Article

Retrograde degeneration of neurite membrane structural integrity of nerve growth cones following in vitro exposure to mercury

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Abstract

Inhalation of mercury vapor (Hg0) inhibits binding of GTP to rat brain tubulin, thereby inhibiting tubulin polymerization into microtubules. A similar molecular lesion has also been observed in 80% of brains from patients with Alzheimer disease (AD) compared to age-matched controls. However the precise site and mode of action of Hg ions remain illusive. Therefore, the present study examined whether Hg ions could affect membrane dynamics of neurite growth cone morphology and behavior. Since tubulin is a highly conserved cytoskeletal protein in both vertebrates and invertebrates, we hypothesized that growth cones from animal species could be highly susceptible to Hg ions. To test this possibility, the identified, large Pedal A (PeA) neurons from the central ring ganglia of the snail Lymnoea stagnalis were cultured for 48 h in 2 ml brain conditioned medium (CM). Following neurite outgrowth, metal chloride solution (2 microl) of Hg, Al, Pb, Cd, or Mn (10(-7) M) was pressure applied directly onto individual growth cones. Time-lapse images with inverted microscopy were acquired prior to, during, and after the metal ion exposure. We demonstrate that Hg ions markedly disrupted membrane structure and linear growth rates of imaged neurites in 77% of all nerve growth cones. When growth cones were stained with antibodies specific for both tubulin and actin, it was the tubulin/microtubule structure that disintegrated following Hg exposure. Moreover, some denuded neurites were also observed to form neurofibrillary aggregates. In contrast, growth cone exposure to other metal ions did not effect growth cone morphology, nor was their motility rate compromised. To determine the growth suppressive effects of Hg ions on neuronal sprouting, cells were cultured either in the presence or absence of Hg ions. We found that in the presence of Hg ions, neuronal somata failed to sprout, whereas other metalic ions did not effect growth patterns of cultured PeA cells. We conclude that this visual evidence and previous biochemical data strongly implicate Hg as a potential etiological factor in neurodegeneration.

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... At the top of the known neurotoxins, mercury in various forms is perhaps the most studied of the toxins linked to disorders of the brain and body, especially during prenatal and early postnatal development [3,[13][14][15][16][17]. However, with no danger of being contradicted we can assert categorically that governmental guidelines from different agencies concerning "safe" exposures are dramatically inconsistent with each other as well as with studies showing that, once inside the body very tiny doses, amounts measured in parts per billion, many times smaller than those recommended as safe in any published government estimates, have been shown to be harmful especially during early development [3,5,[18][19][20]. ...
... The American Dental Association reports that mercury fillings have been placed in "the teeth of more than 100 million Americans" and continues to claim on its official website in 2016 that mercury containing dental "amalgam is a valuable, viable and safe choice" [136]. Given that it has long been known that dental amalgam is the main source of body mercury [16,128], it should be unsurprising that one in six babies at birth in the U.S. already have a sufficient body burden of mercury to cause neurological impairment [108,109]. In 1989, Snapp showed that the blood mercury level could be reduced by 50% in just 2 months by removing all mercury/silver amalgam tooth fillings from teeth, even though in this study all participants (n <10) initially experienced a transient increase in blood mercury following removal [137]. ...
... It is not widely known by the general public that mercury vapor exposure from dental amalgam has been demonstrated to exceed the sum of all other exposure sources for human mercury body burden [16,128]. Less well known is research showing that metallic mercury can be transferred from a mother to her fetus via the placenta and supplied to the newborn via mercury accumulation in breast milk [129,130,133]. ...
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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.
... At the top of the known neurotoxins, mercury in various forms is perhaps the most studied of the toxins linked to disorders of the brain and body, especially during prenatal and early postnatal development [3,[13][14][15][16][17]. However, with no danger of being contradicted we can assert categorically that governmental guidelines from different agencies concerning "safe" exposures are dramatically inconsistent with each other as well as with studies showing that, once inside the body very tiny doses, amounts measured in parts per billion, many times smaller than those recommended as safe in any published government estimates, have been shown to be harmful especially during early development [3,5,[18][19][20]. ...
... The American Dental Association reports that mercury fillings have been placed in "the teeth of more than 100 million Americans" and continues to claim on its official website in 2016 that mercury containing dental "amalgam is a valuable, viable and safe choice" [136]. Given that it has long been known that dental amalgam is the main source of body mercury [16,128], it should be unsurprising that one in six babies at birth in the U.S. already have a sufficient body burden of mercury to cause neurological impairment [108,109]. In 1989, Snapp showed that the blood mercury level could be reduced by 50% in just 2 months by removing all mercury/silver amalgam tooth fillings from teeth, even though in this study all participants (n <10) initially experienced a transient increase in blood mercury following removal [137]. ...
... It is not widely known by the general public that mercury vapor exposure from dental amalgam has been demonstrated to exceed the sum of all other exposure sources for human mercury body burden [16,128]. Less well known is research showing that metallic mercury can be transferred from a mother to her fetus via the placenta and supplied to the newborn via mercury accumulation in breast milk [129,130,133]. ...
Article
Full-text available
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
... At the top of the known neurotoxins, mercury in various forms is perhaps the most studied of the toxins linked to disorders of the brain and body, especially during prenatal and early postnatal development [3,[13][14][15][16][17]. However, with no danger of being contradicted we can assert categorically that governmental guidelines from different agencies concerning "safe" exposures are dramatically inconsistent with each other as well as with studies showing that, once inside the body very tiny doses, amounts measured in parts per billion, many times smaller than those recommended as safe in any published government estimates, have been shown to be harmful especially during early development [3,5,[18][19][20]. ...
... The American Dental Association reports that mercury fillings have been placed in "the teeth of more than 100 million Americans" and continues to claim on its official website in 2016 that mercury containing dental "amalgam is a valuable, viable and safe choice" [136]. Given that it has long been known that dental amalgam is the main source of body mercury [16,128], it should be unsurprising that one in six babies at birth in the U.S. already have a sufficient body burden of mercury to cause neurological impairment [108,109]. In 1989, Snapp showed that the blood mercury level could be reduced by 50% in just 2 months by removing all mercury/silver amalgam tooth fillings from teeth, even though in this study all participants (n <10) initially experienced a transient increase in blood mercury following removal [137]. ...
... It is not widely known by the general public that mercury vapor exposure from dental amalgam has been demonstrated to exceed the sum of all other exposure sources for human mercury body burden [16,128]. Less well known is research showing that metallic mercury can be transferred from a mother to her fetus via the placenta and supplied to the newborn via mercury accumulation in breast milk [129,130,133]. ...
Article
Full-text available
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.
... The total inhibition of Aβ fibrillization at 1:1 Hg(II)/Aβ 40 ratio (Figures 1 and 2) shows that small amounts of mercury in a critical location can have a large impact on Aβ aggregation. As Hg poisoning correlates with a variety of adverse effects on developing neurites [153], neurotransmission [154], and cognitive function [97,155], the amount of Hg that enters the brain after exposure events clearly has biological impact [10,88,90,94]. While Hg(II) ions do not easily pass the blood-brain barrier (BBB), metallic vapor mercury does [100]. ...
... Mercury could conceivably affect AD pathology without directly interacting with the Aβ peptides themselves [90,94], for example, via toxic molecular mimicry [157], by promoting the aggregation of the tau fragment R2 [101] and phosphorylation of the tau protein as observed in SHSY5Y neuroblastoma cells [87], or via interactions between other forms of Aβ and Hg than those studied here. MeHg and Hg(II) ions bind to and affect the functions of important intracellular biomolecules with essential thiol (−SH) and selenohydryl (−SeH) groups, such as cysteine, homocysteine, metallothioneins, selenoproteins, glutathione (GSH), tubulin, ion channel proteins, transporters, metabolic enzymes, and N-methyl-D-aspartate (NMDA) receptors, thereby influencing or even damaging various tissues including nerve cells [94,97,153,157,158]. Hg exposure furthermore increased the release of Aβ in SHSY5Y neuroblastoma cells [87], which may promote Aβ aggregation. ...
