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Chronic administration of aluminum-fluoride or sodium-fluoride to rats in drinking water: Alterations in neuronal and cerebrovascular integrity
Abstract
This study describes alterations in the nervous system resulting from chronic administration of the fluoroaluminum complex (AlF3) or equivalent levels of fluoride (F) in the form of sodium-fluoride (NaF). Twenty seven adult male Long-Evans rats were administered one of three treatments for 52 weeks: the control group was administered double distilled deionized drinking water (ddw). The aluminum-treated group received ddw with 0.5 ppm AlF3 and the NaF group received ddw with 2.1 ppm NaF containing the equivalent amount of F as in the AlF3 ddw. Tissue aluminum (Al) levels of brain, liver and kidney were assessed with the Direct Current Plasma (DCP) technique and its distribution assessed with Morin histochemistry. Histological sections of brain were stained with hematoxylin & eosin (H&E), Cresyl violet, Bielschowsky silver stain, or immunohistochemically for beta-amyloid, amyloid A, and IgM. No differences were found between the body weights of rats in the different treatment groups although more rats died in the AlF3 group than in the control group. The Al levels in samples of brain and kidney were higher in both the AlF3 and NaF groups relative to controls. The effects of the two treatments on cerebrovascular and neuronal integrity were qualitatively and quantitatively different. These alterations were greater in animals in the AlF3 group than in the NaF group and greater in the NaF group than in controls.
... However, apart from the alteration of the hard parts of the body such as teeth and bones through fluorosis, very few studies have linked the fluoride toxicity to physiological dysfunction. These studies have shown that the toxicity of fluoride impacts the nervous system by causing a neurological disorder with cardiac convulsions and arrest [16,17]. These convulsions can increase the heart rate and therefore increase the blood pressure with an impact on the antioxidant system. ...
... The average of Cd and Pb contents exceeds the standard limits set by WHO (< 5 μg/L) at Agbodrafo, Kpeme and Goumoukope. However, the average of Cd [13][14][15][16][17][18][19][20] contents is lower than the limit value (< 5 μg/L) at Gbodjome and Aneho whereas for Pb, it is only at Gbodjome that an average of the contents below the limit value (< 100 μg/L) has been obtained [25]. Blood fluoride levels increased significantly (P < 0.05) at Agbodrafo and Aneho relative to Gbodjome but, this increase is very significant (P < 0.001) at Kpeme and Goumoukope compared to Gbodjome (Table 3). ...
... There are very few studies concerning fluoride toxicity on cardiovascular system. Indeed, the toxicity of fluorides has been proven on the kidneys functioning [15][16][17][38][39][40][41][42][43][44] and on the endocrine system especially on the decline in the thyroid gland activity [15,17] and the insulin secretion inhibition [42]. Similarly, fluoride has been incriminated at very high levels in the occurrence of cancers [17,43] and paralysis [43]. ...
... Chronic fluoride exposure leads to neurodegeneration in the brain, causing learning disabilities and memory deficits, and alters the activities of enzymes in the brain [13]. Fluorideassociated neurotoxicity has been seen in animal models [18]. ...
... Fluorides can cross blood-brain and placental barriers [22]. Due to maternal exposure during lactation, fluoride enters the circulation of pups through the mother's milk [18,23]. The level of fluoride in the mother's milk is found to be increased in fluorosis endemic areas [24]. ...
... All these conditions are idiopathic in nature. Histopathological changes due to fluoride exposure have been reported in enteric neurons [15] and in fetal brain [18]. Exposure to fluoride during dynamic stages of fetal development induces alteration in the gastrointestinal tract (GIT) due to changes in cell differentiation and subcellular organization [28]. ...
Children born in fluorosis endemic areas usually suffer from gastrointestinal complications and are unable to attain normal growth as per their age group. The enteric nervous system (ENS) controls gut movement and functions. It is highly vulnerable to any ingested toxins. Based on observations, it was hypothesized that fluoride exposure during pregnancy and lactation might induce ENS developmental defects. The aim of this study is to investigate the effects of fluoride exposure during pregnancy and lactation on ENS of the first-generation rat pups. After confirmation of pregnancy, female rats were divided into 3 groups and kept on normal water (group 1), 50 ppm of fluoride (group 2), and 100 ppm of fluoride (group 3). The fluoride exposure started at the start of pregnancy and continued until lactation. On the 21st post-natal day, the pups were euthanized and the gut tissue and blood were harvested and subjected to fluoride measurement, oxidative stress estimation, histopathological and ultrastructural analysis, TUNEL, and immunofluorescence. The quantitative expressional analysis of embryonic lethal abnormal vision-like 4 (ELAVL4) (a pan-neuronal marker) and glial fibrillary acidic protein (GFAP) (a glial cell marker) genes was performed by RT-qPCR. An increase in oxidative stress, subcellular and cellular injuries, and apoptosis in enteric neuronal, glial, and epithelial cells was observed in the distal colon of the first-generation pups. Ganglionic degeneration, reduced expression of HuC/D and GFAP, altered colon muscle layer thickness, and tissue edema were observed in the fluoride-treated groups compared with the control. Fluoride exposure during prenatal and lactation period leads to subcellular and cellular injuries due to increased oxidative stress and apoptosis in the ENS. The reduction in the number of neurons and glia due to increased apoptosis may cause alterations in ENS development.
... However, apart from the alteration of the hard parts of the body such as teeth and bones through fluorosis, very few studies have linked the fluoride toxicity to physiological dysfunction. These studies have shown that the toxicity of fluoride impacts the nervous system by causing a neurological disorder with cardiac convulsions and arrest [16,17]. These convulsions can increase the heart rate and therefore increase the blood pressure with an impact on the antioxidant system. ...
... There are very few studies concerning fluoride toxicity on cardiovascular system. Indeed, the toxicity of fluorides has been proven on the kidneys functioning [15][16][17][38][39][40][41][42][43][44] and on the endocrine system especially on the decline in the thyroid gland activity [15,17] and the insulin secretion inhibition [42]. Similarly, fluoride has been incriminated at very high levels in the occurrence of cancers [17,43] and paralysis [43]. ...
... Similarly, fluoride has been incriminated at very high levels in the occurrence of cancers [17,43] and paralysis [43]. In addition, the neurotoxicity of fluoride has also been demonstrated [16,39] with migraines, depressions and extreme fatigue [17], in muscle toxicity by convulsions followed by coma and cardiac arrest [45]. Beyond that, studies have shown the role of fluorides in increasing the severity of diabetes [17]. ...
... 83 Of above studies, 13,16,17,18,19 a considerable number of investigations specifically pointed out that there is an immediate effect of excess fluoride on tubular area of the kidney. 16,[19][20][21][22][23][24][25][26][27][28]36,39,40,53 Fluoride inhibits tubular reabsorption primarily in the medullary portion of the ascending limb of Henle's loop, and this was proven by examination of renal tubular site of action of fluoride, using clearance techniques on Fischer 344 rats. 23 Fluorides affect the functioning of many enzyme pathways, and this has been shown by in vivo experiments. ...
... Congruent with the glomerular changes was deposition of protein in the tubules. Kidney disorders were found in both groups 36 22 One-month old female Swiss albino mice were given 60 and 120 ppm NaF in their drinking water for 30 days Elevated fluoride in drinking water affects mammalian neurotransmitter functions as well as antioxidant systems 37 23 Uremic rats with surgically induced renal insufficiency, received 0 mg/mL, 5 mg (0.26 mmol/ L), 15 mg (0.79), or 50 mg/mL (2.63 mmol/L) of fluoride in their drinking water for 3 or 6 months There were no clinically adverse, fluoride-induced, extra-skeletal physiological, biochemical, or genetic effects of chronic exposure to common levels of fluoride in these rats 38 24 Fed small amount of NaF to rats with chronic fluorosis Tubular degeneration on kidneys observed 16 25 Treated 0.05% NaF to 226 white rats for 3-56 days "Kidney changes consisted primarily in dilatation of the Henle loops in the juxtacortical area of the medulla, soon followed by a flattening of the epithelium in the convoluted tubules in the cortex and a distention of the tubules, possibly due to some kind of 'stop' in the Henle loops." 39 26 Fed NaF with stock diet to rats Dilation of the Henle loops, followed by dilation of the convoluted tubules and later by inflammation NaF fed group showed chronic kidneys damages, but another group showed recovery when NaF was withdrawn from the diet 40 27 Fed 0-100 ppm NaF in water to weanling rats Mortality was observed. ...
... 34 In addition to sodium fluoride, reports on adverse effects on the kidneys by fluorinated compounds such as methoxyflurane, monofluorophosphate, and aluminum fluoride further confirm the toxicity of fluorides on kidneys. 23,35,36 Some experiments claimed that the withdrawal of fluoride from the diet leads to the recovery of kidneys, 40 giving some hope to people and animal who were adversely affected by excess fluoride. It is shown that there were no clinically adverse, fluoride-induced, extra skeletal physiological, biochemical, or genetic effects of chronic exposure to common levels of fluoride in rats. ...
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.
... Both elements can induce changes in the physiological processes (Benyettou et al., 2017) and it is well evident that Al and F are potent neurotoxic elements (Choi et al., 2015;Farhat et al., 2017;Ge et al., 2019). Aluminium capacity to cross the BBB increases in the presence of fluoride (Varner et al., 1998). These elements can cross the BBB and retain in the brain tissues, thereby, inducing oxidative stress, which alters antioxidant enzymes such as glutathione peroxidase, glutathione, glutathione reductase, glutathione-s-transferase activities (Julka and Gill, 1996;Vani and Reddy, 2000), and this would be more extensive in their combination (Kaur et al., 2009). ...
... These elements can cross the BBB and retain in the brain tissues, thereby, inducing oxidative stress, which alters antioxidant enzymes such as glutathione peroxidase, glutathione, glutathione reductase, glutathione-s-transferase activities (Julka and Gill, 1996;Vani and Reddy, 2000), and this would be more extensive in their combination (Kaur et al., 2009). This results in, changes in the antioxidant defence system causing prominent damage to the neural cells and alterations in the various brain regions (Ge et al., 2019;Nalagoni and Karnati, 2016;Varner et al., 1998) leading to neurodegenerative disorders (Narayanaswamy and Piler, 2010;Lu et al., 2017). Butterfield and Boyd-Kimball, (2005) reported a strong association between oxidative stress signs such as lipid peroxidation, protein content alterations, altered glutathione levels, reduced GST activity and neurodegenerative disorders such as Alzheimer's disease. ...
Aluminium and Fluoride, known to form a strong complex, are being used widely in many industries. Both elements are involved in the pathogenesis of neurodegenerative disorders by inducing oxidative stress. Many experimental studies reported neuroprotective properties of resveratrol (Res). In this study, we examined the ameliorative effects of resveratrol on aluminiumfluoride-induced oxidative stress in the conventional and preclinical models. AlCl3 (100 mg/kg bw)+ NaF (10 mg/kg bw), AlCl3 (100 mg/kg bw) + NaF (10 mg/kg bw) + Res (30 mg/kg bw), and Res (30mg/kg bw) were administered for II, III and IV groups respectively and group-I was served as control for 8 weeks. The results showed considerable (p<0.05) alterations in protein content andoxidative markers (GPx, GST, GR, GSSH) in group-II whereas a significant (p<0.05) reversal was observed in group III. Taken together, the above findings indicate that resveratrol significantly alleviated the aluminium and fluoride-induced oxidative stress through its ameliorative efficacy.
... The simultaneous administration of both elements produced aggregates of hippocampal neurons. In a study carried out by Varner et al (1998) they observed deposition of Al in the kidneys of rats and postulated role of AlFx complex in the transport and penetration of Al across the blood-brain barrier. A series of investigation have proven that AlFx is a brain toxin as well as neurotoxic (Varner et al., 1998). ...
... In a study carried out by Varner et al (1998) they observed deposition of Al in the kidneys of rats and postulated role of AlFx complex in the transport and penetration of Al across the blood-brain barrier. A series of investigation have proven that AlFx is a brain toxin as well as neurotoxic (Varner et al., 1998). Hence, the study reports the protective effects of resveratrol against aluminium and fluoride induced structural and degenerative changes in cortex and hippocampus in rat brain. ...
Metals such as aluminum and Fluoride have been implicated in the etiology of several neurodegenerative disorders. Resveratrol, a natural polyphenol, exerting a wide range of biological and pharmacological activities including its antioxidative properties against neurodegenerative disorders through its ability to lessen oxidative stress. Rats were divided into 4 groups. Group-I was served as control. Group-II was intoxicated with Alcl3 (100 mg/kg b.w) along with Sodium fluoride (10 mg/kg b.w). Group-III was administered with Alcl3 (100 mg/kg b.w) + Sodium fluoride (10 mg/kg b.w) + resveretrol (30 mg/kg b.w). Group-IV was administered with resveretrol (30 mg/kg b.w) alone for 8 weeks. The obtained results showed significant oxidative stress induced neuronal damage in cerebral cortex and hippocampus in intoxicated rats where as significant reduction in neuronal damage in the rats administered with resveratrol against aluminium along with fluoride. Hence, the results of the present study reveal that the resveratrol has potential neuroprotective properties to reverse the cortical and hippocampal neuronal damage induced by aluminum and fluoride intoxication.
... Recently, we have also reported that curcumin reversed the free radicals generation in rats exposed to NaF . The developmental fluoride exposure crosses the BBB due to the immaturity of BBB (Varner, Jensen, Horvath, & Issacon, 1998). The continued exposure of fluoride alters the integration of blood vascular system in brain leading to deprivation of the brain nourishment and oxygen supply to brain (Mullenix, Denbesten, Schunior, & Kernan, 1995). ...
... Mullenix et al., (1995) reported the accumulation of fluoride in the hippocampus region. Varner et al. (1998) announced altered structures in the CA1 and CA4 areas of the hippocampus but not in CA2 and CA3 areas. Recently, Sudhakar et al., (2017) showed a histological alteration in the NaF-intoxicated brain of rats. ...
Introduction: Curcumin, a yellow-pigment, found in the popular Indian spice turmeric (Curcuma longa), poses pharmaceutical applications due to its anti-inflammatory, antioxidant, and chemoprotective properties. Excessive fluoride causes fluorosis leading to neurodegeneration and associated behavioral deficits, particularly in children. This study aimed at investigating the neuroprotective ability of curcumin on sodium fluoride (NaF)-related alterations of acetylcholine, catecholamines, histological changes in hippocampus and behavior of rats exposed to NaF during pre- and post-natal period.
