Abstract
Using Sprague-Dawley rats and rat PC12 cells treated with sodium fluoride (NaF), we investigated the effects of SIK2-CRTC1 signaling on the neurobehavioral toxicity induced by fluoride. The in vivo results demonstrated that NaF treatment induced anxiety- and depression-like behaviors in juvenile rats, resulting in histological and ultrastructural abnormalities in the rat hippocampus and medial prefrontal cortex. Moreover, NaF exposure induced neuronal loss and excessive apoptosis. We also found that NaF elevated the expression of SIK2 and reduced the expression of CRTC1, brain-derived neurotrophic factor (BDNF), and VGF. The in vitro results showed that NaF suppressed cell viability, induced SIK2-CRTC1 signaling dysfunction, and caused excessive apoptosis in PC12 cells. Notably, targeted knockout of SIK2 with SIK2-siRNA or blocking of SIK2-CRTC1 signaling with 7,8-dihydroxyflavone (7,8-DHF) (as well as venlafaxine) can reduce apoptosis and increase cell viability in vitro. These findings suggest that neuronal death resulting from abnormal SIK2-CRTC1 signaling contributes to neurobehavioral toxicity induced by fluoride.
Graphical Abstract
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Effects of chronic fluorosis on the brain.
Highlights Reviewing the mechanism of brain injury caused by chronic fluorosis is of great significance for protecting residents in fluorosis endemic areas. Abstract This article reviews the effects of chronic fluorosis on the brain and possible mechanisms. We used PubMed, Medline and Cochraine databases to collect data on fluorosis, brain injury,
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The Effect of Chronic Fluorosis on Calcium Ions and CaMKIIa, and c-fos Expression in the Rat Hippocampus.
This study investigated neurotoxicity of chronic fluorosis in the rat hippocampus. Newly weaning, male, Sprague-Dawley (SD) rats were administered 15, 30, and 60 mg/L sodium fluoride (NaF) solution (fluorine ion concentration 8.25, 16.50, and 33.00 mg/L, respectively), and tap water, for 18 months. The neurotoxicological mechanism was examined with a focus on intracellular
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Impaired V-ATPase leads to increased lysosomal pH, results in disrupted lysosomal degradation and autophagic flux blockage, contributes to fluoride-induced developmental neurotoxicity.
Highlights NaF exposure caused developmental neurotoxicity. NaF-induced neuronal apoptosis results from autophagic flux blockage. Raised lysosomal pH disrupting lysosomal degradation caused autophagic flux blockage. V-ATPase is a crucial factor regulating neuronal lysosomal pH. Upregulation of V-ATPase alleviate NaF-induced developmental neurotoxicity. Fluoride is capable of inducing developmental neurotoxicity, yet its mechanisms
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Molecular mechanism of brain impairment caused by drinking-acquired fluorosis and selenium intervention
This study investigated the molecular mechanism of brain impairment induced by drinking fluoridated water and selenium intervention. Results showed that the learning and memory of rats in NaF group significantly decreased. Moreover, the number of apoptotic cells, the expression levels of Cytc mRNA and protein, and the expression levels of
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NaF-induced neurotoxicity via activation of the IL-1B/JNK signaling pathway.
Excessive fluoride exposure can induce neuron apoptosis that is associated with neurodegenerative changes, but the mechanisms remain elusive. It has been suggested that chronic fluoride-induced microglia activation contributes to neuronal damage by producing pro-inflammatory cytokines. IL-1B, a pro-inflammatory cytokine released by activated microglia, is capable of inducing JNK phosphorylation and
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Fluoride Affects Learning & Memory in Animals
An association between elevated fluoride exposure and reduced intelligence has now been observed in 65 IQ studies. Although a link between fluoride and intelligence might initially seem surprising or random, it is actually consistent with a large body of animal research. This animal research includes the following 45 studies (out
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Fluoride & IQ: 76 Studies
• As of July 18, 2022, a total of 85 human studies have investigated the relationship between fluoride and human intelligence. • Of these investigations, 76 studies have reported that elevated fluoride exposure is associated with reduced IQ in humans. • The studies which reported an association of reduced IQ with exposure
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Fluoride's Effect on Fetal Brain
The human placenta does not prevent the passage of fluoride from a pregnant mother's bloodstream to the fetus. As a result, a fetus can be harmed by fluoride ingested pregnancy. Based on research from China, the fetal brain is one of the organs susceptible to fluoride poisoning. As highlighted by the excerpts
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Fluoride's Direct Effects on Brain: Animal Studies
The possibility that fluoride ingestion may impair intelligence and other indices of neurological function is supported by a vast body of animal research, including over 40 studies that have investigated fluoride's effects on brain quality in animals. As discussed by the National Research Council, the studies have consistently demonstrated that fluoride, at widely varying concentrations, is toxic to the brain.
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Fluoride: Developmental Neurotoxicity.
Developmental Neurotoxicity There has been a tremendous amount of research done on the association of exposure to fluoride with developmental neurotoxicity. There are over 60 studies reporting reduced IQ in children and several on the impaired learning/memory in animals. And there are studies which link fluoride to Attention Deficit Hyperactivity Disorder. Teaching
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