Article
Full-text available
Brains and blood of Alzheimer’s disease (AD) patients have shown elevated mercury concentrations, but potential involvement of mercury exposure in AD pathogenesis has not been studied at the molecular level. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils. Aβ peptide fibrillization is known to be modulated by metal ions such as Cu(II) and Zn(II). Here, we study in vitro the interactions between Aβ peptides and Hg(II) ions by multiple biophysical techniques. Fluorescence spectroscopy and atomic force microscopy (AFM) show that Hg(II) ions have a concentration-dependent inhibiting effect on Aβ fibrillization: at a 1:1 Aβ·Hg(II) ratio only non-fibrillar Aβ aggregates are formed. NMR spectroscopy shows that Hg(II) ions interact with the N-terminal region of Aβ(1–40) with a micromolar affinity, likely via a binding mode similar to that for Cu(II) and Zn(II) ions, i.e., mainly via the histidine residues His6, His13, and His14. Thus, together with Cu(II), Fe(II), Mn(II), Pb(IV), and Zn(II) ions, Hg(II) belongs to a family of metal ions that display residue-specific binding interactions with Aβ peptides and modulate their aggregation processes.
... In vitro studies involving exposure to CH 3 Hg + have revealed dysfunction in the biochemical processes that trigger Alzheimer's disease and axonal degeneration [45,46]. This may be due to the fact that CH 3 Hg + has the highest body distribution in humans, when compared with other Hg derivatives. ...
... This may be due to the fact that CH 3 Hg + has the highest body distribution in humans, when compared with other Hg derivatives. In humans, CH 3 Hg + intoxication leads to reduction of visual field, bronchitis, pneumonitis, tremors, salivation and intense gingivitis [45]. It has also been shown that high intake of Hg through non-fat products is associated with an increased risk of heart failure, arrhythmias, myocardial infarction, coronary heart disease and cardiovascular disease [47]. ...
... It has been demonstrated that Hg exposure in subtoxic concentration (100 nM) induces glial fibers formation, although the effect was more expressed in aluminum (Al)-treated cells (Toimela and Tähti 2004). Exposure to Hg was also shown to precipitate disintegrations in both tubulin and microtubule structures and increase the formation of neurofibrillary aggregates in pedal A neurons coming from the central ring ganglia of the snail (Lymnaea stagnalis) (Leong et al. 2001). ...
... At an age above 35 years, the risk for the onset of AD in DS is increased by a factor of 3 to 5 compared to the general population (Hartley et al. 2015;Wiseman et al. 2015). Also, research on neurons has demonstrated that among manganese (Mn), cadmium (Cd), aluminum (Al), iron (Fe), lead (Pb), and mercury (Hg), only Hg at low concentrations induced the hallmark of abnormal tubulin aggregation seen in Alzheimer's disease (Leong et al. 2001). The association between APOE genotypes and the risk of dementia in DS are still to be fully explored. ...
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Mercury (Hg), which is a non-essential element, is considered a highly toxic pollutant for biological systems even when present at trace levels. Elevated Hg exposure with the growing release of atmospheric pollutant Hg and rising accumulations of mono-methylmercury (highly neurotoxic) in seafood products have increased its toxic potential for humans. This review aims to highlight the potential relationship between Hg exposure and Alzheimer's disease (AD), based on the existing literature in the field. Recent reports have hypothesized that Hg exposure could increase the potential risk of developing AD. Also, AD is known as a complex neurological disorder with increased amounts of both extracellular neuritic plaques and intracellular neurofibrillary tangles, which may also be related to lifestyle and genetic variables. Research reports on AD and relationships between Hg and AD indicate that neurotransmitters such as serotonin, acetylcholine, dopamine, norepinephrine, and glutamate are dysregulated in patients with AD. Many researchers have suggested that AD patients should be evaluated for Hg exposure and toxicity. Some authors suggest further exploration of the Hg concentrations in AD patients. Dysfunctional signaling pathways in AD and Hg exposure appear to be interlinked with some driving factors such as arachidonic acid, homocysteine, dehydroepiandrosterone (DHEA) sulfate, hydrogen peroxide, glucosamine glycans, glutathione, acetyl-L carnitine, melatonin, and HDL. This evidence suggests the need for a better understanding of the relationship between AD and Hg exposure, and potential mechanisms underlying the effects of Hg exposure on regional brain functions. Also, further studies evaluating brain functions are needed to explore the long-term effects of subclinical and untreated Hg toxicity on the brain function of AD patients.
... Whether the mercury to which he was exposed was the primary cause of the series of strokes that eventually killed him cannot be known, but the toxin to which he was exposed is known to cause brain and nerve damage leading to stress, an irregular heartbeat, circulatory disease, and strokes (Houston, 2011). Mercury poisoning damages all the body's organs and especially the nerves (see the video titled "How Mercury Destroys the Brain" and the experiment published in Neuroreport by Leong, Syed, and Lorscheider, 2001). In particular, mercury poisoning interferes directly with one of the main proteins of the myelin that is so critical to the proper functioning of nerves. ...
... The cytoskeleton consists mainly of microtubules of about 25 nm in diameter made of tubulin molecules and microfilaments of about 7 nm in diameter made of actin. It is important to keep in mind that the tubulin structures are also built of the same type of proteins used in the insulation of the tiniest of neural fibrils in our bodies (Leong et al., 2001). ...
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An introduction to human anatomy and physiology with a view toward the special interests of speech-language pathologists and audiologists in the highest level of human intelligence as expressed in our uses of language. This book offers up-to-date theory and research on human biosignaling systems and their involvement in all that is distinctive about the human language capacity and our abilities to communicate with each other. Available at http://www.sentiapublishing.com/health-sciences/human-anatomy-and-physiology-for-speech-language-pathologists-and-audiologists-2nd-edition-oller-online-textbook/
... Hg causes neuronal axons to degenerate because Hg disrupts the structure of the axon, causing it to break apart and depolymerize [35][36][37][38]. As a consequence, the axons degenerate. ...
... Furthermore, the effect that Hg has on microtubules and the subsequent axonal degeneration is unique to very low-concentrations of Hg. Other toxic metals at very low concentrations, e.g., Pb, manganese (Mn), cadmium (Cd), and aluminum (Al), do not show this effect [38]. ...
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(1) Background: Hyperkinetic syndrome of childhood (HKSoC) is an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) category in which the majority of the children are also diagnosed under the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR), where the umbrella term is “Attention-Deficit and Disruptive Behavior Disorders”. The diagnostic criteria for HKSoC are developmentally inappropriate inattention, hyperactivity, and impulsivity. Some studies have implicated mercury (Hg) exposure as a risk factor. (2) Methods: This hypothesis testing study; using the Vaccine Safety Datalink; assessed the toxicological effects of bolus exposure to organic-Hg from Thimerosal-containing vaccines (TCVs) by examining the relationship between Thimerosal-preserved hepatitis B vaccines (TM-HepB) given at varying levels and at specific intervals in the first six months after birth and the risk of a child being diagnosed with HKSoC. (3) Results: Children diagnosed with HKSoC were significantly more likely to be exposed to increased organic-Hg from TM-HepB doses given within the first month (odds ratio = 1.45; 95% confidence interval (CI) = 1.30–1.62); within the first two months (odds ratio = 1.43; 95% CI = 1.28–1.59); and within the first six months (odds ratio = 4.51; 95% CI = 3.04–6.71) than controls. (4) Conclusion: The results indicate that increasing organic-Hg exposure from TCVs heightens the risk of a HKSoC diagnosis.
... Mercury is a pro-oxidant that causes oxidative stress, thus diminishing the brain's antioxidant activity, increasing AβPP expression, and inducing glial cell reactivity [42]. Inorganic mercury, as well as having a direct neurotoxic effect on axons [44], also induces the hyperphosphorylation of Tau protein [45] as well as the production of insoluble Betaamyloid 40 and 42 [46]. In addition, it could also disrupt glutamatergic metabolism [47]. ...
... Findings from animal and experimental studies suggest that mercury is a causative factor in a number of NDD, in particular multiple sclerosis (MS) [49][50][51] and AD [44,45,[52][53][54]. There is still, however, some debate on this matter because of the absence of sufficient post-mortem and epidemiological evidence [41,[55][56][57][58]. ...