Methods: Pregnant albino Wistar rats were chosen and divided into four groups. The experimental period lasted 53 days (i.e. the gestational period of 23 days and post-gestational period of 30 days), at which the control group received normal tap water, the experimental group received NaF (20 ppm/kg bw) through drinking water, and the protective groups received curcumin (10 mg and 20mg/kg bw) by gavage and NaF (20 ppm/kg bw) through drinking water. Behavioral study (open field test) was done using postnatal pups aged 21 and 30 days. The brains of postnatal pups aged 1, 7, 14, 21, and 30 days were collected and used for biochemical analysis and those of pups aged 14, 21, and 30 days were used for histopathological analysis.
Results: NaF-exposed rats showed a significant (p
... Данные нашей работы подтверждают, что длительная интоксикация Fв относительно небольших дозах также способна индуцировать патологические процессы в нейронах гиппокампа. Подтвержде- нием этому могут служить и результаты работы [28], в которой появление клеток-«теней» и снижение численной плотности нейронов в областях СА1 и СА4 гиппокампа крыс были обнаружены после 52-недельной интоксикации 1 мг/л F -. ...
... Причиной истощения нейронального слоя зон СА3 и СА1 гиппокампа у крыс, получавших избыток F -, вероятно, являются многочисленные патоморфологические изменения нейронов, типичные для гибнущих клеток -нарушение ядерной и плазматической мембран, различная степень патологии вещества Ниссля, набухание или сморщивание клеток, появление нейронов с винтообразными отростками (рис. 1, 3). Литературные данные [4,5,11,13,14,16,18,21,25,26,[28][29][30] также показали, что потребление животными избыточных доз Fприводило к сморщиванию, атрофии, хроматолизу, глиозу, некрозу или нейронофагии нейрональных клеток, пикнозу и смещению ядер к периферии, исчезновению дендритов, частичной демиелинизации. ...
... Rats and mice exposed to high fluoride (≥ 50 ppm, or 2.5 mM) showed decreased nicotinic acetylcholine receptor expression, lowered acetyl cholinesterase activity, and damaged myelin and microtubules (Long et al. 2002;Basha and Sujitha 2012;Niu et al. 2015Niu et al. , 2018. Nonetheless, tests done with ≤ 50 ppm (2.5 mM) fluoride showed no significant brain damage (Varner et al. 1998;Shivarajashankara et al. 2002). ...
... Rats exposed to 10 ppm NaF and 100 ppm AlCl 3 in combination for 30 days showed neuronal shrinkage and inhibition of acetylcholinesterase activity (Akinrinade et al. 2015). Furthermore, aluminum fluoride was found to cause more histopathological changes to brain tissue than sodium fluoride alone, particularly in the neocortex and hippocampus (Varner et al. 1998;NRC 2006). However, it is also possible that the neurotoxicity is due to free aluminum. ...
Fluoride is ubiquitously present throughout the world. It is released from minerals, magmatic gas, and industrial processing, and travels in the atmosphere and water. Exposure to low concentrations of fluoride increases overall oral health. Consequently, many countries add fluoride to their public water supply at 0.7–1.5 ppm. Exposure to high concentrations of fluoride, such as in a laboratory setting often exceeding 100 ppm, results in a wide array of toxicity phenotypes. This includes oxidative stress, organelle damage, and apoptosis in single cells, and skeletal and soft tissue damage in multicellular organisms. The mechanism of fluoride toxicity can be broadly attributed to four mechanisms: inhibition of proteins, organelle disruption, altered pH, and electrolyte imbalance. Recently, there has been renewed concern in the public sector as to whether fluoride is safe at the current exposure levels. In this review, we will focus on the impact of fluoride at the chemical, cellular, and multisystem level, as well as how organisms defend against fluoride. We also address public concerns about fluoride toxicity, including whether fluoride has a significant effect on neurodegeneration, diabetes, and the endocrine system.
... Adult rodents subjected to long-term F À (10-200 mg/L NaF) treatment also developed a variety of neuropathological changes such as weakened neurogenesis, shrinkage and decreased number of neurons in all brain regions, loss of molecular and glial layers, increased cell gap, lysis of glial cells, appearance of ghost-like cells, chromatolysis and "ballooned" shape of Purkinje cells (Shashi 2003;Zhang et al. 2013;Akinrinade et al. 2015a;Wang et al. 2018a;Jiang et al. 2019). Presence of cells-ghosts and decrease of neuronal density in CA1 and CA4 areas of hippocampus were described even after prolonged 52-weeks intoxication with low F À dose (1 ppm) (Varner et al. 1998). However, no differences in the number of pyramidal neurons was observed in the medial prefrontal cortex of adult rats intoxicated with 5-20 mg NaF/kg BW for a month (Pulungan et al. 2018). ...
... F À -induced ultrastructural changes observed in rodent brain cells include involution of neuronal cell membrane, enlargement of perykarion filled with vacuoles and organelle remains, appearance of spheroid bodies in the neuroplasm due to which the nuclei are shifted to axons, decrease and loss of Nissl substance, enlargement of endoplasmic reticulum, invagination of nuclear membrane, damage to DNA in the form of marginal condensation, chromatolysis, and pyknosis of nuclear material, formation of autophagosomes (Varner et al. 1998;Bhatnagar et al. 2002;Shashi 2003;Chouhan et al. 2010;Flora et al. 2012;Akinrinade et al. 2015b;Yan et al. 2016;Wang et al. 2018a;Niu et al. 2018a). Fragmentation and vacuolization of mitochondria, shortening of their diameter, swelling and disappearance of cristae were observed in the cortical neurons of rats intoxicated with 10-50 mg NaF/L for 6 months (Lou et al. 2013) and in hippocampus of mice given 10-100 mg/L NaF for 2 months ). ...
Although actively disputed and questioned, it has been proposed that chronic exposure to inorganic fluoride (F⁻) is toxic for brain. The major question for this review was whether an excessive F⁻ intake is causally related to adverse neurological and cognitive health conditions in human beings and animals. The paper systematically and critically summarizes the findings of the studies showing positive associations between F⁻ intoxication and various intellectual defects, as well as of those which attempted to clarify the nature of F⁻ neurotoxicity. Many works provide support for a link between pre- and postnatal F⁻ exposure and structural and functional changes in the central nervous system responsible for neurological and cognitive disorders. The mechanisms suggested to underlie F⁻ neurotoxicity include the disturbances in synaptic transmission and synaptic plasticity, premature death of neurons, altered activities of components of intracellular signaling cascades, impaired protein synthesis, deficit of neurotrophic and transcriptional factors, oxidative stress, metabolic changes, inflammatory processes. However, the majority of works have been performed on laboratory rodents using such F⁻ doses which are never exist in the nature even in the regions of endemic fluorosis. Thus, this kind of treatment is hardly comparable with human exposure even taking into account the higher rate of F⁻ clearance in animals. Of special importance are the data collected on humans chronically consuming excessive F⁻ doses in the regions of endemic fluorosis or contacting with toxic F⁻ compounds at industrial sites, but those works are scarce and often criticized due to low quality. New, expertly performed studies with repeated exposure assessment in independent populations are needed to prove an ability of F⁻ to impair neurological and intellectual development of human beings and to understand the molecular mechanisms implicated in F⁻-induced neurotoxicity.
... In 1998, Varner et al. showed in Brain Research that giving rats water containing fluoride at 1 ppm led to kidney damage, brain damage, and a greater uptake of aluminum into the brain, and increased the formation of beta amyloid deposits often characteristic of Alzheimer's disease [120]. The aluminum level in the brains of the fluoride-treated group was double that of the controls. ...
... Histopathological changes similar to those traditionally associated with Alzheimer's disease are also seen in rats chronically exposed to AlF 3 . Because fluoride can increase the uptake of aluminum into bones [121] and the brain [120], in organisms with healthy selfregulating mechanisms, aluminum can consequently appear to reduce the measurable presence of fluoride in bodily fluids [4,117], whereas it is actually being sequestered by certain vulnerable target tissues. ...
Despite enjoying a high standard of living, the United States ranks 46th among nations reporting infant survival rates to the World Health Organization. Among factors that increase infant mortality are environmental toxicants. Toxic metals such as mercury, aluminum, and lead interact synergistically with uoride compounds to produce metal fuoride complexes (e.g., AlF3 and AlF4−). Such toxicants act as biophosphate mimetics disrupting biological signaling processes governing development, immune defenses, and ordinary maintenance systems. Sources for the metals include mother’s mercury amalgams, mercury and aluminum in injected medicines, and lead contaminated drinking water. All of them are made even more toxic by fuorides as evidenced recently by water contamination in Flint, Michigan. Fluorides interact with other toxins increasing their harmful impact. Among the interactants are glyphosate and phosphate containing fertilizers that end up in the food and water because of their widespread use in agriculture. The negative synergy for neonates in the U.S. is increased by the hepatitis B injection containing both mercury and aluminum, and infant formula contaminated with aluminum and the glyphosate in genetically modified soy milk reconstituted with water containing fluoride, aluminum, lead, and other toxic substances. The harmful interactions of such chemicals are associated with rising infant mortality in the U.S. We propose, therefore, a modest but urgent policy change: under TSCA §5, silicofluoride addition to public water supplies should be suspended.
... In 1998, Varner et al. showed in Brain Research that giving rats water containing fluoride at 1 ppm led to kidney damage, brain damage, and a greater uptake of aluminum into the brain, and increased the formation of beta amyloid deposits often characteristic of Alzheimer's disease [120]. The aluminum level in the brains of the fluoride-treated group was double that of the controls. ...
... Histopathological changes similar to those traditionally associated with Alzheimer's disease are also seen in rats chronically exposed to AlF 3 . Because fluoride can increase the uptake of aluminum into bones [121] and the brain [120], in organisms with healthy selfregulating mechanisms, aluminum can consequently appear to reduce the measurable presence of fluoride in bodily fluids [4,117], whereas it is actually being sequestered by certain vulnerable target tissues. ...
p>Despite enjoying a high standard of living, the United States ranks 46th among nations reporting infant survival rates to the World Health Organization. Among factors that increase infant mortality are environmental toxicants. Toxic metals such as mercury, aluminum, and lead interact synergistically with fluoride compounds to produce metal fluoride complexes (e.g., AlF3 and AlF4−). Such toxicants act as biophosphate mimetics disrupting biological signaling processes governing development, immune defenses, and ordinary maintenance systems. Sources for the metals include mother’s mercury amalgams, mercury and aluminum in injected medicines, and lead contaminated drinking water. All of them are made even more toxic by fluorides as evidenced recently by water contamination in Flint, Michigan. Fluorides interact with other toxins increasing their harmful impact. Among the interactants are glyphosate and phosphate containing fertilizers that end up in the food and water because of their widespread use in agriculture. The negative synergy for neonates in the U.S. is increased by the hepatitis B injection containing both mercury and aluminum, and infant formula contaminated with aluminum and the glyphosate in genetically modified soy milk reconstituted with water containing fluoride, aluminum, lead, and other toxic substances. The harmful interactions of such chemicals are associated with rising infant mortality in the U.S. We propose, therefore, a modest but urgent policy change: under TSCA §5, silicofluoride addition to public water supplies should be suspended.
</p
... Some research suggests that there is a possibility for systemic fluorosis in patients with diminished renal function due to impaired excretion of F - (Nanayakkara et al. 2020). Several other studies have shown that excess Fhas an immediate negative impact on the tubular region of the kidney (Cittanova et al.2002;Lindemann, Pindborg and Poulsen 1959;Lu et al. 2000;Pindborg 1957;Varner et al. 1998) and it hinders tubular reabsorption mostly in the medullary region of the ascending limb of the loop of Henle (Roman et al. 1977); however, holistic studies are lacking. The creatinine, uric acid and urea levels indicate the filtration efficiency of the kidney and their elevated levels suggests impaired kidney function. ...
... Some research suggests that there is a possibility for systemic fluorosis in patients with diminished renal function due to impaired excretion of F - (Nanayakkara et al. 2020). Several other studies have shown that excess Fhas an immediate negative impact on the tubular region of the kidney (Cittanova et al.2002;Lindemann, Pindborg and Poulsen 1959;Lu et al. 2000;Pindborg 1957;Varner et al. 1998) and it hinders tubular reabsorption mostly in the medullary region of the ascending limb of the loop of Henle (Roman et al. 1977); however, holistic studies are lacking. The creatinine, uric acid and urea levels indicate the filtration efficiency of the kidney and their elevated levels suggests impaired kidney function. ...
... However, overexposure to fluoride can lead to fluorosis [19,20], acute gastric and kidney problems [21]. Fluoride is also associated with diseases like Alzeimer's disease [22]. ...
A new rhodamine functionalized fluorogenic Schiff base CS was synthesized and its colorimetric and fluorescence responses toward various metal ions were explored. The sensor exhibited highly selective and sensitive colorimetric and "off-on" fluorescence response towards Al 3 þ in the presence of other competing metal ions. These spectral changes are large enough in the visible region of the spectrum and thus enable naked-eye detection. Studies proved that the formation of CS-Al 3 þ complex is fully reversible and can sense to AcO À /F À via dissociation. The results revealed that the sensor provides fluorescence "off-on-off" strategy for the sequential detection of Al 3 þ and AcO À /F À .
... Several studies report on fluoride's negative effect on cognition, especially during fetal development and among children [6][7][8]. These studies propose that excess fluoride crosses the blood-brain barrier, causing structural and cognitive alterations in the central nervous system, or during pregnancy when fluoride can cross the placenta, and affect fetal development [9][10][11][12][13]. However, a recent systematic review challenged the quality of these studies and found insufficient evidence to conclude that fluoride is associated with neurological damage [14]. ...
