibiting the expression of genes TGFBR2 and SMAD3.

Environmentally induced diseases like skeletal fluorosis first and foremost need to be prevented by taking measures to reduce exposure to the toxin. Also, finding treatments that are effective for skeletal fluorosis and other bone loss type disorders are needed, especially since recovery of bone tissue can be near impossible. Because epigenetic modifications are reversible, there is hope that identifying the epigenetic mechanisms involved in these diseases may someday lead to better diagnostic tools and novel treatments that can grant a more favorable prognosis.

Source: Daiwile AP et. al. (Jan 2018). Role of fluoride induced histone trimethylation in development of skeletal fluorosis. Environ Toxicol Pharmacol. 57:159-165.