... Early-life MeHg poisoning may interfere in neurodevelopment, as both prenatal and postnatal MeHg biomarkers have been revealed to be associated with lower cognitive performance among children [70,71]. Notably, several studies with indigenous Amazonian children also support an association between hair MeHg levels and reduced scores in cognitive and neurodevelopmental scales [16,[73][74][75][76]. Furthermore, MeHg has been implied to lead to neurodegeneration, as it may induce hallmark neuropathological changes seen in Alzheimer's disease [77,78]. In fact, a prospective cohort with 2136 subjects demonstrated that baseline serum mercury levels were associated with the incidence of mild cognitive impairment, after correcting for fish oil intake (OR 2.56; 95%CI 1.003-6.5) ...
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Widespread contamination of the Amazon basin with mercury has been reported to occur since at least the mid-80s due to heavy gold mining activity. Although initial studies have indicated that this may lead to deleterious neurological consequences to the indigenous populations living in the region, further research is needed to better characterize the neurological burden of such long-term exposure. With this aim, a cross-sectional exploratory study has been conducted with the Yanomami indigenous population residing in a northern Amazon region. All participants underwent a structured interview; detailed neurological examination, including assessment for cognitive, motor, coordination, and sensory functions; and laboratorial testing for serum hemoglobin, blood glucose, and methylmercury levels in hair samples. This study enrolled 154 individuals of 30.9 ± 16.8 years of age, of which 56.1% were female. Mean methylmercury levels in hair were 3.9 ± 1.7 µg/g. Methylmercury levels in hair > 6.0 µg/g were found in 10.3%. Among participants with hair methylmercury levels ≥ 6.0 μg/g, the prevalences of peripheral neuropathy and reduced cognitive performance were, respectively, 78.8% (95%CI 15–177%, p = 0.010) and 95.9% (95%CI 16–230.8%, p = 0.012) higher than those of individuals with lower levels. These results suggest that chronic mercury exposure may lead to significant and potentially irreversible neurotoxicity to Yanomami population living in the northern Amazon basin.
... Moreover, based on Issa and colleagues' study, mercury has toxic effects on oligodendroglia cells, which are affected in MS disease (28). In addition, mercury contributes to the cytoskeleton structure development destruction process in nerve cells (18,29). Neurons, especially sensitive ones, can be damaged by methylmercury (22,30). ...
Article
Multiple sclerosis (MS) is an acquired inflammatory and neurodegenerative immuno-mediated disorder of the central nervous system (CNS) characterized by inflammation, demyelination, and primary or secondary axonal degeneration. Epidemiological studies have suggested that both genetic and non-genetic risk factors are involved in the etiology of MS. Non-genetic factors include infections, vaccinations, nutritional habits, hormonal factors, and physical and chemical agents. Toxic environmental factors have been proposed to play a considerable role in MS pathogenesis. This review explored pieces of evidence and potential mechanisms of action for some toxic factors such as heavy metals, organic solvents (OSs), tobacco smoking, plastic monomers, additives, and pesticides. The obtained findings provide us with the potential for prevention, especially for people at greater risk such as individuals exposed to these toxic factors. It should be noted that further investigations are needed to find precise mechanisms of causality in humans and to develop defensive approaches.
... 1,2 Mercury vapor and organic Hg readily pass through membranes such as the blood−brain− barrier and the placental barrier, and thus become distributed throughout the entire human body including the fetus. 7−9 Developing neurites 10 and growing organs seem to be particularly susceptible to Hg damage, and Hg exposure is therefore especially harmful for children and fetuses. 11 −15 The molecular mechanisms underlying Hg toxicity remain unclear, 16 but appear to include toxic molecular mimicry 8 and blocking of antioxidants 17 especially in the mitochondria. ...
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Mercury intoxication typically produces more severe outcomes in people with the APOE-ε4 gene, which codes for the ApoE4 variant of apolipoprotein E, compared to individuals with the APOE-ε2 and APOE-ε3 genes. Why the APOE-ε4 allele is a risk factor in mercury exposure remains unknown. One proposed possibility is that the ApoE protein could be involved in clearing of heavy metals, where the ApoE4 protein might perform this task worse than the ApoE2 and ApoE3 variants. Here, we used fluorescence and circular dichroism spectroscopies to characterize the in vitro interactions of the three different ApoE variants with Hg(I) and Hg(II) ions. Hg(I) ions displayed weak binding to all ApoE variants and induced virtually no structural changes. Thus, Hg(I) ions appear to have no biologically relevant interactions with the ApoE protein. Hg(II) ions displayed stronger and very similar binding affinities for all three ApoE isoforms, with K D values of 4.6 μM for ApoE2, 4.9 μM for ApoE3, and 4.3 μM for ApoE4. Binding of Hg(II) ions also induced changes in ApoE superhelicity, that is, altered coil-coil interactions, which might modify the protein function. As these structural changes were most pronounced in the ApoE4 protein, they could be related to the APOE-ε4 gene being a risk factor in mercury toxicity.
... Previous research has shown that chemical ligands activate the receptors on growth cones that ultimately initiate the intracellular signals cascade to direct cytoskeletal changes [51]. The cytoskeleton of the growth cone comprises Actin and tubulin microtubule; this cytoskeleton of the growth cone is highly sensitive to change in the extracellular environment [52]. The changes in the organization of the Actin and tubulin in the cytoskeleton cause the change in morphology and motility of the growth cone [53][54][55]. ...
Article
Calcium ion (Ca2+) and Calmodulin (CaM) are important signaling molecules that have been shown to play a significant role in a wide variety of neuronal functions, including neurite outgrowth of axon and dendrites. The growth cone is located on the tip of the growing neurite. The morphology and motility of the growth cone depend on Ca2+ and the stimulation of Ca2+ dependent protein kinases (CaMK) in developing neurons. CaM-kinase II (CaMKII) is a member of the CaMK family, and it is highly expressed in the cytosol of developing neurons, including the growth cone. We hypothesized that CaMKII activity could be necessary for growth cones morphology and motility. To test this possibility, the identified Pedal A (PeA) neurons from the central ring ganglia of the freshwater pond snail Lymnaea stagnalis were cultured for 24 hrs -48 hrs in a 2 ml brain conditioned medium. Following neurite outgrowth, we have examined the effect of CaMKII inhibitor on growth cone structure and motility rate by using a CaMKII specific inhibitor KN-93 and its inactive analog KN-92; both drugs were pressure applied directly onto individual growth cones. Here we demonstrate that inhibition of CaMKII dramatically changes the morphology and motility of growth cone in cultured neurons. Growth cones of neurons treated with KN-93 exhibit collapsed morphology. In contrast, growth cone exposure to KN-92 did not affect growth cone morphology and motility rate. Taken together, the data presented here provide the first direct evidence for the involvement of CaMKII activity to maintain growth cone morphology and motility in the freshwater pond snail Lymnaea stagnalis.
... The exposure to 4-hydroxy-2(E)-nonenal, a major product of lipid peroxidation reduced the goth of neurite by disintegrating the microtubules (Neely, Sidell, Graham, & Montine, 1999). Similarly, the mercury treatment-induced neuronal membrane degeneration by affecting the microtubule integrity (Leong, Syed, & Lorscheider, 2001). The N-homocysteinylated Tau was observed to have a reduced affinity for tubulin which leads to neurodegeneration (Karima et al., 2012). ...
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The neuronal cytoskeleton plays a crucial role in maintaining cell integrity and functioning of neurons. Cytoskeleton deformities have been reported to be associated with neurodegenerative diseases thus; cytoskeleton can be targeted for therapeutic strategies. The therapeutic application of photosensitive molecule is termed as Photodynamic therapy (PDT). PDT has been applied in the field of dermatology, cancer biology and antimicrobial therapy. PDT induces several changes in cells, which include induction of apoptosis, DNA damage, and induction of inflammatory response. PDT has been also reported to modulate cytoskeleton such as actin dynamics. The in‐vitro studies suggested that PDT using dyes such as Toluidine Blue and Rose Bengal effectively modulated the actin cytoskeleton, neurite outgrowth, tubulin and Tau aggregation. In this review, we focused on the effect of photosensitized molecules on various cytoskeleton proteins. We hypothesize that PDT could have potency against Alzheimer's disease and other neurodegenerative disorders. This article is protected by copyright. All rights reserved.