Objective: This study reports on the number and percentage of community water systems (CWSs) meeting fluoride concentration standards set by the U.S. Department of Health and Human Services (DHHS). The study also explored changes in the population exposed to optimally fluoridated water in these systems between 2006 and 2020. Methods: This study analyzed U.S. Centers for Disease Control and Prevention data from 2006 to 2020, tabulating state-specific CWS fluoridation rates, ranking them, and calculating the percent change. Results: In 2020, 72.7% of the US population received CWS water, with 62.9% of those individuals served by a CWS system meeting DHHS fluoridation standards. This compares to 69.2% receiving CWS water in 2006 and 74.6% in 2012. The overall change in those receiving fluoridated water was 1.4%, from 61.5% in 2006 to 62.9% in 2020. State-specific percentages ranged from 8.5% in Hawaii to 100% in Washington DC in 2020 (median: 76.4%). Conclusions: Although endorsed by the American Dental Association, the percentage of individuals receiving fluoridated water did not increase substantially from 2006 to 2020, indicating that there has not been much progress toward meeting the Healthy People 2030 goal that 77.1% of Americans receive water with enough fluoride to prevent tooth decay.
... Fluoride is also associated with diseases like Alzeimer's disease [19]. Thus fluoride has both beneficial as well as toxic effects. ...
... На 11-12 доби розвитку у всіх личинок в'юна (1,1%), які вижили, проявлялися порушення функції нервово-м'язової системи (неспроможність до прямолінійного руху) та аномальні рухи (обертання навколо власного тіла). Відомо також про розвиток вад нервової та м'язової систем у самок щурів лінії Sprague-Dawley під час пізньої вагітності, під час відлучення молодих особин або у дорослих 3-місячних особин [54], появу негативних змін сомато-моторних рефлексів у нащадків щурів лінії Wistar [55] та у дорослих особин самців щурів Long-Evans [56], які отримували фтор у питній воді. Takahashi K. довів, що аніон фториду є не лише однією з причин розвитку вад та порушень функціонування нервово-м'язової системи у дітей із синдромом Дауна [57], а при щоденному вживанні фторидів з питною водою чи їжею є внутрішнім чинником активації процесів старіння у жінок літнього віку. ...
Background: The study of fluoride effects at the cellular level is still essential for biophysics, medicine, and ecology as one of the most common environmental pollutants. Its impact on embryonic objects is poorly understood.
Objectives: The aim of the work was: 1) to study the effect of sodium fluoride (in the minimum concentration to inhibit growth) on the morphological development of loaсh embryos; 2) evaluation of the degree of survival of embryos in the presence of sodium fluoride in the incubation medium and determination of the coefficient Ks.
Materials and methods: Ovulation in loach females (Misgurnus fossilis L.) was stimulated by intramuscular injection of female chorionic gonadotropin (500 units), eggs were obtained by 36 h after stimulation, fertilized in Petri dishes with a suspension of sperm according to Neifach A. A. The stages of development were observed visually used a binocular microscope MBS-9 with a photo camera. The experimental embryos were incubated in Goltfreter's solution with the addition of sodium fluoride to a final minimum concentration to inhibit growth of 500 μmol/l.
Results: Sodium fluoride inhibits the development of loach embryos and leads to developmental defects. The noticeable developmental defects caused by sodium fluoride were a reduction in the size of the larvae's head and tail, low body pigmentation, changes in the eye diameter, and embryonic touch reflex. As a result of the accumulation of fluoride in embryonic cells, on the third day of development, embryonic mortality increased to 88,9%. On 12 days under the action of sodium fluoride, the total number of larvae was about 2%.
Conclusions: The ability of NaF to act as a direct teratogen was tested on the cold-blooded embryo model, the same effect was found by other investigators on the FETAX model. The possibility that sodium fluoride may cause toxic and/or neuromuscular developmental defects in human embryos also should be considered. Avoiding excessive getting of fluoride in the body by limiting the consumption of foods or beverages high in fluoride, the use of fluoride in dental care products, etc. requires detailed assessment.
... However, most of the articles (n = 43) were published from 2000 to 2013 and provided evidence that Al can cause neurotoxicity, in particular after long-term exposure [12,[22][23][24]; in addition, Al can cross the blood-brain barrier and accumulate in neuronal cells [25,26]. Since the exposure form directly influences the absorption of Al [27,28], the consumption of drinking water with high Al concentrations increases the incidence of neurological diseases such as AD [29][30][31][32][33][34][35][36][37]. Content courtesy of Springer Nature, terms of use apply. ...
This study aimed to identify the landscape of current aluminum toxicity based on knowledge mapping of the 100 most-cited articles on toxicological aspects of aluminum in biological organisms. The research was searched in the Web of Science Core Collection (WoS-CC) with publications between 1945 and 2022. Data regarding authorship, title, journal, year of publication, citation count, country, keywords, study design, and research hotspots were extracted and all elected articles were analyzed. Our results showed that among the articles selected, literature review and in vivo studies were the most common study designs. The USA and England were found as the countries with most publications. Alzheimer’s disease (AD), aluminum, and neurotoxicity were found as the most frequent keywords. The articles most cited in world literature suggested that aluminum exposure is associated with Alzheimer’s disease, Parkinson’s disease (PD), dialysis encephalopathy, amyotrophic lateral sclerosis, neurodegeneration changes, cognitive impairment, such as bone damage, oxidative alterations, and cytotoxicity.
... 114 Aer chronic uoride administration, various changes occur in the blood, brain, and liver of animals, including metabolic lesions, abnormal behavior designs, and changed neuronal cerebrovascular integrity. 115 When the groundwater contains uoride of more than 10 mg L −1 , it accelerates more diseases such as neurological problems, hypertension, and cancer, which become challenging for human health. 116 ...
Fluoride contamination has created a drinking water crisis globally. At low concentrations, its presence is essential; however, it becomes toxic to human beings upon consumption of more than 1.5 mg L⁻¹ in mainly contaminated drinking water due to geochemical reactions and geological or anthropogenic factors. To better understand the toxicity of fluoride, in this study, we examine the recent research on the possible negative consequences of excess fluoride on diverse species. A high fluoride concentration in drinking water cause skeletal fluorosis and long-term kidney, brain, thyroid, and liver damages. This review also focuses on the different techniques for the defluoridation of water, such as electro-coagulation, adsorption, membrane processes, etc., and compares their adsorption capabilities under various situations, while their changes in the literature are reviewed. Furthermore, we present the advantages and disadvantages of different methods and conclude that each technique has shortcomings, with no single approach fitting all aspects. The condition of water pollution with fluoride and recently created technology to remove fluoride from water is evaluated, although research on fluoride contamination of water resources has been reviewed in the literature. Alternatively, this study also examines fluorosis mitigation strategies in the global and Indian settings and existing physicochemical and biological mitigation approaches. Also, the research and development results in fluoride clean-up are reviewed. Specifically, the following topics will be covered in this review: (1) fluoride contamination status, (2) consequences of fluoride contamination in drinking water on human health, and (3) current defluoridation technology.
... Fluoride can penetrate readily into the brain and gets accumulated in the tissues producing neurotoxic effects 5 . Chronic exposure of fluoride through drinking water resulted in damage hippocampus of rats and also formation of beta-amyloid plaques 6 . Histomorphometrical observation of rat brain after the administration of high fluoride along with low iodine showed many pyknosed nuclei and decreased Nissl substance which could be due to lipid peroxidation. ...
Prolonged ingestion of fluoride leads to the pathogenesis known as fluorosis. Fluoride exposure leads to neuro degenerative changes such as reduction in the neuronal cell size and number. Exposure to fluoride showed neurodegenerative changes like shrunken neurons, increased in folding of the nuclear membrane, mitochondrial alterations, and dilated rough endoplasmic reticulum cisternae and clusters of vesicles near the Golgi bodies. Present study is to explore the histomorphometric changes of the hippocampus of fluoride induced brain and treated with Ginkgo biloba Extract (GBE). Thirty number (30) adult male Wistar rats were randomly separated into 5 Groups (n=6). Group1 (Control) supplemented with water, 2 to 5 Groups were supplemented with 100ppm of sodium fluoride for 30 days, while the Groups 3, 4, and 5 were Ginkgo biloba extract treated at 50mg/ kg, 100mg/kg and 200mg/kg body weight for 15 days, after sodium fluoride treatment, results showed that, 200mg/kg GBE provided effective and complete protection against fluoride toxicity. From the present study concluded that 50, 100 and 200 mg/kg GBE was significantly attenuated the fluoride induced toxicity in a dose depending manner. Present histomorphometrical study showed delayed neuronal death in the CA1 and CA3 regions of hippocampus of fluoride group that was significantly attenuated by GBE (50,100 and 200 mg/kg) in a dose dependant manner.
... However, apart from the alteration of the hard parts of the body such as teeth and bones through fluorosis, very few studies have tied the fluoride toxicity to the physiological dysfunction. Yet, some authors have reported probable toxicities of fluoride in the kidneys [17][18][19], nervous system [20,21], and implications for the severity of diabetes mellitus [22,23]. Fluorides have also been somewhat incriminated in hormone and endocrine dysfunction [17,22]. ...
Togo's phosphate processing plant at Kpeme discharges waste, containing Cd, Pb, and fluoride, into the sea and on the soil. Heavy metals toxicity on kidneys and the liver has been studied. However, fluoride toxicity on these organs remains to be investigated. The present study deals with the variation in renal and hepatic functioning parameters due to fluoride, Cd and Pb. Totally, 350 volunteers were recruited from five different localities around this phosphate processing plant for sample collection. Cd and Pb contents in blood samples were determined by spectrophotometry and fluoride by the titanium chloride method. Biochemical parameters were measured using Biolab kits. The pollutant contents were elevated in polluted areas where ASAT, ALAT, creatinine, and urea increased, and total protein decreased. Correlation and multivariate tests showed that fluoride is related to the various pathologies mentioned. PCA revealed that phosphate processing in Togo is a source of renal and hepatic toxicity.
... Dicha activación puede conducir a la excitotoxicidad y desencadenar la muerte neuronal y pérdida del potencial sináptico (Lan et al., 2001;Blaylock, 2004). En este sentido, la exposición a 0.5 ppm del complejo flúor/aluminio a ratas macho adultas durante 52 semanas disminuye el volumen de las zonas CA1 y CA4 del hipocampo por la pérdida neuronal (Varner et al., 1998). Kinawy AA. (2019), reportó que la administración del complejo flúor/aluminio (floururo de sodio 150 mg/L y cloruro de aluminio 500 mg/L) en ratas macho del sexto día de gestación hasta el destete, disminuye la actividad del complejo ATPasa-Na+ / K+ y superóxido dismutasa en el hipotálamo e hipocampo, mientras que el NO (óxido nítrico) y la peroxidación lipídica incrementa. ...
Investigaciones en el campo de la Salud Ambiental que abordan temáticas tales como los determinantes de la salud, los agroquímicos utilizados en el estado de Jalisco y las afectaciones al ecosistema en general y a la salud humana específicamente, impactos de la contaminación del aire en la salud, el efecto de la contaminación ambiental por fluoruros sobre los estados afectivos de distintos organismos y los parques como espacios de oportunidades socio-culturales para la salud y bienestar de las personas en las ciudades.
... 457 As a reply to this critique, the authors commented that "the fact that a trace element has beneficial ef fects at low doses in specific tissues does not negate the possibility that neurotoxicity might also be occurring, especially at increased levels of exposure". 458 According to the literature, fluoride is capable of crossing the placenta 459,460 and brain barrier, 461 466 and more behavioral symptoms of inattention but not hyperactivity or impulse control between 3 and 12 years of age. 467 Maternal exposure to fluoride through fluoridated water (C F − = 0.59 mg L −1 ), as measured by MUF during pregnancy, was associated with lower IQ scores (assessed at the age 3−4 years) in offspring in comparison to a control group living in nonfluoridated areas (C F − = 0.13 mg L −1 ). ...
Over the last 100-120 years, due to the ever-increasing importance of fluorine-containing compounds in modern technology and daily life, the explosive development of the fluorochemical industry led to an enormous increase of emission of fluoride ions into the biosphere. This made it more and more important to understand the biological activities, metabolism, degradation, and possible environmental hazards of such substances. This comprehensive and critical review focuses on the effects of fluoride ions and organofluorine compounds (mainly pharmaceuticals and agrochemicals) on human health and the environment. To give a better overview, various connected topics are also discussed: reasons and trends of the advance of fluorine-containing pharmaceuticals and agrochemicals, metabolism of fluorinated drugs, withdrawn fluorinated drugs, natural sources of organic and inorganic fluorine compounds in the environment (including the biosphere), sources of fluoride intake, and finally biomarkers of fluoride exposure.
... F toxicity in the Central and Peripheral Nervous System associated to the ingestion of high doses has been extensively described (Bhatnagar et al. 2006;Blaylock 2004;Mullenix et al. 1995;Shivarajashankara et al. 2002;Tsunoda et al. 2005;Vani and Reddy 2000;Varner et al. 1998). Neurotoxicity can be reported as the first sign of F harmful effects, even in the case of skeletal fluorosis development, compromising the nervous system previously to evident bone abnormalities of excessive ingestion (Mullenix et al. 1995). ...
The enteric nervous system is responsible for controlling the gastrointestinal tract (GIT) functions. Enteric neuropathies are highly correlated to the development of several intestinal disturbances. Fluoride (F) is extensively applied for dental health improvement and its ingestion can promote systemic toxicity with mild to severe GIT symptomatology and neurotoxicity. Although F harmful effects have been published, there is no information regarding noxiousness of a high acute F exposure (25 mg F/kg) on enteric neurons and levels of expression of intestinal proteins in the duodenum. Quantitative proteomics of the duodenum wall associated to morphometric and quantitative analysis of enteric neurons displayed F effects of a high acute exposure. F-induced myenteric neuroplasticity was characterized by a decrease in the density of nitrergic neurons and morphometric alterations in the general populations of neurons, nitrergic neurons, and substance P varicosities. Proteomics demonstrated F-induced alterations in levels of expression of 356 proteins correlated to striated muscle cell differentiation; generation of precursor metabolites and energy; NADH and glutathione metabolic process and purine ribonucleoside triphosphate biosynthesis. The neurochemical role of several intestinal proteins was discussed specially related to the modulation of enteric neuroplasticity. The results provide a new perspective on cell signaling pathways of gastrointestinal symptomatology promoted by acute F toxicity.
