Environmental Neurotoxicology (1992) / Chapter Skim
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2. Biologic Basis of Neurotoxicity
2. Biologic Basis of Neurotoxicity
Pages 21-42
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From page 21... ...
The ultimate goal of neuroscience is to understand how this system functions normally and how subtle perturbations can lead to disease and dysfunction. Observation of the response of experimentally exposed animals or inadvertently exposed humans to neurotoxic chemicals advances our under21 standing of neurobiology while generating information about the consequences of exposure to environmental pollutants.
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From page 22... ...
The arrangement is analogous to the branching of a tree, which increases its reception of sunlight by increasing its total leaf surface area. In most neurons, the axon is a thin, particularly elongated cellular process emanating from the neuronal some and is specialized for the conduction of none signals away from the cell body and toward its synapse with other cells (other neurons, muscle cells, or gland cells)
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From page 23... ...
BIOLOGIC BASIS A) 23 fastbacks ~ Synaptic density / Synaptic vesicles / crotubu us Synaptic c eft ~ / Mitochonoric \: \ ~ M',ochondric \ ~ ~ /~1 ,.
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From page 24... ...
Several types of ion channels are known, but the most common are sodium and potassium channels, which are tiny pores that allow sodium and potassium ions, respectively, to pass through. The action potential is propagated regeneratively along the nerve fiber without loss of amplitude.
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From page 25... ...
Soon the sodium channels start closing and the potassium channels start opening at a high frequency; this brings the membrane potential back to the resting level. During the action potential, sodium ions enter the cell through open sodium channels and potassium ions leave the cell through open potassium channels; the result is a slight imbalance of the internal sodium and potassium concentrations, which is corrected quickly by a metabolic pump that extrudes extra sodium and absorbs potassium.
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From page 26... ...
A, action potential shown approaching axon terminal containing transmitter stored in synaptic boutons.
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From page 27... ...
GENERAL ASPECTS OF NERVOUS SYSTEM STRUCTURE AND FUNCTION The nervous system has two parts: the central nervous system (CNS) and the peripheral nervous system (PNS)
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From page 28... ...
Most nuclei in the nervous system, particularly in the CNS, have relatively intact barriers and thus are protected from some classes of chemicals. Although those barriers exclude many chemicals from the brain, some neurotoxic chemicals can gain access to the CNS via normal uptake mechanisms, if they are structurally similar to endogenous substances normally taken into the brain.
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From page 29... ...
That phenomenon occurs extensively during development: excess neurons and synaptic connections are established, many of which apparently disappear during the modeling of the mature nervous system. The converse also happens: synaptic connections used repeatedly become fixed, and transmission at these locations is facilitated through long-lasting changes in how ion channels or receptors are linlced to second messenger systems.
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From page 30... ...
But the different vulnerabilities of various cells to injury by a given toxicant and the normal roles of susceptible cells determine the biologic markers of effect or clinical manifestations of exposure to a particular neurotoxic chemical. For example, myelin degeneration after exposure to triethyltin or hexachlorophene is manifested as spasticity; effects on neurons in the hippocampus due to exposure to trimethyltin, triethyllead, or methylmercury are associated with learning and memory deficits; degeneration of dopa
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From page 31... ...
Several factors render the nervous system especially vulnerable to chemical assault; they are described briefly in the next few pages. Complexity of Structural and Functional Integration The proper functioning of the nervous system depends critically on complex interactions among different cell types in many anatomic locations that communicate via a variety of electric and chemical signals.
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From page 32... ...
Neurons are unique among cells, in that the cell body not only must maintain the functions normally associated with its own metabolic support, but also must provide support to dendrites ENVIRONMENTAL NEUROTOXICOLOGY and axons, often over relatively vast distances. The axon and synaptic boutons have little ability to synthesize the materials needed to sustain their structure and function, so they depend on delivery of the materials from their parent-cell body (Hammerschlag and Brady, 1989~.
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From page 33... ...
During the rising phase of the and with muscle and gland cells via a large action potential, sodium ions enter the neu number of chemical messengers that interact rons through open sodium channels. During in precisely defined ways with specialized the falling phase, potassium ions leave neu receptor molecules.
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From page 34... ...
Despite differences in the symptoms, both types of pyrethroids have the same major target site: the sodium channel of nerve membrane, i.e., the channel directly responsible for ~enerating action potentials. Pyrethroids cause essentially similar signs PYRETHROIDS TYPE I o Allethrin TYPE 11 O CN '~l,0~o Cl Fenvalerate o ,0, C,N Tetramethrin O ^0~ Phenothrin Brooms Deltamethrin O CN ~0~0~ Cyphenothrin (S 2703 )
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From page 35... ...
Membrane depolarization produces several changes in nervous function: depolarization in sensory neurons sends massive discharges to the central nervous system, causing hypersensitivity to external stimuli and paresthesia or a tingling sensation in the facial skin; depolarization of presynaptic terminals increases transmitter release, thereby disturbing synaptic transmission; and depolarization beyond some magnitude blocks nerve conduction and results in paralysis. In addition to the modified electric behavior of the sodium channels, all the more readily detected changes are biologic markers of exposure to pyrethroids.
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From page 36... ...
classified the neuropathy as a central-peripheral distal axonopathy and observed that myelinated axons were more vulnerable than nonmyelinated axons. Swelling and distal degeneration were most prominent in myelinated axons of the largest diameter.
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From page 37... ...
A number of studies have tested the hypothesis that pyrrole formation is the initial step in the sequence that leads to neurons cent accumulation. Anthony et al.
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From page 38... ...
Conversely, if pyrrole autoxidation and neurofilament cross-linking are required, AcHD would not result in neurotoxicity. When rats were given AcHD, massive pyrrole formation occurred, but neither clinical neurotoxicity nor neurofilament accumulation was observed; the results point strongly to the role of neurofilament crosslinking in the pathogenesis of n-hexane neurotoxicity.
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From page 39... ...
Whether the mechanism of MPP+ cytotoxicity is related to oxidation-reduction cycling, interference with mitochondrial energy production, or some other process, the end result is cell death, particularly death of the dopaminergic neurons of the substantia nigra (Langston and Irwin, 1986~. The marked depletion of dopamine seen in the brain of MPTP-treated it, (NJ CH3 MPTP MAN_ ~ / ~ / ~~ 1 CH 3 MPP~ / 1 CH3 MPDP.
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From page 40... ...
eventually develop parkinsonism, it will open up the possibility that some patients who develop progressive degenerative CNS disease later in life (such as Parkinson's disease, Alzhe~mer's disease, and amyotrophic lateral sclerosis) might have suffered neuronal injury from a toxicant years earlier.
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From page 41... ...
This information is developed further in Chapter 4 to assess available in viva and in vitro testing methods and address the need for efficient means for identifying neurotoxic substances.
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