... Of course, it also needs to be established at what level L. stagnalis can function as a model for medical research such as neurodegenerative disease and be a substitute for standard vertebrate models. Nevertheless, L. stagnalis has already been successfully used to study neurodegenerative disorders associated with memory decline such as Parkinson's and Alzheimer's diseases (39)(40)(41)(42). Such studies demonstrated, for example, that in vivo L. stagnalis parkinsonian models can mimic several etiological properties of Parkinson's disease (39,40). ...
Article
With the increase of life span, normal aging and age-related memory decline are affecting an increasing number of people; however, many aspects of these processes are still not fully understood. Although vertebrate models have provided considerable insights into the molecular and electrophysiological changes associated with brain aging, invertebrates, including the widely recognized molluscan model organism, the great pond snail (Lymnaea stagnalis), have proven to be extremely useful for studying mechanisms of aging at the level of identified individual neurons and well-defined circuits. Its numerically simpler nervous system, well-characterized life cycle, and relatively long life span make it an ideal organism to study age-related changes in the nervous system. Here, we provide an overview of age-related studies on L. stagnalis and showcase this species as a contemporary choice for modeling the molecular, cellular, circuit, and behavioral mechanisms of aging and age-related memory impairment. The general increase of life span supported by rapid advances in medical interventions also resulted in the increase in normal and pathological age-related memory decline affecting a growing number of people with devastating effect, not just to the affected individuals but also their carers, relatives, and the society as a whole. However, there is still very little known about the key molecules, signaling pathways, and cellular changes responsible for the slowing of cognitive functions and/or memory impairment during biological aging. Clearly, there is a great social and economic need to study the mechanisms underlying these neurophysiological processes leading to therapeutic interventions. The complexity of events associated with normal age-related changes and pathological conditions in the nervous system cannot be overestimated. There are numerous imaging studies in mamma-lian species, including humans, investigating changes in brain activity related to aging; but due to the complexity of the mammalian brain, it is difficult to study these changes at the level of defined circuits and individual neurons. Investigating the electrical activities of hippocampal pyramidal cells, the Nobel Prize Laurate Eric Kandel had already recognized that the human brain did not provide the best opportunity to understand the cellular and molecular mechanisms leading to the generation of functions such as learning and memory. In 1962, he visited the invertebrate laboratory of Paris led by Ladislav Tauc where they worked together on the marine mollusc Aplysia californica. Kandel realized that this animal is capable of simple forms of learning such as sensitization and habituation and the learning-induced changes could readily be studied in isolated brain preparations. This allowed mapping and translating be-havioral learning and memory storage onto synaptic events such as heterosynaptic facilitation (1-4) that could be analyzed at the level of single cells and molecular cascades. This pioneering work led to the discovery of several cellular and molecular processes underlying learning and memory that also served as a basis for research on age-related memory decline. Building on the findings of A. californica, research using the gastropod mollusc Lymnaea stagnalis (Figure 1) furthered the knowledge on learning-related processes induced by different asso-ciative paradigms and established this species as a favored model for Downloaded from https
... Of course, it also needs to be established at what level L. stagnalis can function as a model for medical research such as neurodegenerative disease and be a substitute for standard vertebrate models. Nevertheless, L. stagnalis has already been successfully used to study neurodegenerative disorders associated with memory decline such as Parkinson's and Alzheimer's diseases (39)(40)(41)(42). Such studies demonstrated, for example, that in vivo L. stagnalis parkinsonian models can mimic several etiological properties of Parkinson's disease (39,40). ...
Article
With the increase of life span, normal ageing and age-related memory decline are affecting an increasing number of people; however, many aspects of these processes are still not fully understood. Although vertebrate models have provided considerable insights into the molecular and electrophysiological changes associated with brain ageing, invertebrates, including the widely recognised molluscan model organism, the great pond snail (Lymnaea stagnalis) have proven to be extremely useful for studying mechanisms of ageing at the level of identified individual neurons and well-defined circuits. It’s numerically simpler nervous system, well-characterized life cycle and relatively long lifespan make it an ideal organism to study age-related changes in the nervous system. Here, we provide an overview of age-related studies on L. stagnalis and showcase this species as a contemporary choice for modelling the molecular, cellular, circuit, and behavioural mechanisms of ageing and age-related memory impairment.
... This results in increased levels of Aβ in the hippocampus and decreased levels in the CSF region advocating that removal of a pathogenic peptide from the brain gets reduced (Kim et al. 2014). The structural integrity of neurons and neurites is completely distorted by Hg ions besides the binding of guanosine triphosphate (GTP) to β tubulin also gets inhibited which in turn reduces the biological activity causing microtubule degeneration as exhibited in AD brain homogenates (Leong et al. 2001;Haley 2007). In human nutrition, arsenic (As) represents an essential element; however, at higher doses, it affects both cognitive and neurodevelopmental functions (Nielsen 2000;Tyler and Allan 2014). ...
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Neurodegenerative disorders are commonly erratic influenced by various factors including lifestyle, environmental, and genetic factors. In recent observations, it has been hypothesized that exposure to various environmental factors enhances the risk of Alzheimer’s disease (AD). The exact etiology of Alzheimer’s disease is still unclear; however, the contribution of environmental factors in the pathology of AD is widely acknowledged. Based on the available literature, the review aims to culminate in the prospective correlation between the various environmental factors and AD. The prolonged exposure to the various well-known environmental factors including heavy metals, air pollutants (particulate matter), pesticides, nanoparticles containing metals, industrial chemicals results in accelerating the progression of AD. Common mechanisms have been documented in the field of environmental contaminants for enhancing amyloid-β (Aβ) peptide along with tau phosphorylation, resulting in the initiation of senile plaques and neurofibrillary tangles, which results in the death of neurons. This review offers a compilation of available data to support the long-suspected correlation between environmental risk factors and AD pathology. .
... 14,15 Animal models have shown that brain neprilysin plays a leading role in Ab degradation. 16,17 Reduced neprilysin expression and enhanced APP expression have also been observed in the hippocampus of patients with early-onset familial AD. 15,17 Recently, many metals have been suggested as risk factors related to the AD pathogenesis, and the concentrations of different metals, including aluminum, iron and copper, were evaluated in brains affected by AD. 18,19 Some studies have found a link between mercury exposure and neurological degeneration, 20 oxidative stress and cell cytotoxicity. 21,22 A marked increase in mercury concentrations in AD brains was shown in some autopsy investigations. ...
Article
Mercury is a highly poisonous heavy metal found in the environment abundantly in its inorganic form. Although some pieces of evidence have been provided about the possible role of inorganic mercury in the pathology of Alzheimer’s disease (AD), its effect on cognitive and mitochondrial functions have not yet been completely understood. Thus, the purpose of the present study was to examine the effects of chronic exposure to mercuric chloride (0.4, 0.8 and 1.6 mg/kg/day for 3 weeks) through drinking water (by gavage) on spatial learning and memory and hippocampal mitochondrial function in beta-amyloid treated rats (1µg/µL per side, intrahippocampally). Acquisition and retention of spatial memory were evaluated by the Morris water maze (MWM) test. Several parameters of hippocampal mitochondrial function were also measured. The results indicated that mercury impaired spatial learning, memory and aggravated Aβ-induced memory impairments are in a concentration-dependent manner. Further, mercury exposure resulted in a significant increase in ROS generation, MMP collapse, mitochondrial swelling, glutathione oxidation, lipid peroxidation, outer membrane damage, reduced cytochrome c oxidase (complex IV) activity and elevated ADP/ATP ratio in the rats' hippocampus. The findings of the current study revealed that chronic mercury exposure leads to mitochondrial dysfunction which results in spatial memory impairments. The results also showed that mercury can potentiate the toxic effects of Aβ on spatial memory and hippocampal mitochondrial function.
... Scientists also found that other metals, including aluminium, did not cause the damage. "Amyloid plaques" were considered as diagnostic markers in previous research for Alzheimer's disease (24). It has been reported that elderly people without dementia had 2.7 fillings whereas those with dementia or Alzheimer's disease had 7.8 fillings (1). ...