... Dicha activación puede conducir a la excitotoxicidad y desencadenar la muerte neuronal y pérdida del potencial sináptico (Lan et al., 2001;Blaylock, 2004). En este sentido, la exposición a 0.5 ppm del complejo flúor/aluminio a ratas macho adultas durante 52 semanas disminuye el volumen de las zonas CA1 y CA4 del hipocampo por la pérdida neuronal (Varner et al., 1998). Kinawy AA. (2019), reportó que la administración del complejo flúor/aluminio (floururo de sodio 150 mg/L y cloruro de aluminio 500 mg/L) en ratas macho del sexto día de gestación hasta el destete, disminuye la actividad del complejo ATPasa-Na+ / K+ y superóxido dismutasa en el hipotálamo e hipocampo, mientras que el NO (óxido nítrico) y la peroxidación lipídica incrementa. ...
... Humans can be exposed to fluoride (F) through water, air, fish, vitamin supplements, agrochemicals (organofluorides), and some dental products (Buzalaf et al., 2011;Dhar and Bhatnagar, 2009;Hagmann, 2008;Varner et al., 1998). Although this semi-essential mineral element plays a key role in preventing tooth caries, the excessive exposure to F has been associated with adverse reactions such as fluorosis (Miranda et al., 2018;Shenoy et al., 2019), which is considered an endemic public health problem in several nations and can also affect bones and soft tissues such as the brain, liver, kidney, gonads, and spinal cord (Ozsvath and Bio/Technology, 2009). ...
Long-term exposure to high concentrations of fluoride (F) can damage mineralized and soft tissues such as bones, liver, kidney, intestine, and nervous system of adult rats. The high permeability of the blood-brain barrier and placenta to F during pregnancy and lactation may be critical to neurological development. Therefore, this study aimed to investigate the effects of F exposure during pregnancy and lactation on molecular processes and oxidative biochemistry of offspring rats' hippocampus. Pregnant Wistar rats were randomly assigned into 3 groups in accordance with the drinking water received: G1 - deionized water (control); G2 - 10 mg/L of F and G3 - 50 mg/L of F. The exposure to fluoridated water began on the first day of pregnancy and lasted until the 21st day of breastfeeding (when the offspring rats were weaned). Blood plasma samples of the offspring rats were collected to determine F levels. Hippocampi samples were collected for oxidative biochemistry analyses through antioxidant capacity against peroxyl (ACAP), lipid peroxidation (LPO), and nitrite (NO2-) levels. Also, brain-derived neurotrophic factor (BDNF) gene expression (RT-qPCR) and proteomic profile analyses were performed. The results showed that exposure to both F concentrations during pregnancy and lactation increased the F bioavailability, triggered redox imbalance featured by a decrease of ACAP, increase of LPO and NO2- levels, BDNF overexpression and changes in the hippocampus proteome. These findings raise novel questions regarding potential repercussions on the hippocampus structure and functioning in the different cognitive domains.
... The Al exposure has been associated to biological systems damage and it certainly can be considered a toxic agent. Some studies suggest that chronic exposure to Al can cause neurological and cognitive impairment and learning-memory dysfunction and is thought to be related to Alzheimer's disease [2,[7][8][9][10]. ...
Several studies indicate aluminum (Al) as a potent toxicant, mainly related to central nervous system disorders. However, investigations about the Al effects over salivary glands are still scarce. In this way, the present study aimed to investigate whether the Al chloride (AlCl3) is able of triggering oxidative stress in parotid and submandibular glands of mice and also, if any morphological impairment is observed. For this, twenty mice were divided into two groups: Exposed group (EG), which received 18.5 mg/kg of AlCl3 by intragastric gavage for 60 days and control group (CG), which received distilled water by intragastric gavage during the same period of time. After that, levels of reduced glutathione (GSH) and malonaldehyde (MDA) were analyzed and we performed morphological analyses by evaluating the area of parenchyma, stroma, acini, and ducts in both glands. Statistical analyses were performed by Student’s t test and two-way ANOVA, adopting p < 0.05. No abnormal body weight was observed and data indicates that although both major salivary glands are susceptible to Al-induced oxidative stress, by increasing MDA and reducing GSH, only submandibular glands decreased the parenchyma and increased stroma area. Moreover, the submandibular glands showed smaller total area of acini and higher total area of ducts, in comparison with the control group. Notably, AlCl3 induces oxidative stress in both glands, however, submandibular glands showed to be more susceptible to Al effects than parotid glands. Our study gives evidences about Al toxicity in parotid and submandibular glands and claims for new investigations to understand more mechanisms of Al-induced toxicity.
... There are several mechanisms by which fluoride exposure may contribute to kidney dysfunction. First, studies with adult rats have shown that chronic low-level fluoride exposure can lead to glomerular hypercellularity and mesangial cell proliferation (Varner et al., 1998), reduced kidney enzyme activity (Sullivan, 1969), interstitial nephritis, and renal tubule hypertrophy and hyperplasia (McCay et al., 1957). Increased apoptosis and tubular epithelial damage, including necrosis, have also been observed among children with high fluoride exposures (Quadri et al., 2018). ...
Background:
Hepato- and nephrotoxicity of fluoride have been demonstrated in animals, but few studies have examined potential effects in humans. This population-based study examines the relationship between chronic low-level fluoride exposure and kidney and liver function among United States (U.S.) adolescents. This study aimed to evaluate whether greater fluoride exposure is associated with altered kidney and liver parameters among U.S. youth.
Methods:
This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (2013-2016). We analyzed data from 1983 and 1742 adolescents who had plasma and water fluoride measures respectively and did not have kidney disease. Fluoride was measured in plasma and household tap water. Kidney parameters included estimated glomerular filtration rate (calculated by the original Schwartz formula), serum uric acid, and the urinary albumin to creatinine ratio. Liver parameters were assessed in serum and included alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen, gamma-glutamyl transferase, and albumin. Survey-weighted linear regression examined relationships between fluoride exposure and kidney and liver parameters after covariate adjustment. A Holm-Bonferroni correction accounted for multiple comparisons.
Results:
The average age of adolescents was 15.4 years. Median water and plasma fluoride concentrations were 0.48 mg/L and 0.33 μmol/L respectively. A 1 μmol/L increase in plasma fluoride was associated with a 10.36 mL/min/1.73 m2 lower estimated glomerular filtration rate (95% CI: -17.50, -3.22; p = 0.05), a 0.29 mg/dL higher serum uric acid concentration (95% CI: 0.09, 0.50; p = 0.05), and a 1.29 mg/dL lower blood urea nitrogen concentration (95%CI: -1.87, -0.70; p < 0.001). A 1 mg/L increase in water fluoride was associated with a 0.93 mg/dL lower blood urea nitrogen concentration (95% CI: -1.44, -0.42; p = 0.007).
Conclusions:
Fluoride exposure may contribute to complex changes in kidney and liver related parameters among U.S. adolescents. As the study is cross-sectional, reverse causality cannot be ruled out; therefore, altered kidney and/or liver function may impact bodily fluoride absorption and metabolic processes.
... Several epidemiologic studies have demonstrated an association between fluoride and aluminum, administered separately or in combination, and neurobehavioral deterioration in populations living in regions with endemic environmental pollution (Akinrinade, Memudu, & Ogundele, 2015;Kraus & Forbes, 1992;Varner, Jensen, Horvath, & Isaacson, 1998;Yazdi, Sharifian, Dehghani-Beshne, Momeni, & Aminian, 2011). The association between long-term aluminum and fluoride or aluminum/ fluoride intake in the drinking water and the development of Alzheimer's disease has been suggested (Belojevic & Jakovljevic, 1998;Ge et al., 2018;Zhu et al., 2016). ...
Background: This study highlights the potential toxic effects of aluminum chloride and sodium fluoride (NaF), given to pregnant female rats, on the development of the brain neurotransmission systems in their offspring. Pregnant female rats received a daily dose of NaF (0.15 g/L) or AlCl 3 (0.5 g/L) in the drinking deionized water, either separately or in combination with each other, starting from the 6th day of gestation till the end of the breastfeeding period. After weaning, the male offspring were divided into two subgroups; in the first one, the offspring continued to have the same treatments in their drinking water at the same dose levels, as were provided to the mothers, until the age of 70 days of postnatal life. In the second subgroup, the pups were provided with a drinking deionized water without the treatments for a similar period of time. At the end of the experimental period, the contents of the brain monoamine neurotransmitters, as well as the acetylcholinesterase (AChE) activity, were assessed in the cerebral cortex, hippocampus, and hypothalamus. In addition, the offspring were subjected to the exploratory behavioral test. Results: The results revealed that sodium fluoride and aluminum chloride induced sever perturbation and imbalance in the neurotransmission systems under investigation. The pattern of change and severity differed with the different brain areas. The combination of the two pollutants exerted general synergistic impacts with different specific response in the different brain area.
... These elements possess a high capacity to penetrate the blood-brain barrier and retain in the brain tissues of the developing brain and induce developmental disorders (Ge et al. 2018). It has been reported that fluoride increases aluminum capacity to cross the blood-brain barrier, thereby, causing prominent reduction in neuronal density, damage to neuronal cells, and alterations in the neuronal and cerebrovasculature architecture (Varner et al. 1998;Nalagoni and Karnati 2016) Moreover, both fluoride and aluminum compounds enhance the cellular oxidative stress, and their deleterious effects were reported to be more extensive when they were administered simultaneously (Kaur et al. 2009;Nalagoni and Karnati 2016). This results in alterations in the antioxidant defense system and leads to serious damage to neuronal tissue and neurodegenerative disorders (Campbell et al. 2004;Kawahara 2005;Jyoti et al. 2007;Kumar et al. 2009;Narayanaswamy and Piler 2010;Lu et al. 2017). ...
Aluminum is widely used in industry and in cooking utensils, especially in countries with low economic and social standards. Fluoride is also used in industry, a major component of toothpaste and is added to the drinking water in many countries to fight teeth decay and cavities. Consequently, the coexistence of aluminum and fluoride is highly probable. Growing evidence indicates that environmental pollutants during the early stages of embryonic development may reprogram the offspring’s brain capabilities to encounter oxidative stress during the rest of their postnatal life. This study investigated the impact of sodium fluoride (NaF, 0.15 g/L) and aluminum chloride (AlCl3, 500 mg/L) added, individually or in combination, to the deionized drinking water starting from day 6 of gestation until just after weaning, or until the age of 70 days postnatal life. A significant decline was observed in tissue contents of vitamin C, reduced glutathione, GSH/GSSH ratio, and the total protein, as well as in the activities of Na⁺/K⁺-ATPase and superoxide dismutase (SOD) in almost all cases. On the contrary, lipid peroxidation and NO, as total nitrate, exhibited a significant increase in comparison with the corresponding control. Based on the present results, administration of Al and NaF, alone or in combination abated the quenching effects of the antioxidant system and induced oxidative stress in most brain regions under investigation. In conclusion, aluminum and fluoride are very noxious environmental pollutants that interfere with the proper functions of the brain neurons and their combination together aggravates their hazard.
... Hippocampus and cerebral cortex are two major components which involved in learning and memory process (Vianna et al., 2000). These regions are most affected in NaF intoxication and as a result affect the overall behavior of animal (Varner et al., 1998). ...
Fluoride causes major human health complications and evidence suggests that exposure of fluoride during developmental periods adversely affect neurodevelopment, behavior, and maturity of the brain as these periods are critical for developing stages for CNS. The present study aimed to assess the mechanically induced pain sensitivity, cell morphology, circuitry in terms of neural connections and networks and maturation of neurons under fluorideinduced toxicity with concurrent treatment of protective effects of Abelmoschus moschatus seed extract from day 1 of pregnancy to post-natal day (PND) of a rat with age 30th day. Timed pregnant wistar rats (30) were segregated into six groups, viz. control, sodium fluoride (NaF) (20 ppm), NaF + A. moschatus aqueous extract (AMAE), NaF + A. moschatus ethanolic extract (AMEE), AMAE, and AMEE and treated for 51 days (21 gestational and 30 postnatal days). On postnatal days 1, 7, 14, 21 and 30, rats were assessed for oxidative stress markers (GSH and GSSG) and neurohistology of the brain. Increased threshold levels to the mechanical stimulus were observed in fluoridetreated rats. Brain stained with Congo red, Cresyl violet and Golgi cox for β-amyloid, Nissl substance and synaptic connections respectively showed cells become amyloidosis with decreased Nissl substance and decreased number of neuronal connections in NaF exposed rats. Reduced content of GSH and increased GSSG levels (P < 0.001) were also recorded in NaF treated rats. These alterations were associated with increased production of free radicals and the effect of fluoride on the brain is inversely proportional with age. These changes were ameliorated by supplementation with AMAE and AMEE with anti-oxidant properties, which reduce the production of free radicals from fluoride. Thus, the seed extract of A. moschatus had a protective effect over fluoride induced alteration in neural cell maturation, and the establishment of circuitry, mechanical pain sensitivity, and oxidative stress.
... The research on Fl and the brain that have been studied in humans in India, China, Iran, and Mexico showed that high levels of Fl exposure were associated with IQ deficits in children (NRC, 2006). The animal studies have also documented the considerable evidence on the direct toxic effects of Fl on the brain, even at the low level of 1 ppm Fl in water (Varner, Jensen, Horvath, & Isaacson, 1998). These effects include a reduction in nicotinic acetylcholine receptors, reduction in lipid content, impaired anti-oxidant defense, damage to the hippocampus, Purkinje cells and accumulation of Fl in the pineal gland and the formation of betaamyloid plaques (NRC, 2006). ...
Background
Industrial and agricultural growths in recent years has resulted in the extreme discharge of arsenic into the environment, making arsenic toxicity a major worldwide concern. Oxidative stress is considered the primary mechanism for arsenic toxicity.
Purpose
The main objective of this study was to evaluate sulforaphane protective ability against arsenic-induced hepatotoxicity in rats via PI3K/Akt mediated Nrf2 activation.
Methods
For this purpose, male Wistar rats were divided into six groups of 8 rats each: control, Arsenic (As) (5mg/kg BW), As + SFN (5mg/kg; 20, 40, 80 mg/kg BW) and Vitamin C (As (5mg/kg) +100mg/kg). The animals were gavaged for 28 consecutive days. Liver tissue samples were extracted 24 hours after the last treatment and later analyzed for biochemical, molecular and histological alterations.
Results
Pretreatment with SFN led to decreased levels of ALAD, Ar accumulation, and brought antioxidant enzymes into normal levels without affecting Arsenic metabolism. This was accompanied by stabilizes the apoptotic markers via PI3K/Akt mediated Nrf2 activation as evidenced by western blotting and PCR techniques. Furthermore, SFN pretreatment shield the histoarchitecture of liver tissue in As treated rats.
