Shenoy PS, Sen U, Kapoor S, Ranade AV, Chowdhury CR, Bose B. Sodium fluoride induced skeletal muscle changes: Degradation of proteins and signaling mechanism. Environmental Pollution 2019 Jan;244:534-548. doi: 10.1016/j.envpol.2018.10.034. Epub 2018 Oct 10.
Fluoride is a well-known compound for its usefulness in healing dental caries. Similarly, fluoride is also known for its toxicity to various tissues in animals and humans. It causes skeletal fluorosis leading to osteoporosis of the bones. We hypothesized that when bones are affected by fluoride, the skeletal muscles are also likely to be affected by underlying molecular events involving myogenic differentiation. Murine myoblasts C2C12 were cultured in differentiation media with or without NaF (1 ppm-5 ppm) for four days. The effects of NaF on myoblasts and myotubes when exposed to low (1.5 ppm) and high concentration (5 ppm) were assessed based on the proliferation, alteration in gene expression, ROS production, and production of inflammatory cytokines. Changes based on morphology, multinucleated myotube formation, expression of MyHC1 and signaling pathways were also investigated. Concentrations of NaF tested had no effects on cell viability. NaF at low concentration (1.5 ppm) caused myoblast proliferation and when subjected to myogenic differentiation it induced hypertrophy of the myotubes by activating the IGF-1/AKT pathway. NaF at higher concentration (5 ppm), significantly inhibited myotube formation, increased skeletal muscle catabolism, generated reactive oxygen species (ROS) and inflammatory cytokines (TNF-α and IL-6) in C2C12 cells. NaF also enhanced the production of muscle atrophy-related genes, myostatin, and atrogin-1. The data suggest that NaF at low concentration can be used as muscle enhancing factor (hypertrophy), and at higher concentration, it accelerates skeletal muscle atrophy by activating the ubiquitin-proteosome pathway.
Dharmaratne RW. Exploring the role of excess fluoride in chronic kidney disease: A review. Hum Exp Toxicol. 2018 Nov 25:960327118814161. doi: 10.1177/0960327118814161.
This review covers nearly 100 years of studies on the toxicity of fluoride on human and animal kidneys. These studies reveal that there are direct adverse effects on the kidneys by excess fluoride, leading to kidney damage and dysfunction. With the exception of the pineal gland, the kidney is exposed to higher concentrations of fluoride than all other soft tissues. Therefore, exposure to higher concentrations of fluoride could contribute to kidney damage, ultimately leading to chronic kidney disease (CKD). Among major adverse effects on the kidneys from excessive consumption of fluoride are immediate effects on the tubular area of the kidneys, inhibiting the tubular reabsorption; changes in urinary ion excretion by the kidneys disruption of collagen biosynthesis in the body, causing damages to the kidneys and other organs; and inhibition of kidney enzymes, affecting the functioning of enzyme pathways. This review proposes that there is a direct correlation between CKD and the consumption of excess amounts of fluoride. Studies particularly show immediate adverse effects on the tubular area of human and animal kidneys leading to CKD due to the consumption of excess fluoride. Therefore, it is very important to conduct more investigations on toxicity studies of excess fluoride on the human kidney, including experiments using human kidney enzymes, to study more in depth the impact of excess fluoride on the human kidney. Further, the interference of excess fluoride on collagen synthesis in human body and its effect on human kidney should also be further investigated.
Hewavithana PB, Jayawardhane WM, Gamage R, Goonaratna C. Skeletal fluorosis in Vavuniya District: an observational study. The Ceylon medical journal. 2018 Sep 30;63(3):139-142.
BACKGROUND: The WHO recommended safe upper limit for fluoride in drinking water is 1.5 mg/l. Groundwater sources in many parts of Sri Lanka often exceed this limit. The high fluoride content of groundwater and high environmental temperatures in Vavuniya District predispose to pre-skeletal fluorosis and skeletal fluorosis in adults.
OBJECTIVES: To identify residents of Vavuniya District with clinical features of pre-skeletal and skeletal fluorosis; to describe their clinical, biochemical and radiographic features; to determine the fluoride content of blood and urine in individuals with established diagnoses, and of their drinking water.
METHODS: In 98 volunteers we detected 60 with clinical features of pre-skeletal and skeletal fluorosis. Clinical examination, biochemical and radiographic investigations were performed. Forty four with confounding factors were excluded. The balance 16 had radiographic investigation for fluoride bone disease, and assessment of clinical features for pre-skeletal fluorosis. The radiographic criteria of skeletal fluorosis were trabecular haziness, osteosclerosis, osteophytes, cortical thickening and ligamentous or muscle attachment ossification. All 16 had “spot” samples of 15 ml of venous blood taken for biochemical tests and fluoride estimation; and 30 ml of urine, and water from 16 dug wells for fluoride.
RESULTS: The 16 selected (11 males) had BMI between 20.6 and 31.9 kg/m2, and were between 22 and 84 years (x̅ = 59.9 + 20.4). They used water from domestic dug wells for drinking. All had adequate renal function. All serum and urine samples had raised fluoride levels way above the reference ranges for serum (0.02 – 0.18 mg/l) and urine (0.6 – 2.0 mg/l). The 16 water samples showed a mean fluoride content of 2.90 +0.93 mg/l.
INTERPRETATION: In a cohort of 60 individuals in Vavuniya with symptoms suggestive of skeletal fluoride toxicity, 6 had skeletal fluorosis, 10 had pre-skeletal fluorosis, and groundwater sources had fluoride levels much higher than WHO recommended upper limit for drinking water. Residents in Vavuniya are predisposed to pre-skeletal and skeletal fluorosis. All 16 had been misdiagnosed as various types of arthritis.