Article
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The practise of dentistry involves working with patients, who come to us with specific dental problem with a blind faith in us. It is very important that we dentists see our patients as human beings first and not just as a set of teeth. It is rightly said, “Mouth is a Mirror of the Health”. Many of the oral diseases are also associated with systemic conditions including stress, diabetes, genetic disorders or age related diseases. Care should be also emphasized on the surrounding environment which equally contributes to the health of the patient. The aim of this article is to create awareness on the human aspect of our patients, to look beyond teeth and the things we can do to care for our patients as a whole and also the environment.
... Some Hg compounds have been shown to cause neurotoxicity, affecting the usual maturity of the central nervous system [76]. In vitro studies with animals have shown that methylmercury can affect the biological processes thought to be involved in Alzheimer's disease [77]. Cadmium has also been established to generate free radicals in the brain [78]. ...
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The drive for development and modernization has come at great cost. Various human activities in developed and developing countries, particularly in sub-Saharan Africa (SSA) have given rise to environmental safety concerns. Increased artisanal mining activities, illegal refining, use of leaded petrol, airborne dust, arbitrary discarding and burning of toxic waste, absorption of production industries in inhabited areas, inadequate environmental legislation, and weak implementation of policies, have given rise to the incomparable contamination and pollution associated with heavy metals in recent decades. This review evaluates the public health effects of heavy metals and their mixtures in SSA. This shows the extent and size of the problem posed by exposure to heavy metal mixtures in regard to public health.
... Mercury causes increased A levels, tau protein hyperphosphorylation, reduced binding of GTP to -tubulin, microtubule degeneration and compromised membrane structural integrity of neurites and neuron growth cones. [165,166] 7. Arsenic Arsenic exposure leads to tau hyperphosphorylation, increase in amyloid beta levels, increased generation of free radicals and increase in the inflammatory process. [167] 8. Selenium High selenium concentration is associated with reduced cholinergic signaling, increased oxidative stress and degeneration of cholinergic neurons. ...
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Alzheimer’s disease (AD) and multiple sclerosis are major neurodegenerative diseases, which are characterized by the accumulation of abnormal pathogenic proteins due to oxidative stress, mitochondrial dysfunction, impaired autophagy, and pathogens, leading to neurodegeneration and behavioral deficits. Herein, we reviewed the utility of plant polyphenols in regulating proliferation and differentiation of stem cells for inducing brain self-repair in AD and multiple sclerosis. Firstly, we discussed the genetic, physiological, and environmental factors involved in the pathophysiology of both the disorders. Next, we reviewed various stem cell therapies available and how they have proved useful in animal models of AD and multiple sclerosis. Lastly, we discussed how polyphenols utilize the potential of stem cells, either complementing their therapeutic effects or stimulating endogenous and exogenous neurogenesis, against these diseases. We suggest that polyphenols could be a potential candidate for stem cell therapy against neurodegenerative disorders.
... Very low levels of inorganic mercury lead to the destruction of intracellular microtubules and the degeneration of axons. This dramatic neurodegenerative cascade is specific for mercury and was not found with other metals such as aluminum, cadmium, lead, or manganese [137]. Mercury depletes glutathione [113,138] and impairs mitochondrial function [139][140][141]. ...
Article
Genetic background accounts for only 5 to 10% of the reported cases of Parkinson's disease (PD), while the remaining cases are of unknown etiology. It is believed that environmental factors may be involved in the causality of a large proportion of PD cases. Several PD genes are activated by xenobiotic exposure, and a link between pesticide exposure and PD has been demonstrated. Many epidemiological studies have shown an association between PD and exposure to metals such as mercury, lead, manganese, copper, iron, aluminum, bismuth, thallium, and zinc. This review explores the biological effects, the pathogenetic processes, genetic susceptibilities to metals as well as examining future strategies for PD treatment, such as chelation therapy.
... 36 The mechanisms underlying the loss of neuronal connectivity from Hg exposure are multifold. 37 First, as described by Leong et al,38 Hg binds to the tubulin/microtubule structure of the axon and causes the axon to degenerate. Second, neurons are damaged by Hg-induced oxidative stress. ...
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Background Autism spectrum disorder (ASD), tic disorder (TD), and hyperkinetic syndrome of childhood (attention deficit disorder [ADD]/attention deficit hyperactivity disorder [ADHD]) are disorders recently defined as abnormal connectivity spectrum disorders (ACSDs) because they show a similar pattern of abnormal brain connectivity. This study examines whether these disorders are associated with exposure to thimerosal, a mercury (Hg)-based preservative. Methods A hypothesis testing case-control study evaluated the Vaccine Safety Datalink for the potential dose-dependent odds ratios (ORs) for diagnoses of ASD, TD, and ADD/ADHD compared to controls, following exposure to Hg from thimerosal-containing Haemophilus influenzae type b vaccines administrated within the first 15 months of life. Febrile seizures, cerebral degeneration, and unspecified disorders of metabolism, which are not biologically plausibly linked to thimerosal, were examined as control outcomes. Results On a per 25 μg Hg basis, cases diagnosed with ASD (OR = 1.493), TD (OR = 1.428), or ADD/ADHD (OR = 1.503) were significantly (P < .001) more likely than controls to have received increased Hg exposure. Similar relationships were observed when separated by gender. Cases diagnosed with control outcomes were no more likely than controls to have received increased Hg exposure. Conclusion The results suggest that Hg exposure from thimerosal is significantly associated with the ACSDs of ASD, TD, and ADD/ADHD.
... Some autopsy studies have found increased Hg concentration in brain tissues of AD patients (Mutter et al., 2010;Nakagawa, 1995). It has been reported that inorganic Hg levels of 0.02 ng Hg/g (2 μl 0.1 μMolar Hg in 2 ml substrate) can led to total destruction of intracellular mircrotubuli and degeneration of axons (Leong et al., 2001). Inorganic Hg levels of 36 ng Hg/g(0.18 ...
... Exposure of MeHg to fetal brain is more susceptible to mercury-induced damage than the adult brain (Clarkson et al., 2003). In vitro studies in animals have indicated that MeHg can affect the biochemical processes believed to be involved in Alzheimer's disease (Leong et al., 2001), and axonal degeneration is unique to MeHg (Castoldi et al., 2003). In some recent studies, Cd has also been shown to produce free radicals in the brain (Czarnecki et al., 2012). ...
... It is important to note that the level of mer- cury added to the cell culture in this video was one hundred times lower than is typi- cally detected in the cerebral spinal fl uid of those with mercury/silver amalgam tooth fi llings. A related paper by the researchers is also important because it demon- strated that mercury, and only mercury, produces the neurofi brillary tangles (NFTs) recognized as the major diagnostic hallmark of AD ( Leong et al. 2001 ). ...
Chapter
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All dental amalgam fillings contain approximately 50 % elemental mercury by weight. Concerns about health risks due to continual emissions of mercury vapor from this tooth restorative material have been addressed by dentists, scientists, and government authorities worldwide and have resulted in a range of recommended practices and regulations. By reviewing articles collected by a literature search of the International Academy of Oral Medicine and Toxicology (IAOMT) database and the PubMed database, we identify health risks associated with dental mercury amalgam. We present the science of potential harm as applicable to the general population, pregnant women, fetuses, children, and dental professionals. We specifically address genetic predispositions, mercury allergies, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and other health conditions pertinent to dental mercury exposure. We conclude that reviews and studies of dental amalgam mercury risk should assess biocompatibility with special consideration for all populations and all risk factors.
... Further experimental work showed that these effects can be attenuated by chelators which contain sulfhydryl groups (e.g. dithiothreitol) and it was hypothesized on the basis of these observations, that the effects on tubuli depend on metal binding to sulfhydryl groups of proteins [37]. ...
... To see how potent, view the video How Mercury Damages Nerve Fibrils (view the video at http://commons.ucalgary.ca/mercury/ and see Leong, Syed, & Lorscheider, 2001). The experimental toxicology research plainly supports the toxic stress theory. ...