Conclusion
The present study has provided mechanistic insights to the phytotherapeutic potential of SFN against As-induced liver injury by up-regulating Nrf2 gene via PI3K/Akt signalling pathway.
... The research on Fl and the brain that have been studied in humans in India, China, Iran, and Mexico showed that high levels of Fl exposure were associated with IQ deficits in children (NRC, 2006). The animal studies have also documented the considerable evidence on the direct toxic effects of Fl on the brain, even at the low level of 1 ppm Fl in water (Varner, Jensen, Horvath, & Isaacson, 1998). These effects include a reduction in nicotinic acetylcholine receptors, reduction in lipid content, impaired anti-oxidant defense, damage to the hippocampus, Purkinje cells and accumulation of Fl in the pineal gland and the formation of betaamyloid plaques (NRC, 2006). ...
Arsenic (Ar), a naturally occurring environmental toxicant, is capable of causing acute renal failure as well as renal cancer. Ar is known to exert its toxicity through oxidative stress by generating reactive oxygen species (ROS). Present study investigates the protective efficacy of sulforaphane (SFN) against arsenic induced renal damage via PI3K/Akt mediated Nrf2 functions. Thirty two male Wistar albino rats were randomly divided into four groups (n=8): the control, arsenic (Ar), Sulforaphane+Ar (SFN+Ar), and Sulforaphane (SFN) was orally administrated with Ar (5 mg/kg BW) and SFN (80mg/kg BW) daily for 28 days. Ar induced nephrotoxicity was significantly (P<0.05) increased the levels of ROS, OHdG, Ar accumulation, lipid peroxidation with consistent decreased levels of enzymatic and non-enzymatic antioxidants. Notably, a significant (P<0.05) increase in the apoptotic markers, DNA damage, positive TUNEL cells and dark staining of ICAM in renal tissue with decreased PI3K/Akt/ Nrf2 gene. Moreover, the histopathological and electron microscopic evaluation also supports the biochemical findings showed severe renal damages in rats treated with Ar. Pre-administration of SFN significantly (P<0.05) attenuated the renal ROS, OHdG, lipid peroxidation, DNA damage and increased phase II antioxidants viaPI3K/Akt/ Nrf2 gene as evidenced by appearance of normal histological structures of renal tissue. In conclusion, dietary supplementation of SFN protects against Ar induced nephrotoxicity via PI3K/Akt mediated Nrf2 signaling pathway in rat kidney.
... Although all suppliers are required to provide certificates of analysis and the amounts of contaminants in chemicals added to water as in some countries such as New Zealand (37), this is not always the case all over the world. -In addition, several animal and human studies on fluoride show some neurotoxic (38)(39)(40)(41)(42) and nephrotoxic (43) effects. Other negative effects of fluoride, even when administered in small doses (starting 0.3 ppm), occur on the levels of the thyroid function (44), the skeletal system (45,46) and the reproductive system (47)(48)(49). ...
Fluoride is one of the most abundant elements found in nature. Water is the major dietary source of fluoride. The only known association with low fluoride intake is the risk of dental caries. Initially, fluoride was considered beneficial when given systemically during tooth development, but later research has shown the importance and the advantages of its topical effects in the prevention or treatment of dental caries and tooth decay. Water fluoridation was once heralded as one of the best public health achievements in the twentieth century. Since this practice is not feasible or cost effective in many regions, especially rural areas, researchers and policy makers have explored other methods of introducing fluoride to the general population such as adding fluoride to milk and table salt. Lately, major concerns about excessive fluoride intake and related toxicity were raised worldwide, leading several countries to ban fluoridation. Health-care professionals and the public need guidance regarding the debate around fluoridation. This paper reviews the different aspects of fluoridation, their effectiveness in dental caries prevention and their risks. It was performed in the PubMed and the Google Scholar databases in January 2018 without limitation as to the publication period.
Alüminyum günlük diyetle düzenli olarak alınan, antiperspirantlarda, aşılarda adjuvan olarak kullanılan bir elementtir. Alüminyumun kaynakları, vücuda alınımı ve insan sağlığı üzerindeki zararlı etkileri hakkında bilgi vermek amacıyla PubMed ve SCOPUS veri tabanlarından elde edilen yayınlara dayanan bu derlemede yazarların mesleki ve kişisel deneyimleri ele alınmıştır. Alüminyum, çevrede, gıda maddelerinde ve içme suyunda doğal olarak bulunur. Alüminyum için referans değerleri aşma olasılığı özellikle mesleki maruziyeti olan kişilerde daha yüksektir. Buna bağlı olarak alüminyum kaynakçıları ve alüminyum endüstrisindeki işçilerin idrarlarında alüminyum konsantrasyonları yüksek seviyelerde bulunmuştur. Ancak, işçiler üzerinde yapılan nöropsiko mantıksal (dikkat, öğrenme, hafıza) testlerinde demansla tezahür eden ensefalopati bulunamamıştır. Alzheimer hastalığı olan kişilerin beyinlerinde yüksek alüminyum içeriği bulunmasına rağmen, bunun hastalığın bir nedeni veya etkisi olup olmadığı belirsizliğini korumaktadır. Alüminyumun kanserojenlik etkisi konusunda da çelişkili sonuçlar vardır. Alüminyum içeren antiperspiranların meme kanserini teşvik ettiği iddiası bilimsel verilerle desteklenememiştir. Alüminyumun kritik yan etkisi ancak insanlarda ve hayvanlarda nörotoksisite gösterilerek belirlenebilir. Buna Alzheimer tipi demansın patofizyolojisi ile aynı olmayan demans sendromlu ensefalopati dahildir. Alüminyum içeren ter önleyiciler ile meme riski arasındaki ilişki, geniş çaplı epidemiyolojik kanser çalışmalarından elde edilebilir.
In the following, I will consider the impact of aluminum on two major systems, the central nervous system (CNS) and the immune system, across the life span. The article will discuss the presence of aluminum in the biosphere, its history, and the sources of the element. These include food, water cosmetics, some vaccines, and a range of other sources. I will also consider aluminum’s unique chemistry. Finally, in humans and animals, I will consider how aluminum may impact the CNS at various levels of organization and how it may be involved in various neurological disease states across the life span. These disorders include those of infancy and childhood, such as autism spectrum disorder (ASD), as well as those in adulthood, such as in Alzheimer’s disease. The bidirectional nature of CNS–immune system interactions will be considered and put into the context of neurological disorders that have an autoimmune component. I will argue that the exposure to humans and animals to this element needs to be reduced if we are to diminish some CNS and immune system disorders.KeywordsAluminum bioavailabilityCentral nervous systemImmune systemAutoimmunityAutism spectrum disorder
Water is the principal source of human exposure to fluoride (F). The high permeability of the placenta and blood-brain barrier to F during the intrauterine life up to the end of lactation may be crucial to neurological fetus development.
Therefore, this study explores the effects of 5 and 10 mg/l F exposure during entire gestation and lactation periods, through neurobehavioral and biochemical tests performed on 90-day-old male offspring rats. The present study shows that pre and peri-natal exposure to F doses that are in the range of those found in groundwater sources in Argentina affects long-term memory and leads to a depressive-like behavior in 90-day-old male pup.
Furthermore, the purpose of the investigation was to find out the possible biochemical changes through which the pre and peri-natal F-administration could generate such behavioral variations. We found alterations in transaminases, acetylcholinesterase, and alkaline phosphatase enzymes activity in specific brain areas (the prefrontal cortex, the striatum, and the hippocampus), together with findings regarding misbalanced oxidative stress.
In conclusion, F exposure during the early stages of rat development alters brain-oxidative stress markers as well as the activity of enzymes implicated in cholinergic and glutamatergic systems. These molecular changes could contribute to the neurobehavioral alterations described in the present investigation.
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, and pathogenesis. A large number of in vivo and in vitro studies and epidemiological investigations have found that chronic fluorosis can cause brain damage, resulting in abnormal brain structure and brain function.Chronic fluorosis not only causes a decline in concentration, learning, and memory, but also has mental symptoms such as anxiety, tension, and depression. Several possible mechanisms that have been proposed: the oxidative stress and inflammation theory, neural cell apoptosis theory, neurotransmitter imbalance theory, as well as the doctrine of the interaction of fluorine with other elements. However, the specific mechanism of chronic fluorosis on brain damage is still unclear. Thus, a better understanding of the mechanisms via which chronic fluorosis causes brain damage is of great significance to protect the physical and mental health of people in developing countries, especially those living in the endemic areas of fluorosis. In brief, further investigation concerning the influence of fluoride on the brain should be conducted as the neural damage induced by it may bring about a huge problem in public health, especially considering growing environmental pollution.
The main goal of this thesis is to decrease the concentration of fluoride in drinking water in El Oued region using the precipitation method.
full thesis structured into two main parts
Theoretical Part:
Chapters 1. Generalities about the element fluoride
Chapters 2. Methods for determining fluoride in water
Chapters 3. Fluoride Reduction Techniques
Experimental part:
Chapters 1. Devices and methods
Chapters 2. Results and discussion
A number of seemingly harmless substances can become poisons, depending on the dose. This is essentially true of fluoride and the exposure of the biological system to it. Fluoride has been known and used as an anti-cariogenic agent over the decades in dental practice. Many communities and municipal authorities had advocated for fluoride supplements in water sources to boost the health of the teeth especially in children. However, fluoride is now known to be toxic at specific concentrations, hence the dose and poison phenomenon. The ecosystem is exposed to fluoride in diverse sources, naturally from volcanic eruptions, marine aerosols, minerals and artificially from combination of other elements. High environmental levels of fluoride have been reported geographically from different parts of the world and have been associated with elevated levels of fluoride in the biological host. Both naturally and anthropogenic sources has been found to be toxic, at high and prolonged exposure, to humans, through food, water and air pollution, especially during early development and growth. These toxic levels have been associated with clinical manifestations in different body parts such as bones, teeth, kidney, liver, endocrine, including the brain. We hereby highlighted some local sources (natural and artificial) of fluoride in the ecosystem and then bring to fore its neurotoxic effects. We hope to increase fluoride neurotoxicity awareness as a public health concern especially in developing countries like Nigeria. There is a need for more advocacy and research on prevailing environmental levels, associated pathophysiology and risk-benefit of fluoride toxicity, especially on developmental fluoride toxicity by ecotoxicologists in collaboration with neuroscientists.
An optical probe 1 has been synthesized comprising naphthalimide unit conjugated with Schiff base, exhibiting excited state intramolecular proton transfer and intramolecular charge transfer as a potential sensor for Al³⁺ and F⁻ ions using standard spectroscopic techniques. The probe 1 exhibited local and charge-transfer excitation at 340 nm and 460 nm, respectively. On excitation at 460 nm, probe 1 displayed two emission bands at 510 nm and 610 nm, accompanied by Stokes‘ shift of 50 nm and 150 nm, respectively. The solvatochromic effect and theoretical calculation depicted that the representative emissions resulted from the ESICT/ESIPT phenomenon. Upon addition of Al³⁺ ions, the charge transfer excitation at 460 nm was enhanced ratiometrically to local excitation at 340 nm and showed a color change from orange to yellow. Similarily, probe 1.Al³⁺ displayed emission enhancement at 540 nm in H2O/CH3CN (1:9; v/v) and showed a color change from yellow to blue-green emission. Following the detection of Al³⁺ ions, hydrolysis of probe 1 to its reacting precursors was observed. The detection of Al³⁺ ions was also demonstrated in surfactant-containing water. The limit of detection (LOD) of probe 1 (H2O/CH3CN (1:9; v/v)) towards Al³⁺ ions was measured to be 3.2 × 10⁻⁸ M. The probe 1 displayed a ratiometric absorption response towards F⁻ ions with a new peak at 570 nm and showed a color change from orange to purple. The probe 1.F⁻ displayed a decrease in emission at 635 nm. The LOD of probe 1 (CH3CN) towards F⁻ ions was measured to be 7.5 × 10⁻⁷ M.
Water is the most important nutrient for rangeland livestock. However, competition with municipalities, industry, and other water users often results in grazing livestock being forced to use water supplies that are less than perfect. Surface water in western rangleands are often contaminated by mineral extraction, irrigation runoff and other human activities. Mineral contaminants in drinking water are additive with similar contaminants in feedstuffs. The goal of this article is to provide producers and veterinarians with the basic background to make informed decisions about whether a given water supply is "safe" for livestock.
Excess fluoride intake has been linked with various pathological conditions. The objective of the present study was to understand the role of fluoride in neurotoxic, neuroinflammatory, and neurodegenerative changes in the brain tissue of Wistar rats. Wistar rats were fed with water containing 20–100 ppm (ppm) sodium fluoride (NaF). An array of neurotransmitters (acetylcholine, dopamine, epinephrine, norepinephrine, serotonin, histamine, and glutamate) expression levels were estimated with respect to different fluoride concentrations. Additionally, its effect on the expression levels of specific neuroinflammatory markers (iNOS, COX-2, TNF-α, PKC, VEGF, and HSP-70) in brain tissues of Wister rats was assessed. An increase in NaF concentration resulted in increased fluoride deposition in the brain which in turn caused increase levels of epinephrine, histamine, serotonin, and glutamate and decreased levels of norepinephrine, acetylcholine, and dopamine in a dose-dependent manner. Tissue fluoride levels of the hippocampus, neocortex, cerebellum, spinal cord, and sciatic nerve increased significantly in fluoride fed rats. Transmission electron microscopy in the experimental animals revealed axon deterioration, myelin sheath degeneration, and dark cells with scanty cytoplasm in the spinal cord and sciatic nerve. Additionally, vacuolated swollen mitochondria were observed in the neocortex, hippocampus, and cerebellum. Results suggest excess fluoride intake modulates a set of biological marker and promote neuroinflammatory and neurodegenerative condition in Wister rats. Therefore, we conclude that the accumulation of NaF alters the neurological function which leads to neurodegenerative disorders.