Huan Zuo, Liang Chen, Ming Kong, Lipeng Qiu, Peng Lü, Peng Wu, Yanhua Yang, Keping Chen. Toxic effects of fluoride on organisms. Life Sciences
Volume 198, 1 April 2018, Pages 18-24
Accumulation of excess fluoride in the environment poses serious health risks to plants, animals, and humans. This endangers human health, affects organism growth and development, and negatively impacts the food chain, thereby affecting ecological balance. In recent years, numerous studies focused on the molecular mechanisms associated with fluoride toxicity. These studies have demonstrated that fluoride can induce oxidative stress, regulate intracellular redox homeostasis, and lead to mitochondrial damage, endoplasmic reticulum stress and alter gene expression. This paper reviews the present research on the potential adverse effects of overdose fluoride on various organisms and aims to improve our understanding of fluoride toxicity.
Daiwile AP, Tarale P, Sivanesan S, Naoghare PK, Bafana A, Parmar D, Kannan K. Role of fluoride induced epigenetic alterations in the development of skeletal fluorosis. Ecotoxicology and environmental safety. 2018 Nov 20;169:410-417. doi: 10.1016/j.ecoenv.2018.11.035.
Fluoride is an essential trace element required for proper bone and tooth development. Systemic high exposure to fluoride through environmental exposure (drinking water and food) may result in toxicity causing a disorder called fluorosis. In the present study, we investigated the alteration in DNA methylation profile with chronic exposure (30 days) to fluoride (8 mg/l) and its relevance in the development of fluorosis. Whole genome bisulfite sequencing (WGBS) was carried out in human osteosarcoma cells (HOS) exposed to fluoride. Whole genome bisulfite sequencing (WGBS) and functional annotation of differentially methylated genes indicate alterations in methylation status of genes involved in biological processes associated with bone development pathways. Combined analysis of promoter DNA hyper methylation, STRING: functional protein association networks and gene expression analysis revealed epigenetic alterations in BMP1, METAP2, MMP11 and BACH1 genes, which plays a role in the extracellular matrix disassembly, collagen catabolic/organization process, skeletal morphogenesis/development, ossification and osteoblast development. The present study shows that fluoride causes promoter DNA hypermethylation in BMP1, METAP2, MMP11 and BACH1 genes with subsequent down-regulation in their expression level (RNA level). The results implies that fluoride induced DNA hypermethylation of these genes may hamper extracellular matrix deposition, cartilage formation, angiogenesis, vascular system development and porosity of bone, thus promote skeletal fluorosis.
Till C, Green R, Grundy JG, Hornung R, Neufeld R, Martinez-Mier EA, Ayotte P, Muckle G, Lanphear B. Community Water Fluoridation and Urinary Fluoride Concentrations in a National Sample of Pregnant Women in Canada. Environmental health perspectives. 2018 Oct;126(10):107001. doi: 10.1289/EHP3546.
BACKGROUND: Fluoride exposures have not been established for pregnant women who live in regions with and without community water fluoridation.
OBJECTIVE: Our aim was to measure urinary fluoride levels during pregnancy. We also assessed the contribution of drinking-water and tea consumption habits to maternal urinary fluoride (MUF) concentrations and evaluated the impact of various dilution correction standards, including adjustment for urinary creatinine and specific gravity (SG).
METHODS: We measured MUF concentrations in spot samples collected in each trimester of pregnancy from 1,566 pregnant women in the Maternal-Infant Research on Environmental Chemicals cohort. We calculated intraclass correlation coefficients (ICCs) to assess variability in MUF concentrations across pregnancy. We used regression analyses to estimate associations between MUF levels, tea consumption, and water fluoride concentrations as measured by water treatment plants.
RESULTS: Creatinine-adjusted MUF values were almost two times higher for pregnant women living in fluoridated regions compared with nonfluoridated regions. MUF values tended to increase over the course of pregnancy using both unadjusted values and adjusted values. Reproducibility of the unadjusted and adjusted MUF values was modest . The municipal water fluoride level was positively associated with creatinine-adjusted MUF, accounting for 24% of the variance after controlling for covariates. Higher MUF concentrations correlated with numbers of cups of black but not green tea. Urinary creatinine and SG correction methods were highly correlated and were interchangeable in models examining predictors of MUF.
CONCLUSION: Community water fluoridation is a major source of fluoride exposure for pregnant women living in Canada. Urinary dilution correction with creatinine and SG were shown to be interchangeable for our sample of pregnant women.
Wei Q, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L. A mini review of fluoride-induced apoptotic pathways. Environ Sci Pollut Res Int. 2018 Oct 18. doi: 10.1007/s11356-018-3406-z.
Fluorine or fluoride can have toxic effects on bone tissue and soft tissue at high concentrations. These negative effects include but not limited to cytotoxicity, immunotoxicity, blood toxicity, and oxidative damage. Apoptosis plays an important role in fluoride-induced toxicity of kidney, liver, spleen, thymus, bursa of Fabricius, cecal tonsil, and cultured cells. Here, apoptosis activated by high level of fluoride has been systematically reviewed, focusing on three pathways: mitochondrion-mediated, endoplasmic reticulum (ER) stress-mediated, and death receptor-mediated pathways. However, very limited reports are focused on the death receptor-mediated apoptosis pathways in the fluoride-induced apoptosis. Therefore, understanding and discovery of more pathways and molecular mechanisms of fluoride-induced apoptosis may contribute to designing measures for preventing fluoride toxicity.