Conference Paper
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This document contains the abstracts of presentations and writings contributed by the named persons and others at the Sertoma International Conference on Autism Spectrum Disorders. The purpose of the conference was to address the following question: Why is the number of new severe diagnoses still skyrocketing? It can't be all genetic. Human genes don't change that fast. Childhood autism is now more common than spina bifida, cancer, Down syndrome, or any other childhood disorder (Muhle, et aI., 2004, Pediatrics 1/3). The graph on the front page shows data through 2003 but the CDC reported February 9, 2007 that the red line of autism is still climbing in 2007. About 40% of the new cases are severe and criteria for those cases have hardly changed in 50 years. [Follow up research and publications show that at the time of this writing, July 22, 2016, the autism epidemic has only gotten more intense. All efforts to make it go away by creative statistics, burying the number of real cases by performing pretend searches that find "no evidence" that the number of severe cases is increasing, and so forth, have failed. The fact is that diagnoses placing individuals on the autism spectrum continue to increase. More importantly, issues raised in the presentations at this conference pointed to causal factors that are not plausibly deniable.]
... It is generally supposed that genetic factors are involved along with critical toxic triggers. The mercury vapors being off-gased from dental amalgam are implicated (Leong, Syed, & Lorscheider 2001) along with organomercurials of the ethyl and methyl varieties which are known to exacerbate neurological disease conditions such as Alzheimer's and Parkinson's disease across the board. ...
Chapter
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In language assessment, the task is only made more difficult by the existence of communication disorders. According to Michael Kane (2011), “finding that an examinee had a disability that had not been adequately accommodated could undermine a standard interpretive argument.” How should we interpret scores, ratings, or any language assessment for persons with communication disorders? Is it possible to do so based on the expected ranges and milestones associated with persons who do not have any known disorder or disability? For instance, can a “nonverbal” person with severe “infantile autism” be judged with assessment procedures that are designed for application to normally developing individuals of comparable physical and chronological maturity? Is a differently calibrated scale required for the person with autism? If a newly discovered problem could overturn a standard interpretation of a score, rating, or assessment procedure, just how many distinct language assessment procedures should there be and how are they to be determined?
... Further experimental work showed that these effects can be attenuated by chelators which contain sulfhydryl groups (e.g. dithiothreitol) and it was hypothesized on the basis of these observations, that the effects on tubuli depend on metal binding to sulfhydryl groups of proteins [37]. ...
... Podle autoptických studií mají jedinci s více než 12 amalgámovými výplněmi 10krát vyšší koncentrace rtuti v různých tkáních včetně mozku ve srovnání s lidmi s maximálně 3 plombami (4). Anorganická rtuť již v koncentracích 20 pg Hg/g tkáně (2 μl 0,1 μM roztoku Hg ve 2ml substrátu) vede k úplné destrukci intracelulárních mikrotubulů a k degeneraci axonů (5). Přitom neexistuje korelace mezi hladinami rtuti v krvi, moči, koncentracemi ve tkáních a klinickými symptomy. ...
Article
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Environmental factors are one of the causes of increased incidence of allergic, autoimmune, degenerative and demyelinating diseases. These also include highly reactive metal ions being slowly released from dental fillings and other implants or those contained in products of daily needs. In susceptible individuals they activate T-lymphocytes and trigger a chronic systemic inflammatory response. Production of cytokines and increased oxidative stress lead to changes in tissues and organs. Clinically it may present with non-specific range of gradually progressive, very stubborn and “unexplained” symptoms which are difficult to investigate but significantly impair quality of life. In addition to routine toxicological testing the diagnostics is based mainly on the Melisa test. This proves the reactivity of memory cells of the immune system to the appropriate metal. Removal of incompatible materials leads to long-term health improvement in most of the patients.
... Podle autoptických studií mají jedinci s více než 12 amalgámovými výplněmi 10krát vyšší koncentrace rtuti v různých tkáních včetně mozku ve srovnání s lidmi s maximálně 3 plombami (4). Anorganická rtuť již v koncentracích 20 pg Hg/g tkáně (2 μl 0,1 μM roztoku Hg ve 2ml substrátu) vede k úplné destrukci intracelulárních mikrotubulů a k degeneraci axonů (5). Přitom neexistuje korelace mezi hladinami rtuti v krvi, moči, koncentracemi ve tkáních a klinickými symptomy. ...
Article
Full-text available
Environmental factors are one of the causes of increased incidence of allergic, autoimmune, degenerative and demyelinating diseases. These also include highly reactive metal ions being slowly released from dental fillings and other implants or those contained in products of daily needs. In susceptible individuals they activate T-lymphocytes and trigger a chronic systemic inflammatory response. Production of cytokines and increased oxidative stress lead to changes in tissues and organs. Clinically it may present with non-specific range of gradually progressive, very stubborn and "unexplained" symptoms which are difficult to investigate but significantly impair quality of life. In addition to routine toxicological testing the diagnostics is based mainly on the Melisa test. This proves the reactivity of memory cells of the immune system to the appropriate metal. Removal of incompatible materials leads to long-term health improvement in most of the patients (1).
... only 38 percent of the patients were alive one year after placement of a feeding tube. For acutely ill patients with severe dementia, there was no survival advantage among patients who received a feeding tube during their index hospitalization, compared with those without a feeding tube (Leong et al., 2001). With or without a feeding tube, these patients have a 50 percent six-month median mortality rate. ...
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Progressive mental deterioration in old age has been recognized and described throughout history. However, it was not until 1906 that a German physician, Dr. Alois Alzheimer, specifically identified a collection of brain cell abnormalities as a disease. One of Dr. Alzheimer's patients died after years of severe memory problems, confusion and difficulty understanding questions. Upon her death, while performing a brain autopsy, the doctor noted dense deposits surrounding the nerve cells (neuritic plaques). Inside the nerve cells he observed twisted bands of fibers (neurofibrillary tangles). Today, this degenerative brain disorder bears his name, and when found during an autopsy, these plaques and tangles mean a definite diagnosis of Alzheimer's disease (AD). Since its discovery more than 100 years ago, there have been many scientific breakthroughs in AD research. In the 1960s, scientists discovered a link between cognitive decline and the number of plaques and tangles in the brain. The medical community then formally recognized Alzheimer's as a disease and not a normal part of aging. In the 1970s, scientists made great strides in understanding the human body as a whole, and AD emerged as a significant area of research interest. This increased attention led in the 1990s to important discoveries and a better understanding of complex nerve cells in the brains of AD patients. More research was done on AD susceptibility genes, and several drugs were approved to treat the cognitive symptoms of the disease. There is450 thousan person to contract the Alzheimer disease in Iran. The lifetime risk of Alzheimer disease is estimated to be 1:5-2. More than 15% of individuals older than 65 years have AD, and the prevalence increases to at least 40% in individuals older than 80 years. This study showed that although Alzheimer's cure dosthe can be improved conditions living the reduce stress and increase social activity and especially the control diet,the incidence avoided.The foods in wich substances such as omega 3,omega 6,VitaminA and Vitamin B12,there is more recommended and those 60 years above of age must have there is reduced animals fatty acids severly in the diet of red meat.
... In the nineteenth century there was renewed interest in the pharmaceutical and medical use of snails, and this continued into the twentieth century as well. For example, heterobranchs have been useful for investigations of Alzheimer disease (Alkon et al. 1998, Leong et al. 2001) and synthetic drugs derived from peptides found in Conus venom (e.g., ziconotide) have been recently approved for the treatment of chronic pain. Some freshwater gastropods act as primary hosts to parasitic trematodes such as liver fl ukes (Fasciola and Opisthorchis), lung fl ukes (Paragonimus), or blood fl ukes (Schistosoma). ...
Chapter
This chapter presents an overview and analysis of the phylogeny and evolution of the molluscan class Gastropoda. It explains that Gastropoda is the largest molluscan class and it contains the greatest diversity of described marine species. Estimates of the numbers of extant gastropod species range from a minimum of 40,000 to a maximum of almost 150,000. It describes the gastropod morphology and their significance to humans and provides a summary of the key features of major groups of gastropods.
... To see how potent, view the video How Mercury Damages Nerve Fibrils (view the video at http://commons.ucalgary.ca/mercury/ and seeLeong, Syed, & Lorscheider, 2001). The experimental toxicology research plainly supports the toxic stress theory. ...