In the following, I will consider the impact of aluminum on two major systems, the central nervous system (CNS) and the immune system, across the life span. The article will discuss the presence of aluminum in the biosphere, its history, and the sources of the element. These include food, water cosmetics, some vaccines, and a range of other sources. I will also consider aluminum’s unique chemistry. Finally, in humans and animals, I will consider how aluminum may impact the CNS at various levels of organization and how it may be involved in various neurological disease states across the life span. These disorders include those of infancy and childhood, such as autism spectrum disorder (ASD), as well as those in adulthood, such as in Alzheimer’s disease. The bidirectional nature of CNS–immune system interactions will be considered and put into the context of neurological disorders that have an autoimmune component. I will argue that the exposure to humans and animals to this element needs to be reduced if we are to diminish some CNS and immune system disorders.
Capillary zone electrophoresis was evaluated as a method for the speciation of aluminum in aqueous solution using indirect UV absorption detection. Fluoro- and oxalatoaluminum complexes appeared as sharp and well-defined peaks within the electropherogram of aluminum standard solutions when the appropriate ligand was added. Simultaneous separation of these inorganic and organic aluminum species was achieved with good resolution in a single analytical run within 5 min. Indirect UV detection was achieved at 214 nm with a background electrolyte buffer containing 5 mM imidazole. The average limit of detection was about 10 nM for uncomplexed and complexed aluminum species. Excellent agreement between experimental and theoretical species concentrations (via the thermodynamic speciation model SOILCHEM) was obtained for solutions with varying ligand/aluminum mol ratios and pH values.
All cases of fluoride ingestion in children younger than 12 years old reported to the Rocky Mountain Poison Center between January 1 and December 31, 1986, were retrospectively reviewed. Eighty-seven cases were identified. Eighty-four cases involved accidental ingestion of dental fluoride products in the home (tablets, drops, rinses) in children 8 months to 6 years old. Two older children (8 and 9 years old) became symptomatic after fluoride treatment by a dentist. A 13-month-old child died after ingesting an unknown amount of sodium fluoride insecticide, the only insecticide exposure in our series. Postmortem total serum calcium value was 4.8 mg/dL (normal 8.8 to 10.3). No other patients had serious symptoms or sequelae. Twenty-six (30%) of 87 became symptomatic, with gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain) in 25 patients and drowsiness in 1. Only 3 patients became symptomatic later than 1 hour after ingestion. Analysis of data from 70 cases with sufficient information revealed that as the amount of fluoride ingested increased, the percentage of patients with symptoms increased. Not including the fatal case, 6 patients had serum calcium levels measured, and all were normal. Children who ingested up to 8.4 mg/kg of elemental fluoride in dental products had mild and self-limited symptoms, mostly gastrointestinal.
This summarizes current knowledge of the benefits and risks of fluoride ingestion. The preponderance of evidence indicates that fluoride can reduce the incidence of dental caries and that fluoridation of drinking water can provide such protection. Due to the ubiquitous nature of exposures to fluoride sources other than drinking water, it is currently impossible to draw firm conclusions regarding the independent effect of fluoride in drinking water on caries prevalence using an ecologic study design. Moderate dental fluorosis occurs in 1 to 2% of the population exposed to fluoride at 1 mg/l in drinking water and in about 10% of the population at 2 mg/l; moderate/severe fluorosis occurs in variable percentages ranging up to 33% of the population exposed to fluoride at 2.4 to 4.1 mg/l in drinking water. The issue of whether moderate or severe dental fluorosis represents an adverse health effect is still controversial. There is no evidence of skeletal fluorosis among the general U.S. population exposed to drinking water fluoride concentrations lower than 4 mg/l. Radiographically detected osteosclerosis after chronic exposure to fluoride in drinking water at 8 mg/l was not associated with clinical symptoms. Reports of crippling skeletal fluorosis associated with low concentrations of fluoride in drinking water in tropical countries have been attributed to other dietary factors. The available data suggest that some individuals may experience hypersensitivity to fluoride-containing agents. Further studies on hypersensitivity are required. There is no evidence of increased incidence of renal disease or renal dysfunction in humans exposed to up to 8 mg fluoride per liter in drinking water. Structural changes in kidneys of experimental animals have been detected at doses exceeding 1 to 5 mg fluoride per kilogram per day. Based on four case reports, individuals with renal insufficiency who consume large volumes of naturally fluoridated water at 2 to 8 mg/l are possibly at increased risk of developing skeletal fluorosis. Studies on the effects of fluoride in individuals with renal insufficiency are needed. There is no evidence that chronic exposure to concentrations of fluoride reported to be greater than 2 mg/l in drinking water increases human cancer mortality or incidence. A study of lifetime exposure to fluoride on cancer incidence in rats and mice has been completed, but assessment for cancer has not been completed. There is no evidence that fluoride is genotoxic except in some in vitro assays at cytotoxic concentrations. There is no in vivo evidence that fluoride affects human cellular enzyme activities.(ABSTRACT TRUNCATED AT 400 WORDS)
The toxicity of aluminum in plant and animal cell biology is well established, although poorly understood. Several recent studies have identified aluminum as a potential, although highly controversial, contributory factor in the pathology of Alzheimer disease, amyotrophic lateral sclerosis, and dialysis dementia. For example, aluminum has been found in high concentrations in senile plaques and neurofibrillary tangles, which occur in the brains of subjects with Alzheimer disease. However, a mechanism for the entry of aluminum (Al3+) into the cells of the central nervous system (CNS) has yet to be found. Here we describe a possible route of entry for aluminum into the cells of the CNS via the same high-affinity receptor-ligand system that has been postulated for iron (Fe3+) delivery to neurons and glial cells. These results suggest that aluminum is able to gain access to the central nervous system under normal physiological conditions. Furthermore, these data suggest that the interaction between transferrin and its receptor may function as a general metal ion regulatory system in the CNS, extending beyond its postulated role in iron regulation.
Transducin, the guanyl nucleotide-binding protein of the retinal light-activated cGMP phosphodiesterase system, is structurally and functionally similar to the inhibitory and stimulatory guanyl nucleotide-binding proteins, Gi and Gs, of the adenylate cyclase complex. All are heterotrimers composed of alpha, beta, and gamma subunits. Gs and Gi can be activated by NaF with AlCl3 as well as by agonists acting through specific receptors. The effects of NaF and AlCl3 on transducin were investigated in a reconstituted system consisting of the purified subunits of transducin (T alpha, T beta, gamma) and rhodopsin. NaF noncompetitively inhibited the GTPase activity of T alpha in a concentration- and time-dependent manner. Inhibition by NaF was enhanced synergistically by AlCl3 which alone only slightly inhibited GTPase activity. None of the other anions tested reproduced the effect of fluoride. Fluoride inhibited [3H]guanosine 5'-(beta, gamma-imido)triphosphate binding to T alpha and release of bound GDP. The ADP-ribosylation of T alpha by pertussis toxin and binding of T alpha to rhodopsin, both of which are enhanced in the presence of T beta gamma, were inhibited by NaF and AlCl3. These findings are consistent with the hypothesis that fluoride enhances the dissociation of T alpha from T beta gamma, resulting in the inhibition of GTP-GDP exchange, and therefore, GTP hydrolysis.
Congo/Red deposition with birefringence to polarized light was demonstrated focally in cerebrovascular malformations removed surgically from 4 older patients (ages 85, 74, 74, and 63), and in a spinal cord vascular malformation in a 76-year-old patient. Lesser degrees of Congophilic change were observed in cerebrovascular malformations screened from 4 of 10 patients between the ages of 30 and 59. No Congophilic change was seen in 10 cerebrovascular malformations removed from patients under 30 years of age. Congophilic areas in all cases decorated with W-2 and 85/45 polyclonal antibodies raised to peptide sequences of cerebrovascular beta-amyloid and beta-amyloid of senile plaques from patients with Alzheimer's disease. Thus, the amyloid in these vascular malformations is immunologically related to beta-amyloid protein. This finding provides another indication that vascular beta-amyloid deposition is not specific for Alzheimer's disease and suggests that an existing abnormality of vessels may be a predisposing factor.
Ferritin was isolated from the livers and brains of two groups of rats, one of which was fed aluminum chloride (100 microM) for 1 year in the drinking water. Brain tissue contained about one-third of the amount of ferritin found in the liver. While brain ferritin from normal rats contained 42.1 +/- 14.3 mol of aluminum, that from the aluminum-fed group contained 115.4 +/- 48.3 mol of aluminum per mol of ferritin. Liver ferritin from both groups contained similar amounts of both aluminum and iron, and the amounts were less than that found associated with brain ferritin. Ferritin isolated from the brains of patients who died of Alzheimer disease contained more aluminum and more iron than that from age-matched controls. Human brain ferritin is composed of two types of subunits--about 70% heavy chain (Mr, 22,000) and 30% light chain (Mr, 19,500). The isoelectric focusing pattern of human brain ferritin was considerably different from that of human liver. Only 5 of the 20 brain ferritin bands migrated similarly to the acidic isoferritins from the liver, and the major component of brain ferritin, representing 30% of the total ferritin, had a pI of 8.0.
The clustering pattern of diffuse, primitive and classic beta-amyloid (A beta) deposits was studied in the upper laminae of the frontal cortex of 9 patients with sporadic Alzheimer's disease (AD). A beta stained tissue was counterstained with collagen type IV antiserum to determine whether the clusters of A beta deposits were related to blood vessels. In all patients, A beta deposits and blood vessels were clustered, with in many patients, a regular periodicity of clusters along the cortex parallel to the pia. The classic A beta deposit clusters coincided with those of the larger blood vessels in all patients and with clusters of smaller blood vessels in 4 patients. Diffuse deposit clusters were related to blood vessels in 3 patients. Primitive deposit clusters were either unrelated to or negatively correlated with the blood vessels in six patients. Hence, A beta deposit subtypes differ in their relationship to blood vessels. The data suggest a direct and specific role for the larger blood vessels in the formation of amyloid cores in AD.
Plaques are one of the two lesions found in the brain of patients with Alzheimer disease. Using a synthetic peptide corresponding to rat beta-amyloid-(1-42) (beta A4), circular dichroism (CD) analyses were performed to examine the effect of Na4SiO4 on the conformational state produced by Al3+. A previous study on fragments of neuronal proteins involved in tangle formation had shown a conformational transition from a beta-pleated sheet to a soluble random coil upon addition of Na4SiO4. In the present study, CD measurements showed that the beta-pleated sheet conformation of beta A4 induced by Al3+ was reversed to the random coil soluble form by the addition of Na4SiO4. The tight binding of SiO4(4-) with Al3+ provides the mechanism for this transition. These results provide insight into the role of aluminum in the Alzheimer diseased brain and suggests that investigation of the use of silicates as a therapeutic agent.
Male Long-Evans rats were divided into four groups based on the concentrations of the AIF3 in the drinking water: 0.5 ppm, 5.0 ppm, 50 ppm, or a control solution of double-distilled, de-ionized water. Water was available ad libitum for 45 weeks. Following the behavioral studies, histological, immunohistochemical, and overall brain aluminum (Al) evaluations were made on portions of the brains from these animals. Selected coronal sections were stained by the Bielschowsky silver stain method, the Morin Al-fluorescence procedure, several standard neurohistological methods for cellular proteins, and through the use of several immunohistochemical methods, including ones that reveal neurofilaments and reactive astrocytes (GFAP). This report presents descriptions of the responses of the brains to the toxin exposure in regard to cell loss and other changes in the neocortex and hippocampus. The brain sections were immunohistochemically studied using antibodies both to neurofilament and phosphorylated neurofilament proteins. The three AIF3 groups did not differ from each other in overall brain Al content, but all treated groups had about twice the Al levels as did the control group. There were significant reductions in the number of neurons in the hippocampal CA1 and CA3 areas of the AIF3 treated groups. In addition the cells of the hippocampal formation appeared disorganized and many cells in all subdivisions stained excessively for Nissl-like proteins and that may reflect cellular dysfunction. Cells in the outer layers of the neocortex of the AIF3 groups exhibited darker Nissl staining and were more argentophilic than cells in similar areas from brains of the controls. These intracellular accumulations were not associated with increases in either phosphorylated or non-phosphorylated protein. Reduced numbers of cells evidencing neurofilament reaction product were found selectively in neocortical layer 4. There were large numbers of GFAP-positive cells in the brains of rats from all groups but the number of reactive cells was not greater in the treated animals than in the controls.
Tobias Smollett, author of Humphry Clinker (Smollett, 1771), was greatly concerned about the bodily effects of the use of double salts of aluminum with ammonium and potassium to purify water and as an anticaking agent in flour. However, the use of aluminum salts for the treatment of wounds and the purification of water extended to at least Roman times (Pliny). The first systematic investigation of aluminum toxicity demonstrated that the “point of attack” in aluminum poisoning was the central nervous system (Siem, 1886). In the past 20 years, knowledge about aluminum neurotoxicity and a possible role in Alzheimer’s disease (AD) has rapidly expanded. It is now appropriate to address the question of whether aluminum is a risk factor for Alzheimer’s disease and whether a public health action to reduce human exposure to aluminum would reduce the incidence of Alzheimer’s disease.
Acute intoxication with inorganic fluoride disrupts numerous physiological systems. As a potent acid it acts corrosively on the skin and mucous membranes, producing severe burns. As the most electronegative element it tightly binds many cations essential to homeostasis, producing, for example, profound hypocalcaemia and resultant inhibition of normal blood coagulation. As a metabolic poison it stimulates some enzymes, such as adenylate cyclase, and severely inhibits others, such as Na+-K+-ATPase and the enzymes of carbohydrate metabolism. Death can result from these processes and also from a delayed, explosive hyperkalaemia. Therapy of acute poisoning is aimed first, at preventing the absorption of fluoride by incorporating it into insoluble fluoride compounds; secondly, at enhancing fluoride tolerance by maintaining normal blood pH and electrolytes, and aggressive general support of the toxic patient; and thirdly, at manipulating renal excretion or removing fluoride with dialysis and haemoperfusion. If the poisoned patient can be supported for 24 hours, the prognosis improves markedly, although delayed toxicity can occur.
