The Effect of Chronic Fluorosis on Calcium Ions and CaMKIIα, and c-fos Expression in the Rat Hippocampus

Teng, Yun; Zhang, Jing; Zhang, Zigui; Feng, Jingyi

doi:10.1007/s12011-017-1098-8

Cited by 17 publications

(7 citation statements)

References 45 publications

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“…As the major isoform of CaMKII, CaMKIIα is highly sensitive to intracellular Ca 2+ levels. 11,12 Intracellular Ca 2+ plays a pivotal role in multiple physiological processes and in responding to noxious stimulation and is closely related to cell apoptosis and necrosis. 34,35 In normal physiological conditions, the concentration of Ca 2+ in the extracellular matrix is much higher than the cytoplasmic-free Ca 2+ concentration.…”

Section: Discussionmentioning

confidence: 99%

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Rbfox-1 contributes to CaMKIIα expression and intracerebral hemorrhage-induced secondary brain injury via blocking micro-RNA-124

Shen

et al. 2020

J Cereb Blood Flow Metab

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RNA-binding protein fox-1 homolog 1 (Rbfox-1), an RNA-binding protein in neurons, is thought to be associated with many neurological diseases. To date, the mechanism on which Rbfox-1 worsens secondary cell death in ICH remains poorly understood. In this study, we aimed to explore the role of Rbfox-1 in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) and to identify its underlying mechanisms. We found that the expression of Rbfox-1 in neurons was significantly increased after ICH, which was accompanied by increases in the binding of Rbfox-1 to Ca2+/calmodulin-dependent protein kinase II (CaMKIIα) mRNA and the protein level of CaMKIIα. In addition, when exposed to exogenous upregulation or downregulation of Rbfox-1, the protein level of CaMKIIα showed a concomitant trend in brain tissue, which further suggested that CaMKIIα is a downstream-target protein of Rbfox-1. The upregulation of both proteins caused intracellular-Ca2+ overload and neuronal degeneration, which exacerbated brain damage. Furthermore, we found that Rbfox-1 promoted the expression of CaMKIIα via blocking the binding of micro-RNA-124 to CaMKIIα mRNA. Thus, Rbfox-1 is expected to be a promising therapeutic target for SBI after ICH.

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Section: Discussionmentioning

confidence: 99%

“…6–8 A large number of studies have shown that CaMKIIα is involved in and mediates neuronal death in cerebral ischemia and poisoning (fluorosis), which leads to damage of the nervous system. 9–12…”

Section: Introductionmentioning

confidence: 99%

Rbfox-1 contributes to CaMKIIα expression and intracerebral hemorrhage-induced secondary brain injury via blocking micro-RNA-124

Shen

et al. 2020

J Cereb Blood Flow Metab

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“…In vitro studies have suggested a detrimental effect of fluoride exposure on neurons however, these effects occur at dose levels outside of the expected in vivo range of ppb (Table 4 ) (Zhang et al 2008 (10–40 ppm); Lee et al 2016 (5 mM NaF; 89 ppm F − ); Inkielewicz-Stepniak et al 2012 ; 1.9 and 4.75 ppm F − ). For in vivo exposure, neuronal death or dysfunction was observed in the rat hippocampus (Basha et al 2011 ; Shashi and Kumar 2016 ; Shivarajashankara et al 2002 ; Yan et al 2016 ; Teng et al 2017 ) and neuronal shrinkage in the frontal cortex (Akinrinade et al 2015 ). In the current study, hippocampal neurons displayed a normal morphology with no evidence of neuronal death.…”

Section: Discussionmentioning

confidence: 99%

An Evaluation of Neurotoxicity Following Fluoride Exposure from Gestational Through Adult Ages in Long-Evans Hooded Rats