Conference Paper
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Why is the number of new severe diagnoses still skyrocketing? It can't be all genetic. Human genes doen't change that fast. Childhood autism is now more common that spina bifida, cancer, Down syndrome, or any other childhood disorder (Muhle, et alo., 2004, Pediatrics 113). Data through 2007 shows that the autism diagnosis is still climbing. CDC also reports that about 40% of the new cases are severe. Meantime, criteria for diagnosis have hardly changed in 50 years.
... 21 Nevertheless, in vitro studies have indicated that mercury can affect the biochemical processes believed to be involved in Alzheimer's disease. 22 The problem is that mercury can inhibit various biochemical processes in vitro without having the same effect in vivo. ...
... MeHg (50-100 nM) also increases tau phosphorylation by mechanisms that include reactive oxygen species production (Petroni et al., 2012). Furthermore, disruption of the membrane structure and linear growth rates of neurites were observed in primary cultures of snail neurons exposed to inorganic Hg (Leong et al., 2001). ...
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Levels of amyloid beta (Aβ) in the central nervous system are regulated by the balance between its synthesis and degradation. Neprilysin (NEP) is associated with Alzheimer's disease (AD) by its ability to degrade Aβ. Some studies have involved the exposure to mercury (Hg) in AD pathogenesis; therefore our aim was to investigate the effects on the anabolism and catabolism of Aβ in differentiated SH-SY5Y cells incubated with 1-20 μM of Hg. Exposure to 20 μM of Hg induced an increase in Aβ-42 secretion, but did not increase the expression of the amyloid precursor protein (APP). Hg incubation (10 and 20 μM) increased NEP protein levels, however it did not change NEP mRNA levels nor the levels of the amyloid intracellular domain (AICD) peptide, a protein fragment with transcriptional activity. Interestingly, Hg reduced NEP activity at 10 and 20 μM, and circular dichroism analysis using human recombinant NEP (hrNEP) showed conformational changes after incubation with molar equivalents of Hg. This suggests that the Hg-induced inhibition of NEP activity may be mediated by a conformational change resulting in reduced Aβ-42 degradation. Finally, the comparative effects of lead (Pb, 50 μM), were evaluated. We found a significant increase in Aβ-42 levels and a dramatic increase in APP protein levels, however no alteration in NEP levels was observed nor in the enzymatic activity of this metalloprotease, despite the fact that Pb slightly modified the rhNEP conformation. Overall our data suggest that Hg and Pb increase Aβ levels by different mechanisms. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Despite the efforts made by the World Health Organization to create prevention programs and strategies for heavy metal poisoning, some of these are still frequent, mainly in some work areas. Its effects can range from minimal to lethal for humans, depending on the exposure time and the dose. The health professional is an essential point of contact to detect possible exposure and intoxication with any of these heavy metals, so knowing their symptoms and mechanism of action, metabolism, and treatment is of the utmost importance. In this brief article, some of the most important points to consider as healthcare personnel are summarized.
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Despite the attempts that have started since the 1960s, not even a single cell line of marine molluscs is available. Considering the vast contribution of marine bivalve aquaculture to the world economy, the prevailing viral threats, and the dismaying lack of advancements in molluscan virology, the requirement of a marine molluscan cell line is indispensable. This synthetic review discusses the obstacles in developing a marine molluscan cell line concerning the choice of species, the selection of tissue and decontamination, and cell culture media, with emphasis given on the current decade 2010-2020. Detailed accounts on the experiments on the virus cultivation in vitro and molluscan cell immortalization, with a brief note on the history and applications of the molluscan cell culture, are elucidated to give a holistic picture of the current status and future trends in molluscan cell line development. Supplementary information: The online version contains supplementary material available at 10.1007/s10616-022-00539-x.
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Mercury is one of the most toxic elements and causes a multitude of health problems. It is ten times more toxic to neurons than lead. This study was created to determine if mercury could be causing Alzheimer’s disease (AD) by cross referencing the effects of mercury with 70 factors associated with AD. The results found that all these factors could be attributed to mercury. The hallmark changes in AD include plaques, beta amyloid protein, neurofibrillary tangles, phosphorylated tau protein, and memory loss—all changes that can be caused by mercury. Neurotransmitters such as acetylcholine, serotonin, dopamine, glutamate, and norepinephrine are inhibited in patients with Alzheimer’s disease, with the same inhibition occurring in mercury toxicity. Enzyme dysfunction in patients with Alzheimer’s disease include BACE 1, gamma secretase, cyclooxygenase-2, cytochrome-c-oxidase, protein kinases, monoamine oxidase, nitric oxide synthetase, acetyl choline transferase, and caspases, all which can be explained by mercury toxicity. Immune and inflammatory responses seen in patients with Alzheimer’s disease also occur when cells are exposed to mercury, including complement activation, cytokine expression, production of glial fibrillary acid protein antibodies and interleukin-1, transforming growth factor, beta 2 microglobulins, and phosphodiesterase 4 stimulation. Genetic factors in patients with Alzheimer’s disease are also associated with mercury. Apolipoprotein E 4 allele increases the toxicity of mercury. Mercury can inhibit DNA synthesis in the hippocampus, and has been associated with genetic mutations of presenilin 1 and 2, found in AD. The abnormalities of minerals and vitamins, specifically aluminum, calcium, copper, iron, magnesium, selenium, zinc, and vitamins B1, B12, E, and C, that occur in patients with Alzheimer’s disease, also occur in mercury toxicity. Aluminum has been found to increase mercury’s toxicity. Likewise, similar biochemical factors in AD are affected by mercury, including changes in blood levels of homocysteine, arachidonic acid, DHEA sulfate, glutathione, hydrogen peroxide, glycosamine glycans, acetyl-L carnitine, melatonin, and HDL. Other factors seen in Alzheimer’s disease, such as increased platelet activation, poor odor identification, hypertension, depression, increased incidences of herpes virus and chlamydia infections, also occur in mercury exposure. In addition, patients diagnosed with Alzheimer’s disease exhibit higher levels of brain mercury, blood mercury, and tissue mercury in some studies. The greatest exogenous sources of brain mercury come from dental amalgams. Conclusion: This review of the literature strongly suggests that mercury can be a cause of Alzheimer’s Disease.
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References cited in the book are listed alphabetically. Also there is an index of terms and authors.
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Heavy metal pollution elicits severe environmental concern and health problem worldwide. Mercury is considered as a ubiquitous pollutant due to its versatile application in medicine, industry and cosmetics. Long non-coding RNAs (lncRNAs) are transcripts greater than 200 nt without protein-encoding function. However, little is known about the mechanism of heavy metals-induced non-coding RNA changes in aquatic organisms. To reveal the epigenetic mechanism of mercury toxicity in zebrafish embryos and explore novel specific mercury-toxicological biomarkers, several well-studied lncRNAs were screened by real-time PCR, and the spatial-temporal expression of lncRNAs biomarker was evaluated by in situ hybridization. The nerve system of zebrafish embryos were evaluated by detecting locomotor behavior and the expression of neuro-genes. We identified a mercury responsive lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (malat1), among 5 candidate lncRNAs. HgCl2, MeHg, PbCl2, CdCl2 and K2CrO4 exposure assay showed that malat-1 was a mercury specific induced lncRNAs. Malat1 was highly expressed in the brain region, eyes and notochord of developing zebrafish embryos after exposure to mercury compounds. HgCl2 showed neurobehavior disturbance and changed neuro-genes expression pattern in zebrafish larval. This study provides a biological method to detect inorganic or organic mercury using malat1 as a novel biomarker of mercury contamination and also clues for the exploration of neurotoxicity mechanism of mercury compounds.