Aluminum, present in our drinking water as hydroxide or sulfate, is limited by solubility to 2.5 mg/liter at pH 7.0. This study was carried out to determine if aluminum at doses typically found in drinking water would accumulate in rat tissues if a ligand such as citrate at neutral or acid pH is coadministered, or in the absence of citrate at acid pH. Al(OH)3 or AlCl3 was given ad libitum in drinking water to male Sprague-Dawley rats at 0, 0.1, 2.0, or 100 mg/liter, in 4 mm acetate, pH 3.2 (A), 4 mm citrate, pH 2.6 (C), 4 mm citrate, pH 7.0 (7C), or distilled water, pH 7.0 (W). After 10 weeks, rats were killed and tissues were wet-ashed in nitric acid for determination of aluminum by flameless atomic absorption. Copper, iron, and zinc were determined by flame atomic absorption. Metal ion concentrations in tibia, brain, liver, blood, and kidney did not differ significantly between treatment groups. Aluminum accumulated in intestinal cells of all 100 mg Al/liter rats, with the C group accumulating more aluminum than the A or W groups. In the C group, intestinal aluminum content increased significantly in a dose-dependent manner. Intestinal iron was decreased significantly in all the 100 mg Al/liter groups. Intestinal copper was decreased in the W group at 100 mg Al/liter, with a trend toward a decrease in A and C groups. We conclude that at these low levels studied, aluminum accumulates in intestinal tissue, and that this accumulation is enhanced by citrate ligand. At 100 mg Al/liter, intestinal iron accumulation is decreased, and copper accumulation is marginally decreased.
KURODA, Y. and KAWAHARA, M. Aggregation of Amyloid β-Protein and Its Neurotoxicity: Enhancement by Aluminum and Other Metals. Tohoku J. Exp. Med., 1994, 174 (3), 263-268 - The aggregation of amyloid β-protein has been suggested to enhance its neurotoxicity in cultured hippocampal neurons. We found that aluminum, an epidemiologic risk factor for Alzheimer's disease, promoted the aggregation of synthetic amyloid β-protein (β1-40) using immunoblotting and centrifugation. There were no significant changes by Ca or Mg. Other metals including Zn, Fe caused the small degree of aggregation compared to Al. Furthermore, β1-40 which was aggregated by aluminum was applied on cultured rat hippocampal neurons, and the characteristic deposition of amyloid fibrils was observed on cultured neurons. These results suggested that the degeneration of neurons and the deposition of amyloid β-protein were enhanced by aluminum
We examined the influence of calcium on neurotoxicity of AlCl3 and Al-lactate toward differentiated NB2a/d1 cells. Apart from induction of perikaryal neurofibrillary inclusions, AlCl3 at 1 mM induced no obvious additional signs of toxicity when added to culture medium in the presence of the normal medium CaCl2 content of 1.8 mM, nor when extracellular calcium was decreased by the addition to the medium of 0.9 mM EDTA. Increasing the extracellular CaCl2 concentration by fivefold was only marginally toxic, but in the presence of AlCl3, reduced viable cell numbers by well over 50% as compared to control cultures, and by approximately 50% vs fivefold CaCl2 alone. A twofold increase in extracellular CaCl2 did not increase the percentage of cells exhibiting Bielschowsky-positive perikarya but induced a near doubling in the percentage
of cells exhibiting accumulations in the presence of 1 mM Al-lactate. AlCl3 (1 mM) retards the electrophoretic migration of NF subunits on SDS-gels. This effect was eliminated by withholding CaCl2 from the incubation mixture and including 5 mM EDTA during incubation of cytoskeletons with AlCl3. The presence of CaCl2 alone did not alter NF migration. These findings underscore the possibility that multiple factors, including those that compromise
general neuronal homeostasis, may contribute to neurofibrillary pathology.
We have used circular dichroism spectroscopy to confirm that, in a membrane-mimicking solvent, AβP(1–40) adopts a partially helical conformation and we have demonstrated the loss of this structure in the presence of physiologically relevant concentrations of aluminium. This is the first evidence of a direct biochemical interaction between aluminium and β-amyloid and may have important implications for the pathogenesis of Alzheimer's disease.
Alzheimer's disease is characterized by neurofibrillary tangles and amyloid deposits, with the latter probably occuring because of abnormal accumulation and/or processing of amyloid precursor protein (APP). Aluminumsalts are known to be neurotoxic and to be capable of inducing neurofibrillary tangles. We explored the effects of intraventricular or intrastriatal injections of AlCl3 on the immunodistribution of APP in rat brain. There was a striking and long-lasting accumulation of APP in affected neurites, as well as in activated microglia/macrophages. Abnormal neurites also showed argentophilic changes, neurofilament accumulation, andAlz 50 immunoreactivity. However, no extracellular amyloid fibrils were seen. The results, taken together with previous studies on colchicine, are consistent with the hypothesis that interruption of axoplasmic flow can lead to both APP accumulation and cytoskeletal changes.
The molecular mechanisms of the cytopathology of Alzheimer's disease are very rapidly being elucidated. However, the factors that restrict the effects of this disease to specific neuroanatomical systems are less well understood. In this brief article a possible hypothesis is outlined to explain this apparent specific localization.
Clinical, pathologic, and analytical records from 200 cattle were reviewed to determine if long-term exposures to elevated fluorides resulted in previously unrecognized or unreported pathologic changes, especially skeletal neoplasia. Animals were part of comprehensive field and laboratory investigations of bovine fluorosis conducted by the Utah State University Agricultural Experiment Station over a 25-year period. Records indicated that over 170 cattle included in this review were exposed to dietary fluorides levels in excess of 25 ppm (dry wt), for most of their life span, and these animals exhibited bone fluoride concentrations ranging between 2,000 and 12,500 ppm (dry wt). Although dental and/or skeletal changes were present in most animals, significant soft tissue damage or neoplasia was not observed in any organ system. Renal degeneration and mineralization were slightly more prevalent in range cattle ingesting high fluoride levels, but these changes were not recognized in animals that received high experimental fluoride doses. The absence of significant soft tissue damage or neoplasia in these cattle combined with results of an extensive literature review suggests that environmental fluorides are not significant factors in mammalian carcinogenesis.
Compared with the latter half of the 19th century and the first half of the 20th century, the frequency of fatalities stemming from the ingestion of fluoride compounds has declined dramatically. Since 1978, there have been four fatalities caused by the ingestion of fluoride, all in dental products. The numbers of exposures to fluoride doses that cause concern, however, has increased, as judged by the annual reports of the American Association of Poison Control Centers. The number of reports made to poison control centers has increased from approximately 7700 in 1984 to 10,700 in 1989. Over 3700 persons have been treated in health care facilities for exposure to fluoride during this period, and there have been 133 cases for which the medical outcomes were classified as moderate or major. The sources of fluoride have been limited almost exclusively to fluoride-containing vitamins and dental products. Based on a review of the doses involved in the four fatalities, three of which involved young children, the "probably toxic dose" of fluoride has been set at 5 mg F/kg body weight. For children who are 6 years of age or less, the PTD can be found in single containers of several kinds of dental products. Recommendations that should reduce the frequency of over-exposures to fluoride are described.
Regarding adverse effects due to the chronic intake of fluoride (excluding dental fluorosis), there is no evidence for risk in the US up to the level of intake that is associated with drinking water containing 4 ppm. This statement is based on 1990 or 1991 reports by the NY State Department of Health, the USPHS, and the National Cancer Institute. Two new reports, however, have implicated chronic fluoride intake at relatively low levels in a higher incidence of bone fractures. This relationship requires further study.
Brain uptake of iron-59 and iodine-125-labelled transferrin from blood in the adult rat has been investigated using graphical analysis to determine the blood-brain barrier permeability to these tracers in experiments that lasted between 5 min and 8 days. The blood-brain barrier permeability (K(in)) to 59Fe was 89 x 10(-5) ml/min/g compared to the value of 7 x 10(-5) ml/min/g for 125I-transferrin, which is similar to that of albumin, a plasma marker. The autoradiographic distribution of these tracers in brain was also studied to determine any regional variation in brain uptake after the tracers had been administered either systemically or applied in vitro. No regional uptake was seen for 125I-transferrin even after 24 h of circulation. In contrast, 59Fe showed selective regional uptake by the choroid plexus and extra-blood-brain barrier structures 4 h after administration. After 24 h of circulation, 59Fe distribution in brain was similar to the transferrin receptor distribution, as determined in vitro, but was unlike the distribution of nonhaem iron determined histochemically. The data suggest that brain iron uptake does not involve any significant transcytotic pathway of transferrin-bound iron into brain. It is proposed that the uptake of iron into brain involves the entry of iron-loaded transferrin to the cerebral capillaries, deposition of iron within the endothelial cells, followed by recycling of apotransferrin to the circulation. The deposited iron is then delivered to brain-derived transferrin for extracellular transport within the brain, and subsequently taken up via transferrin receptors on neurones and glia for usage or storage.
The evidence regarding the link between aluminum and Alzheimer's disease is summarized. This evidence suggests strongly that aluminum is one of the etiologic or contributing factors in the occurrence of Alzheimer's disease. One reported study suggests that relatively high fluoride in drinking water plays a preventive role in Alzheimer's disease. The rationale for this is the evidence that aluminum and fluoride compete for absorption in the gut. However, this study had methodologic limitations, and no firm conclusion can be drawn. Further investigation of relatively high fluoride in drinking water as a preventive measure for Alzheimer's disease should receive high priority.
We studied the effects of aluminum salts on the degradation of human neurofilament subunits (NF-H, NF-M, and NF-L, the high, middle, and low molecular weight subunits, respectively) and other cytoskeletal proteins using calcium-activated neutral proteinase (calpain) purified from human brain. Calpain-mediated proteolysis of NF-L, tubulin, and glial fibrillary acidic protein (GFAP), three substrates that displayed constant digestion rates in vitro, was inhibited by AlCl3 (IC50 = 200 microM) and by aluminum lactate (IC50 = 400 microM). Aluminum salts inhibited proteolysis principally by affecting the substrates directly. After exposure to 400 microM aluminum lactate and removal of unbound aluminum, human cytoskeletal proteins were degraded two- to threefold more slowly by calpain. When cytoskeleton preparations were exposed to aluminum salt concentrations of 100 microM or higher, proportions of NF-M and NF-H formed urea-insoluble complexes of high apparent molecular mass, which were also resistant to proteolysis by calpain. Complexes of tubulin and of GFAP were not observed under the same conditions. Aluminum salts irreversibly inactivated calpain but only at high aluminum concentrations (IC50 = 1.2 and 2.1 mM for aluminum lactate and AlCl3, respectively), although longer exposure to the ion reduced by twofold the levels required for protease inhibition. These interactions of aluminum with neurofilament proteins and the effects on proteolysis suggest possible mechanisms for the impaired axoplasmic transport of neurofilaments and their accumulation in neuronal perikarya after aluminum administration in vivo.
The purpose of this study was to design a method by which immunoperoxidase staining can be applied to formalin-fixed, paraffin-embedded tissue sections to demonstrate amyloid deposits in cerebral and systemic amyloidotic tissues. We used anti-prion protein, anti-beta-protein, anti-amyloid A, and anti-prealbumin antisera. The tissue sections were first treated with 100% formic acid for 5, 20, or 60 minutes and the unlabeled immunoperoxidase method (biotin-streptavidin system reagents) was used. This formic acid pretreatment enhanced immunoreactivity of the amyloid deposits which reacted positively with specific antiserum. The specificity of the immunostainings was well preserved. This method can also be used to demonstrate interspecies cross-reactivity, by using anti-human amyloid A and anti-scrapie hamster prion protein antisera, which stained negatively or faintly with amyloid deposits of heterogenous species. The technique is expected to reveal the buried epitopes of amyloid deposits in tissue sections.
Aluminum, present in our drinking water as hydroxide or sulfate, is limited by solubility to 2.5 mg/liter at pH 7.0. This study was carried out to determine if aluminum at doses typically found in drinking water would accumulate in rat tissues if a ligand such as citrate at neutral or acid pH is coadministered, or in the absence of citrate at acid pH. Al(OH)3 or AlCl3 was given ad libitum in drinking water to male Sprague-Dawley rats at 0, 0.1, 2.0, or 100 mg/liter, in 4 mM acetate, pH 3.2 (A), 4 mM citrate, pH 2.6 (C), 4 mM citrate, pH 7.0 (7C), or distilled water, pH 7.0 (W). After 10 weeks, rats were killed and tissues were wet-ashed in nitric acid for determination of aluminum by flameless atomic absorption. Copper, iron, and zinc were determined by flame atomic absorption. Metal ion concentrations in tibia, brain, liver, blood, and kidney did not differ significantly between treatment groups. Aluminum accumulated in intestinal cells of all 100 mg Al/liter rats, with the C group accumulating more aluminum than the A or W groups. In the C group, intestinal aluminum content increased significantly in a dose-dependent manner. Intestinal iron was decreased significantly in all the 100 mg Al/liter groups. Intestinal copper was decreased in the W group at 100 mg Al/liter, with a trend toward a decrease in A and C groups. We conclude that at these low levels studied, aluminum accumulates in intestinal tissue, and that this accumulation is enhanced by citrate ligand. At 100 mg Al/liter, intestinal iron accumulation is decreased, and copper accumulation is marginally decreased.
Oral administration of 0.3% aluminum (citrate or sulfate salt) for 4 weeks significantly elevated adenosine 3',5'-monophosphate (cyclic AMP) levels in rat cortex, hippocampus, striatum and cerebellum. The largest effect observed was a 60% increase in cortical cyclic AMP levels in rats administered aluminum sulfate. The effects of orally administered aluminum on guanosine 3',5'-monophosphate (cyclic GMP) levels were less widespread. Dietary aluminum citrate only elevated cyclic GMP levels in the hippocampus, while aluminum sulfate caused significant increases in the cerebellum, hippocampus and striatum. Aluminum citrate administered i.c.v. (1 mumol, 2 weeks postadministration) elevated cyclic AMP levels in the cortex, but had no effect on cyclic GMP levels. Aluminum administered either orally or i.c.v. had no effect on in vivo acetylcholine levels. However, dietary aluminum citrate significantly reduced choline levels in the cortex, hippocampus and striatum. Aluminum administered i.c.v. had no effect on choline acetyltransferase activity or on high-affinity choline transport. These results indicate that: the metabolism of cyclic AMP and of cyclic GMP are more sensitive to aluminum than are presynaptic cholinergic processes; the metabolism of cyclic AMP is more sensitive to the effects of aluminum than is the metabolism of cyclic GMP; and cortical cAMP metabolism is the most sensitive to the presence of aluminum. Possible consequences of elevated levels of cyclic nucleotides induced by aluminum in the brain are proposed.
