Retrograde degeneration of neurite membrane structural integrity of nerve growth cones following in vitro exposure to mercury.
TL;DR: Williams et al. as discussed by the authors demonstrated that Hg ions markedly disrupted membrane structure and linear growth rates of imaged neurites in 77% of all nerve growth cones, and they concluded that this visual evidence and previous biochemical data strongly implicate Hg as a potential etiological factor in neurodegeneration.
Abstract: Inhalation of mercury vapor (Hg 0 ) 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 Lymnaea stagnalis were cultured for 48 h in 2 ml brain conditioned medium (CM). Following neurite outgrowth, metal chloride solution (2Il) of Hg, Al, Pb, Cd, or Mn (10 ˇ7 M) was pressure applied directly onto individual growth cones. Timelapse 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. NeuroReport 12:733‐737 & 2001 Lippincott Williams & Wilkins.
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TL;DR: Whereas removal of certain forms of mercury, such as that in blood-pressure cuffs, will not cause increased health risks, removal of each of the three major sources described in this article entails health risks and thus poses a dilemma to the health professional.
Abstract: ercury has been used commercially and medically for centuries. In the past it was a common constituent of many medications. It is still used in hospitals in thermometers and blood-pressure cuffs and commercially in batteries, switches, and fluorescent light bulbs. Large quantities of metallic mercury are employed as electrodes in the electrolytic production of chlorine and sodium hydroxide from saline. These uses still give rise to accidental and occupational exposures. 1 Today, however, exposure of the general population comes from three major sources: fish consumption, dental amalgams, and vaccines. Each has its own characteristic form of mercury and distinctive toxicologic profile and clinical symptoms. Dental amalgams emit mercury vapor that is inhaled and absorbed into the bloodstream. Dentists and anyone with an amalgam filling are exposed to this form of mercury. Liquid metallic mercury (quicksilver) still finds its way into homes, causing a risk of poisoning from the vapor and creating major cleanup costs. Humans are also exposed to two distinct but related organic forms, methyl mercury (CH 3 Hg + ) and ethyl mercury (CH 3 CH 2 Hg + ). Fish are the main if not the only source of methyl mercury, since it is no longer used as a fungicide. In many countries, babies are exposed to ethyl mercury through vaccination, since this form is the active ingredient of the preservative thimerosal used in vaccines. Whereas removal of certain forms of mercury, such as that in blood-pressure cuffs, will not cause increased health risks, removal of each of the three major sources described in this article entails health risks and thus poses a dilemma to the health professional. Exposure to mercury from dental amalgams and fish consumption has been a concern for decades, but the possible risk associated with thimerosal is a much newer concern. These fears have been heightened by a recent recommendation by the Environmental Protection Agency (EPA) that the allowable or safe daily intake of methyl mercury be reduced from 0.5 µg of mercury per kilogram of body weight per day, the threshold established by the World Health Organization in 1978, 2 to 0.1 µg of mercury per kilogram per day. 3 Table 1 summarizes the clinical toxicologic features of mercury vapor and methyl and ethyl mercury. It also includes data on inorganic divalent mercury, since this is believed to be the toxic species produced in tissues after inhalation of the vapor. 5 It is also responsible for kidney damage after exposure to ethyl mercury, since ethyl mercury is rapidly converted to the inorganic form. 13 Inorganic mercury as both mercuric and mercurous salts was also the chief cause of acrodynia, a childhood disease that is now mainly of historical interest. 14 The clinical symptoms of acrodynia consist of painful, red, swollen fingers and toes in association with photophobia, irritability, asthenia, and hypertension. It is believed to be a hypersensitivity reaction. m
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TL;DR: The three modern "faces" of mercury are the authors' perceptions of risk from the exposure of billions of people to methyl mercury in fish, mercury vapor from amalgam tooth fillings, and ethyl mercury in the form of thimerosal added as an antiseptic to widely used vaccines.
Abstract: The three modern "faces" of mercury are our perceptions of risk from the exposure of billions of people to methyl mercury in fish, mercury vapor from amalgam tooth fillings, and ethyl mercury in the form of thimerosal added as an antiseptic to widely used vaccines. In this article I review human exposure to and the toxicology of each of these three species of mercury. Mechanisms of action are discussed where possible. Key gaps in our current knowledge are identified from the points of view both of risk assessment and of mechanisms of action.
975 citations
Cites background from "Retrograde degeneration of neurite ..."
...(96) on the effect of mercury on neurite growth also noted the appearance of structures resembling neurofibrillary tangles....