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Zusammenfassung In den meisten Fällen ist die Ursache einer Morbus-Parkinson-Erkrankung unklar. Die konventionellen Behandlungsoptionen sind nicht immer ausreichend oder werden aufgrund unerwünschter Wirkungen von den Patienten abgelehnt. Verschiedene Studien legen den Einfluss von Umweltfaktoren auf die Entstehung neurodegenerativer Erkrankungen wie Morbus Parkinson nahe. Insbesondere Schwermetallbelastungen durch Zahnmaterialien scheinen eine Rolle zu spielen. Mit einer integrativen Therapie, die u. a. die Ernährung, den Mikronährstoffstatus, Schwermetallbelastungen und mögliche neurotrope Infektionen berücksichtigt, kann der Behandlungserfolg erheblich verbessert bzw. die Krankheitsprogression gestoppt werden.
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A reusable multichannel anthraimidazoledione based receptor 1 has been developed as highly selective detection of Cu2+ and Hg2+ in aqueous media. Based on high fluorescence sensitivity for Hg2+, 1 was probed for practical detection of Hg2+ in various drinking water sources wherein trace amount of Hg2+ was detected through fluorescence ‘turn-off’ signalling. Hence, 1 revealed qualitative and quantitative practical detection of HTMs (especially Hg2+) in competitive environment through multichannel signalling response.
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Total atmospheric mercury (TAM) is operationally defined as the sum of gaseous elemental mercury (GEM), gaseous oxidized inorganic mercury (GOIM), which is also called reactive gaseous mercury (RGM), and total filterable mercury (TFM). An annual weekly-integrated time-series of TFM concentrations in ambient air at Alert, Nunavut, Canada from March 1998 to March 1999 is reported in this paper. The observed TFM concentrations ranged from 0 to 0.37 ng m −3 with the highest value occurring in the spring after polar sunrise and the lowest in summer. The average values for the four seasons are 0.086 (March–May), 0.00085 (June–August), 0.0015 (September–November) and 0.013 ng m −3 (December 1998–February 1999) respectively. This pattern is anti-correlated to that of GEM concentration observed at the same location. The GOIM concentration, calculated using the equation [GOIM]=[TAM]−[GEM]−[TFM], is also anti-correlated with GEM concentration. The annual time-series of the TFM operational blank values shows the same temporal pattern as the TFM concentration, with values ranging from 0.00 to 0.011 ng m −3 . These results confirm that, in the polar regions, GEM oxidation and atmospheric deposition of mercury occur mainly in the 3-month period after polar sunrise. Incisive laboratory and field experiments are needed to either confirm or rule out the springtime GEM oxidation/conversion mechanisms proposed in this paper. DOI: 10.1111/j.1600-0889.2004.00107.x
Chapter
Methylmercury, a pollutant produced by various industrial activities, is a potent neurotoxin that has now caused serious contamination issues within our oceans. As a fat-soluble molecule, methylmercury enters the food chain and accumulates in the flesh of the fish that then may end up in our supermarkets. Consuming larger, longer living fish on a regular basis is now known to pose a serious health hazard, especially for children and pregnant women who are consequently advised to limit (or even avoid) the intake of some species such as fresh tuna or marlin.
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Most rhythmic behaviors such as respiration, locomotion, and feeding are under the control of networks of neurons in the central nervous system known as central pattern generators (CPGs). The respiratory rhythm of the pond snail Lymnaea stagnalis is a relatively simple, CPG-based behavior for which the underlying neural elements have been identified. A three-neuron network capable of generating the respiratory rhythm of this air-breathing mollusk has been reconstructed in culture. The intrinsic and network properties of this neural ensemble have been studied, and the mechanism of postinhibitory rebound excitation was found to be important for the rhythm generation. This in vitro model system enables a better understanding of the neural basis of rhythm generation.
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We have found that EDTA and EGTA complexes of Hg2+, which conventional wisdom has assumed are biologically inert, are potentially injurious to the neuronal cytoskeleton. Tubulin, a major protein component of the neuronal cytoskeleton, is the target of multiple toxicants, including many heavy metal ions. Among the mercurials, inorganic mercuric ion (Hg2+) is one of the most potent inhibitors of microtubule polymerization both in vivo and in vitro. In contrast to other heavy metals, the capacity of Hg2+ to inhibit microtubule polymerization or disrupt formed microtubules cannot be prevented by the addition of EDTA and EGTA, both of which bind Hg2+ with very high affinity. To the contrary, the addition of these two chelating agents potentiates Hg2+ inhibition of tubulin polymerization. Results herein show that HgEDTA and HgEGTA inhibit tubulin polymerization by disrupting the interaction of GTP with the E-site of brain beta-tubulin, an obligatory step in the polymerization of tubulin. Both HgEDTA and HgEGTA, but not free Hg2+, prevented binding of [32P]8N3GTP, a photoaffinity nucleotide analog of GTP, to the E-site and displaced bound [32P]8N3GTP at low micromolar concentrations. This complete inhibition of photoinsertion into the E-site occurred in a concentration- and time-dependent fashion and was specific for Hg2+ complexes of EDTA and EGTA, among the chelating agents tested. Given the ubiquity of Hg2+ in the environment and the widespread use of EDTA in foodstuffs and medicine, these mercury complexes may pose a potentially serious threat to human health and play a role in diseases of the neuronal cytoskeleton.
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Microtubule-associated protein tau is abnormally hyperphosphorylated in the brain of patients with Alzheimer's disease (AD) and the abnormal tau is the major protein subunit of paired helical filaments (PHF). The abnormal phosphorylation of tau probably precedes its polymerization into PHF. The abnormal tau does not bind to tubulin, but competes with tubulin in binding to normal tau and thereby inhibits the assembly of microtubules in the affected neurons. The abnormal tau can be dephosphorylated enzymatically and by this way its microtubule assembly promoting activity can be restored. The activities of protein phosphatases might be decreased in the affected neurons in AD brain, allowing the abnormal hyperphosphorylation of tau. Neurofibrillary degeneration can probably be inhibited by increasing the activities of protein phosphatases in the brain of patients with Alzheimer's disease.
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Neurons are highly polarized cells that contain a wealth of cytoplasmic and membrane proteins required for neurotransmission, synapse formation and various forms of neuronal plasticity. Typically, these proteins are differentially distributed over somatic, dendritic and axonal compartments. Until recently, it was believed that all proteins destined for various neuronal sites were synthesized exclusively in the somata and were subsequently targeted to appropriate extrasomal compartments. The discovery of various messenger RNA molecules in both dendrites and axons is suggestive of de novo protein synthesis in extrasomatic regions. The latter process has been demonstrated in few neuronal svrstems, but direct proof for the axonal transcription of a specific protein from a given messenger RNA is still lacking. This lack of fundamental knowledge in the field of cellular and molecular neurobiology is due primarily to both anatomical and experimental difficulties encountered in most animal preparations studied thus far. In this study we developed a neuronal experimental system comprising of individually identified neurons and their isolated axons from the mollusc Lymnaea stagnalis. We injected a foreign messenger RNA encoding a peptide precursor into the isolated axons of cultured neurons; and utilizing cellular, molecular and immunocytochemical techniques, we provide direct evidence for specific protein synthesis in isolated axons. The Lymnaea model provides us with an opportunity to examine the role and specificity of de novo protein synthesis in the extrasomal regions.
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Hg2+ interacts with brain tubulin and disassembles microtubules that maintain neurite structure. Since it is well known that Hg vapor (Hg0) is continuously released from "silver" amalgam tooth fillings and is absorbed into brain, rats were exposed to Hg0 4h/day for 0, 2, 7, 14 and 28 d at 250 or 300 micrograms Hg/m3 air, concentrations present in mouth air of some humans with many amalgam fillings. Average rat brain Hg concentrations increased significantly (11-47 fold) with duration of Hg0 exposure. By 14 d Hg0 exposure, photoaffinity labelling on the beta-subunit of the tubulin dimer with [alpha 32P] 8N3 GTP in brain homogenates was decreased 41-74%, upon analysis of SDS-PAGE autoradiograms. The identical neurochemical lesion of similar or greater magnitude is evident in Alzheimer brain homogenates from approximately 80% of patients, when compared to human age-matched neurological controls. Total tubulin protein levels remained relatively unchanged between Hg0 exposed rat brains and controls, and between Alzheimer brains and controls. Since the rate of tubulin polymerization is dependent upon binding of GTP to tubulin dimers, we conclude that chronic inhalation of low-level Hg0 can inhibit polymerization of brain tubulin essential for formation of microtubules.
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