The effect of aluminum administered intraperitoneally (i.p.) on the levels of peripherally injected 99mTc labelled red blood cells in brain and on the penetration of the blood-brain barrier by radioiodinated serum albumin (RISA), thyroxine, iodide, cortisol, N-Tyr-delta sleep-inducing peptide (N-Tyr-DSIP), growth hormone, thyroid stimulating hormone (TSH), prolactin and human and rat luteinizing hormone was examined. Treatment with aluminum did not alter the brain/blood ratio for either 99mTc red blood cells or RISA, although it did increase the blood levels of RISA. These results show that aluminum caused a contraction in the volume of plasma without altering the vascular space of the brain, disrupting the blood-brain barrier, or increasing the "leakiness" of the blood-brain barrier. Aluminum enhanced the permeability of the blood-brain barrier to labelled prolactin, thyroxine, cortisol, growth hormone, N-Tyr-DSIP and rat luteinizing hormone, but not to labelled TSH, iodide, or human luteinizing hormone, a substance with an octanol coefficient markedly different from that of luteinizing hormone from the rat. Incubation of the peptide with aluminum before injection did not increase penetration, demonstrating that aluminum did not increase the permeability of the blood-brain barrier by acting directly on the peptide. Aluminum, administered intraperitoneally, increased the accuracy of lipophilicity as a predictor of penetration of the blood-brain barrier, but the greatest increase in penetration was seen with thyroxine, a substance which crosses the blood-brain barrier by carrier-mediated transport.(ABSTRACT TRUNCATED AT 250 WORDS)
Although aluminum is neurotoxic, the mechanisms and sites of action are unknown. Using the histochemical stains, morin and Solochrome Azurine, intracellular binding of aluminum was examined in brain tissues of animals with an aluminum induced encephalopathy, in human lymphocytes and in cells of plant meristems. Accumulation of aluminum occurred on chromatin of interphase nuclei and on chromosomes of mitotic cells. These findings suggest that neurofibrillary degeneration following the intracerebral injection of aluminum salts in experimental animals may be the results of interactions between aluminum and chromatin.
In the early stages of an aluminum induced dementia model a positive correlation exists between the occurrence of neurofibrillary degeneration (NFD) in hippocampus, entorhinal and neocortex and the rate of conditioned avoidance response acquisition. Quantitative measurements from appropriate electronmicrographs indicate that the density of microtubules in a region of NFD is profoundly reduced. At the stage in the encephalopathy in which short-term retention and acquisition are impaired the EEG and averaged visual evoked potentials were normal. The observations suggest that a nonelectrical activity of neurons, important to the learning-memory mechanism, may be altered by the effects of aluminum chloride. The disorganization of the dendritic microtubular system is postulated to alter dendroplasmic flow and supports the hypothesis that the translocation of synaptically active agents by the cytoplasmic streaming mechanism may subserve a component of the associative learning mechanism.
Three kinds of cerebral vascular deformities, i.e. glomerular-loop formations, vascular bundles and wickerworks, were described preliminarely in a previous study. In the present work, their occurrence has been studied in a large file of autopsies (231 cases). The changes were rarely observed in subjects under the age of 60, but were very common after the age of 70. They were almost equally distributed in the two sexes. They were not particularly correlated to high heart weight, high degree of cerebral arteriosclerosis or to low brain weight. Vascular wickerworks were much commoner in subjects with vascular bundles than in those without. The glomerular loops occurred as a rule together with marked spiralling and may be looked upon as products of excessive spiralling. The influence of the vascular deformities upon the cerebral circulation has been calculated partly on the basis of model experiments and partly by using Poiseuille's law. Each glomerular loop may reduce the blood flow in the artery in question by about 60%. The vascular bundles and wickerworks probably reduce the flow to about 10% of the capacity of a single vessel of the same diameter. Because the deformities only affect about one-tenth of the arteries, they probably do not influence the total cerebral blood flow more than the generalized spiralling, which affects almost all arteries in cases with glomerular loops, and probably reduces the total flow by about 10%.
The pathogenesis of the neuropsychiatric manifestations of systemic lupus erythematosus (SLE) remains an enigma. The observation that many of the lymphocytotoxic antibodies in SLE are also brain-reactive has led to the hypothesis that central nervous system (CNS) lupus, like the autoimmune hematologic manifestations of SLE, is due to the direct effects of autoantibodies to cell membrane antigens. Studies of neuron-reactive antibodies in SLE sera and cerebrospinal fluid support that hypothesis and suggest that the diffuse neuropsychiatric manifestations require the co-existence of serum antibodies to nerve cells and an alteration in the blood-brain barrier that allows those antibodies to enter the CNS.
Activation of the purified guanine nucleotide-binding regulatory component (G/F) of adenylate cyclase by F- requires the presence of Mg2+ and another factor. This factor, which contaminates commercial preparations of various nucleotides and disposable glass test tubes, has been identified as Al3+. In the presence of 10 mM Mg2+ and 5 mM F-, AlCl3 causes activation of G/F with an apparent activation constant of approximately 1-5 muM. The requirement for Al3+ is highly specific; of 28 other metals tested, only Be2+ promoted activation of G/F by F-.
The progressive deposition of the beta-amyloid peptide in the brain and its microvasculature is an invariant feature of Alzheimer's disease that appears to precede the onset of dementia by many years. It had been assumed that the proteolytic release of beta-amyloid peptide from the transmembrane region of its large precursor protein was an aberrant event, requiring prior membrane injury. However, it has recently been shown that beta-amyloid peptide is continuously secreted from healthy neural and non-neural cells in culture and circulates in human CSF and blood. The finding that beta-amyloid peptide is a normal, soluble product of cellular metabolism has led to many dynamic studies of its formation and clearance in health and in genetic forms of Alzheimer's disease, and should facilitate the design of amyloid-inhibiting therapeutics.
Amyloid beta-protein is the major component of senile plaques in the brains of Alzheimer's disease and has an intrinsic tendency to form insoluble aggregates. The aggregation of amyloid beta-protein has been suggested to enhance its neurotoxicity and to play a key role in the amyloid deposition. Here we show, using gel-electrophoresis and immunoblotting, that the aggregation of synthetic amyloid beta-protein (beta 1-40) is promoted by aluminum, a suspected risk factor in Alzheimer's disease. High molecular weight aggregates were observed, and the amount of precipitated protein was estimated using high performance liquid chromatography. The results suggest the possibility that aluminum directly influences the process of aggregation and the deposition of senile plaques.
The purpose of this article is to review evidence that inflammatory and immune mechanisms are important in the pathophysiology of Alzheimer's disease and to suggest new treatment strategies.
The authors review the English-language literature of the last 10 years pertaining to the pathophysiology of Alzheimer's disease.
There is ample evidence supporting the hypothesis that inflammatory and immune mechanisms are involved in tissue destruction in Alzheimer's disease. Acute phase proteins are elevated in the serum and are deposited in amyloid plaques, activated microglial cells that stain for inflammatory cytokines accumulate around senile plaques, and complement components including the membrane attack complex are present around dystrophic neurites and neurofibrillary tangles.
Clinical trials of anti-inflammatory/immunosuppressive drugs are necessary to determine whether alteration of these inflammatory mechanisms can slow the progression of Alzheimer's disease.
1. Aluminum is neurotoxic in humans and animals and alters formation of inositol phosphate (IP) second messengers following in vivo or in vitro exposure. 2. Several components of the IP signalling system including G-proteins, phosphatidylinositol-specific phospholipase C (PI-PLC), protein kinase C (PKC) and Ca2+ homeostasis are susceptible to inhibition/disruption by aluminum compounds. 3. Recent evidence suggests that, despite its effects on other components, competitive inhibition by aluminum of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis by PI-PLC underlies its effects on agonist-stimulated IP generation.
Several lines of evidence suggest that neurotoxic beta A4 amyloid deposits are of prime importance in the pathogenesis of Alzheimer's disease. Epidemiologically determined risk factors such as Down's syndrome, head injury and apoE allelic status can be explained on the basis of this hypothesis. However, there are difficulties with the hypothesis--amyloid accumulation may be necessary, but is not sufficient to produce the neuronal damage seen in Alzheimer's disease. The association between aluminum exposure and Alzheimer's disease remains unproven and is considered to be increasingly peripheral to recent developments in our understanding of the disease.
Recent evidence indicates that the neurotoxic metal aluminum interferes with the phosphoinositide second messenger system in adult rats both in vitro and in vivo. We have examined the age-related effects of aluminum chloride (AlCl3) on receptor-stimulated inositol phosphate (IP) accumulation in brain slices from neonatal and adult rats in vitro. Carbachol-stimulated (1 mM) IP accumulation was greatest in frontal cortex slices from 7 day old rats, decreased in 14 day old and 21 day old rats, and was lowest in adults (120 days old). AlCl3 (500 microM) inhibited both basal and carbachol-stimulated IP accumulation in neonatal and adult rats. The effects of AlCl3 were concentration-related and produced significant decreases (15-25%) in IP accumulation at 500 and 1000 microM. The concentration-response curve for AlCl3 was similar in 7 day old and adult rats. AlCl3 reduced carbachol-, norepinephrine- and quisqualate-stimulated IP accumulation in both 7 day old and adult rats. The effects of 500 microM AlCl3 were examined on carbachol-stimulated IP accumulation in slices prepared from frontal cortex, hippocampus, striatum, and cerebellum. Although IP accumulation was greater in slices from the 7 day old rats compared to adults in each tissue, AlCl3 (500 microM) decreased IP accumulation by approximately 20% in all regions at both ages. Aluminum produced concentration-dependent inhibition of phospholipase C in cortical homogenates which was similar in 7 day old and adult rats. These results show that in vitro exposure to aluminum decreases IP accumulation through a mechanism which is not age-dependent.
Neurofilaments accumulated in perikarya and dendrites of anterior horn cells and Purkinje cells of rabbit treated by aluminum chloride were analysed with a variety of techniques. Four different monoclonal antibodies against phosphorylated and nonphosphorylated epitopes on neurofilament H subunit were used to compare phosphorylation state of these accumulated neurofilaments with that of axonal neurofilaments. Although immunoblotting revealed no significant difference in phosphorylation between control and aluminum-treated brains, accumulated neurofilaments were immunocytochemically more phosphorylated than control perikaryal or dendritic neurofilaments. With detailed analysis of cryothin-section immunogold labeling, accumulated neurofilaments were, however, significantly less phosphorylated than axonal neurofilaments. With quick-freeze deep etching, core filaments of accumulated neurofilaments are as dense as axonal neurofilaments but much less regularly aligned. Cross-bridges of accumulated neurofilaments were less frequent and more branched than those of axonal neurofilaments, and when examined with combined immunocytochemistry and deep etching, were less phosphorylated. These results suggest that there is a relationship between the phosphorylation and the structural organization of neurofilaments. The phosphorylation of neurofilament H subunit may be necessary for formation of frequent and straight cross-bridges and resulting regular alignment of core filaments.
The effect of various metal ions on aggregation of human recombinant amyloid precursor protein (APP) in vitro was investigated based on characterizations of altered migration on SDS-PAGE or immunoblots. Most biological metal ions tested had no significant effect on aggregation of APP. In contrast, AlCl3 in particular promoted aggregation of APP or APP-CT105 in a dose dependent manner. This effect of AlCl3 on APP mobility shift was prevented or reversed by the metal chelator, EDTA. Amorphous aggregates were observed in AlCl3 treated APP when examined by EM. These results suggest that aluminum may play a role in the pathogenesis of AD by directly promoting aggregation of APP.
We have developed an in situ mammalian model for evaluating environmental contamination using wild cotton rats. In a series of experiments, 200 male cotton rats were captured during 4 collection periods (spring 1991 = 35; fall 1991 = 60; spring 1992 = 53; fall 1992 = 52). A total of 103 of these cotton rats were captured from control sites, and the remaining 97 were captured from an abandoned oil refinery. All sites were located in the vicinity of Cyril, Oklahoma. There were alterations in the incisors of cotton rats captured from the refinery site. Normal color of cotton rat incisors is deep yellow-orange, which is imparted by a pigment normally produced by ameloblasts. Grossly, the upper incisors of 37 of 97 rats and lower incisors of 54 of 97 rats were affected. The affected incisors were white, chalky, and thin with striations and erosions of the enamel. Microscopic examination revealed that there were dysplastic and necrotic changes in the ameloblasts. The bone fluoride levels were significantly higher in rats captured from the refinery as compared to the rats captured from the control sites.
We inoculated 5- to 6-week old New Zealand white rabbits intracisternally with either 100, 250, 500, 750, or 1000 micrograms of AlCl3 or 0.9% NaCl and correlated the extent of cervical motor neuron neurofilamentous inclusion formation at 48 h postinoculation with alterations in neurofilament (NF) mRNA levels. RNA was isolated from cervical spinal cord by the guanidine isothiocyanate method and individual RNA samples were normalized for poly(A+) content. Northern blot analysis was performed with cDNA probes for light (NFL), medium (NFM), and heavy (NFH) neurofilament subunit protein or with oligonucleotide probes for alpha-tubulin or actin. No significant alteration in the levels of alpha-tubulin, actin, or NFH mRNA were observed, regardless of the aluminum dose. In contrast, dose-dependent reductions in NFL and NFM mRNA levels occurred in direct proportion to the extent of neurofilamentous inclusion formation. While inoculums of NaCl or 100 or 250 micrograms AlCl3 induced neither inclusion formation or alterations in mRNA levels, both inclusion formation and reductions in the levels of NFL and NFM mRNA occurred thereafter, becoming maximal with inoculums of 1000 micrograms AlCl3. These experiments indicate that intracisternally administered AlCl3 acutely suppresses NFL and NFM mRNA levels without affecting those of NFH. This pattern is in distinct contrast to the uniform reductions of all NF mRNA transcript levels during neurogenesis or following axotomy, indicating a specific effect of aluminum upon steady-state levels of NF mRNA that correlates with the induction of neurofilamentous aggregates.
Acute or chronic aluminum neurotoxicity experiments in the rabbit suggest that aluminum can induce phosphorylation of neurofilamentous proteins. This may result in abnormal resistance to degradation or transport of neurofilament protein and so to the accumulation of neurofilaments in abnormal cells. The possible importance of this process in ALS is considered in relation to the neurofilamentous abnormalities characteristic of intraneuronal inclusions in ALS and in other neurodegenerative disorders.