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...(96) observed that mercuric ions added in vitro to cultured neurons inhibited outgrowth and disruptedmembrane structure....
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568 citations
TL;DR: Considerable attention was given in this review to pediatric methylmercury exposure and neurodevelopment because it is the most thoroughly investigated Hg species.
477 citations
Cites background from "Retrograde degeneration of neurite ..."
...Leong et al. (2001), for example, found that Hg2+ ions suppressed neuronal somata sprouting, thus inhibiting neurite growth in snails....
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TL;DR: An account of the current knowledge about the individual metal induced cognitive dysfunction mechanisms and common Mode of Actions (MOAs) of quaternary metal mixture (Pb, Cd, As, MeHg) are illustrated to help advancement in mixture toxicology and development of next generation predictive model (such as PBPK/PD) combining both kinetic and dynamic interactions of metals.
290 citations
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TL;DR: The hypothesis that neuronal processes underlying more subtle aspects of axon growth and synaptogenesis may be down-regulated chronically in mature neurons is suggested.
Abstract: Elongation ofaxons and active remodeling of their terminal arbors under lies the assembly of neural circuits during development, determines the success or fai lure of nerve regeneration, and may contribute to some forms of synaptic plast icity in adult brains. For most neurons, elongation of a principal axon is confined to a few days or weeks during development. Remodeling of axon terminal arbors also is most pronounced during transient "critical periods" late in development, although some forms of synaptic remodeling continue throughout lif e (Lichtman et aI19 87). Once past these epochs of axon elongation and dynamic sorting of synaptic terminals, it might be possible to stabilize principal axon branches or their terminal arbors by inactivating some of the molecular processes required for growth and synaptogenesis. Selective inactivation or retention of some growth-related processes in maturing neurons might then define some limits on the mechanisms available for synaptic remodeling in the adult nervous system. Studies of axon regeneration in vivo and in tissue culture indicate that some aspects of axon growth are indeed repressed in many adult neurons but can be re-induced under some conditio ns. Although such studies have considered primarily the elongation of primary axons, they also raise the possibility that neuronal processes underlying more subtle aspects of axon growth and synaptogenesis may be down-regulated chronically in mature neurons. At the molecular level, periods of axon outgrowth during devel opment and re-induction of axon growth for regeneration are correlated with large and specific changes in synthesis of a few proteins transported into the growing axons. This suggests the hypothesis that
1,154 citations
TL;DR: A three-neuron network capable of generating the respiratory rhythm of this air-breathing mollusk has been reconstructed in culture and enables a better understanding of the neural basis of rhythm generation.
Abstract: 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.
407 citations
230 citations
TL;DR: Under these conditions, the two primary neuronal phenotypes, electrical excitability and complex neuronal architecture, could be affected independently in adult molluscan neurons cultured in vitro.
Abstract: Isolated neurons from adult central ganglia of the snail Helisoma were cultured in vitro in modified Liebowitz L-15 medium. Such neurons displayed electrical excitability comparable to that in acutely dissected ganglia. Isolated neurons remained spherical in defined medium throughout culture durations up to 2 weeks. This static morphology was contrasted by the significant neuritic outgrowth which occurred from neurons maintained in medium with co-cultured intact Helisoma brains or in brain conditioned medium. A morphological sequence of growth cone formation and neurite extension occurred only in the presence of a conditioning factor(s) with a mode of action which included tight binding of the conditioning factor to the substratum. Under these conditions, the two primary neuronal phenotypes, electrical excitability and complex neuronal architecture, could be affected independently in adult molluscan neurons cultured in vitro.
207 citations
TL;DR: Animal and human experiments demonstrate that the uptake, tissue distribution, and excretion of amalgam Hg is significant, and that dental amalgam is the major contributing source to Hg body burden in humans.
Abstract: For more than 160 years dentistry has used silver amalgam, which contains approximately 50% Hg metal, as the preferred tooth filling material. During the past decade medical research has demonstrated that this Hg is continuously released as vapor into mouth air; then it is inhaled, absorbed into body tissues, oxidized to ionic Hg, and finally covalently bound to cell proteins. Animal and human experiments demonstrate that the uptake, tissue distribution, and excretion of amalgam Hg is significant, and that dental amalgam is the major contributing source to Hg body burden in humans. Current research on the pathophysiological effects of amalgam Hg has focused upon the immune system, renal system, oral and intestinal bacteria, reproductive system, and the central nervous system. Research evidence does not support the notion of amalgam safety.
178 citations