%0 Journal Article
%T Molecular Mechanisms of Cytotoxicity and Apoptosis Induced by Inorganic Fluoride
%A Natalia Ivanovna Agalakova
%A Gennadii Petrovich Gusev
%J ISRN Cell Biology
%D 2012
%R 10.5402/2012/403835
%X Fluoride (F) is ubiquitous natural substance and widespread industrial pollutant. Although low fluoride concentrations are beneficial for normal tooth and bone development, acute or chronic exposure to high fluoride doses results in adverse health effects. The molecular mechanisms underlying fluoride toxicity are different by nature. Fluoride is able to stimulate G-proteins with subsequent activation of downstream signal transduction pathways such as PKA-, PKC-, PI3-kinase-, Ca2+-, and MAPK-dependent systems. G-protein-independent routes include tyrosine phosphorylation and protein phosphatase inhibition. Along with other toxic effects, fluoride was shown to induce oxidative stress leading to excessive generation of ROS, lipid peroxidation, decrease in the GSH/GSSH ratio, and alterations in activities of antioxidant enzymes, as well as to inhibit glycolysis thus causing the depletion of cellular ATP and disturbances in cellular metabolism. Fluoride triggers the disruption of mitochondria outer membrane and release of cytochrome c into cytosol, what activates caspases-9 and -3 (intrinsic) apoptotic pathway. Extrinsic (death receptor) Fas/FasL-caspase-8 and -3 pathway was also described to be implicated in fluoride-induced apoptosis. Fluoride decreases the ratio of antiapoptotic/proapoptotic Bcl-2 family proteins and upregulates the expression of p53 protein. Finally, fluoride changes the expression profile of apoptosis-related genes and causes endoplasmic reticulum stress leading to inhibition of protein synthesis. 1. Introduction Fluorine (F), a member of the halogen family, is the most electronegative and reactive of all the elements of Periodic table. Elemental fluorine does not exist in nature but forms inorganic and organic compounds called fluorides representing approximately 0.06¨C0.09% of the Earth¡¯s crust. Fluorides are released into environment through a combination of natural and anthropogenic processes; therefore, their concentrations in the environment are highly variable. Natural processes include the weathering and dissolution of fluoride-rich minerals, emissions from volcanoes, geothermal activity, and marine aerosols [1, 2]. Fluoride levels in surface waters depend on geographical location and proximity to emission sources but are generally low, ranging from 0.01 to 0.3£¿mg/L in freshwater and from 1.2 to 1.5£¿mg/L in seawater. However, high fluoride concentrations (3£¿mg/L and greater) are common in the groundwaters at many geographical areas rich with fluoride-containing rocks. These regions include East African Rift system (from Jordan in
%U http://www.hindawi.com/journals/isrn.cell.biology/2012/403835/