et al. 2018

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At elevated levels, fluoride (F−) exposure has been associated with adverse human health effects. In rodents, F− exposure has been reported to induce deficits in motor performance and learning and memory. In this study, we examined Long-Evans hooded male rats maintained on a standard diet (20.5 ppm F−) or a low F− diet (3.24 ppm F−) with drinking water exposure to 0, 10, or 20 ppm F− from gestational day 6 through adulthood. At postnatal day 25, brain F− levels were 0.048 or 0.081 μg/g and femur 235 or 379.8 μg/g for 10 and 20 ppm F−, respectively. Levels increase with age and in adults, levels for plasma were 0.036 or 0.025 μg/ml; for the brain 0.266 or 0.850 μg/g; and for the femur, 681.2 or 993.4 μg/g. At these exposure levels, we observed no exposure-related differences in motor, sensory, or learning and memory performance on running wheel, open-field activity, light/dark place preference, elevated plus maze, pre-pulse startle inhibition, passive avoidance, hot-plate latency, Morris water maze acquisition, probe test, reversal learning, and Y-maze. Serum triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) levels were not altered as a function of 10 or 20 ppm F− in the drinking water. No exposure-related pathology was observed in the heart, liver, kidney, testes, seminal vesicles, or epididymides. Mild inflammation in the prostate gland was observed at 20 ppm F−. No evidence of neuronal death or glial activation was observed in the hippocampus at 20 ppm F−.Electronic supplementary materialThe online version of this article (10.1007/s12640-018-9870-x) contains supplementary material, which is available to authorized users.

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“…There was also no significant difference in the number of pyramidal neurons in the medial prefrontal cortex cells after administration of 5, 10, and 20 mg/kg b.w./day of oral NaF solution (Pulungan et al 2018). Other studies observed neuronal death or dysfunction in the rat hippocampus at concentrations of 10-120 mg/L NaF in drinking water (Basha et al 2011;Chen et al 2018a;Sharma et al 2018a;Shashi and Kumar 2016;Teng et al 2018;Wang et al 2018;Yan et al 2016;Zhao et al 2019), an influence on neurotransmitter signaling (Dong et al 2017;Sun et al 2018), and induction of oxidative stress in the brain (Bartos et al 2018;Dong et al 2017). Further studies also reported stimulation of microglia following fluoride exposure (Shuhua et al 2012;Yan et al 2013Yan et al , 2016Yang et al 2018).…”

Section: Neurobehavioral Studies and Neurotoxicitymentioning

confidence: 92%

Toxicity of fluoride: critical evaluation of evidence for human developmental neurotoxicity in epidemiological studies, animal experiments and in vitro analyses

et al. 2020

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Recently, epidemiological studies have suggested that fluoride is a human developmental neurotoxicant that reduces measures of intelligence in children, placing it into the same category as toxic metals (lead, methylmercury, arsenic) and polychlorinated biphenyls. If true, this assessment would be highly relevant considering the widespread fluoridation of drinking water and the worldwide use of fluoride in oral hygiene products such as toothpaste. To gain a deeper understanding of these assertions, we reviewed the levels of human exposure, as well as results from animal experiments, particularly focusing on developmental toxicity, and the molecular mechanisms by which fluoride can cause adverse effects. Moreover, in vitro studies investigating fluoride in neuronal cells and precursor/stem cells were analyzed, and 23 epidemiological studies published since 2012 were considered. The results show that the margin of exposure (MoE) between no observed adverse effect levels (NOAELs) in animal studies and the current adequate intake (AI) of fluoride (50 µg/kg b.w./day) in humans ranges between 50 and 210, depending on the specific animal experiment used as reference. Even for unusually high fluoride exposure levels, an MoE of at least ten was obtained. Furthermore, concentrations of fluoride in human plasma are much lower than fluoride concentrations, causing effects in cell cultures. In contrast, 21 of 23 recent epidemiological studies report an association between high fluoride exposure and reduced intelligence. The discrepancy between experimental and epidemiological evidence may be reconciled with deficiencies inherent in most of these epidemiological studies on a putative association between fluoride and intelligence, especially with respect to adequate consideration of potential confounding factors, e.g., socioeconomic status, residence, breast feeding, low birth weight, maternal intelligence, and exposure to other neurotoxic chemicals. In conclusion, based on the totality of currently available scientific evidence, the present review does not support the presumption that fluoride should be assessed as a human developmental neurotoxicant at the current exposure levels in Europe.

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The Effect of Chronic Fluorosis on Calcium Ions and CaMKIIα, and c-fos Expression in the Rat Hippocampus

Cited by 17 publications

References 45 publications

Rbfox-1 contributes to CaMKIIα expression and intracerebral hemorrhage-induced secondary brain injury via blocking micro-RNA-124

Rbfox-1 contributes to CaMKIIα expression and intracerebral hemorrhage-induced secondary brain injury via blocking micro-RNA-124

An Evaluation of Neurotoxicity Following Fluoride Exposure from Gestational Through Adult Ages in Long-Evans Hooded Rats

Toxicity of fluoride: critical evaluation of evidence for human developmental neurotoxicity in epidemiological studies, animal experiments and in vitro analyses

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