Neurotoxicity

Neurotoxicity refers to the direct or indirect effect of chemicals that disrupt the nervous system of humans or animals. Numerous chemicals can produce neurotoxic diseases in humans, and many more are used as experimental tools to disturb or damage the nervous system of animals. Some act directly on neural cells, others interfere with metabolic processes on which the nervous system is especially dependent. Some disrupt neural function, others induce maldevelopment or damage to the adult nervous system. Perturbations may appear and disappear rapidly, evolve slowly over days or weeks and regress over months or years, or cause permanent deficits. Neurotoxicity is usually self-limiting after exposure ceases and rarely progressive in the absence of continued exposure, although there may be a significant delay between exposure and manifestation of neurotoxic effects.

s0010 Introduction p0010 Neurotoxicity refers to the direct or indirect effect of chemicals that disrupt the nervous system of humans or animals. Numerous chemicals can produce neurotoxic disease in humans, and many more are used as experimental tools to disturb or damage the nervous system of animals. Some act directly on neural cells, others interfere with metabolic processes on which the nervous system is especially dependent. Some disrupt neural function; others induce maldevelopment or damage to the adult nervous system. Perturbations may appear and disappear rapidly, evolve slowly over days or weeks and regress over months or years, or cause permanent deficits. Neurotoxicity is usually self-limiting after exposure ceases and rarely progressive in the absence of continued exposure, although there may be a significant delay between exposure and manifestation of neurotoxic effects.
s0015 Occurrence p0015 Chemicals with the potential to disrupt the mammalian nervous system may occur naturally (neurotoxins) or arise by synthesis (neurotoxicants). While chemicals with neurotoxic potential are conveniently termed 'neurotoxins' or 'neurotoxicants,' this is not an intrinsic property but rather the description of an effect that may occur if the tissue concentration exceeds a certain threshold. Biological chemicals with neurotoxic properties often have high target specificity and toxic potency, discrete biological actions, and are among the best understood mechanistically. Examples of chemicals with direct or indirect neurotoxic potential are found in bacteria, algae, fungi, plants, coelenterates, insects, arachnids, molluscs, amphibians, reptiles, fish, and certain mammals ( Table 1). p0020 Other less potent naturally occurring substances exhibit neurotoxic effects when encountered in large concentration for sufficient periods of time. Examples include metals (arsenic, lead, mercury) and certain compounds containing these elements (methylmercury) ( Table 2). Some elements (manganese, selenium) and compounds (vitamin B6) in this group, while neurotoxic in sustained heavy doses, are required in smaller amounts to support normal physiological function, including that of the nervous system. Natural substances (thiaminase) that interfere with required substances (thiamine) are also associated with neurological disease in animals and humans. p0025 Synthetic chemicals with neurotoxic potential ( Table 2) are most commonly encountered in the form of prescription (ethambutol, isoniazid, vincristine) and over-the-counter pharmaceutical agents (bismuth preparations), domestic products used in antidandruff shampoos (pyridinethione), fragrance raw materials (2,6-dinitro-3-methoxy-4-tert-butyltoluene), pyrolysis products in broiled, baked, or fried food (acrylamide), beverages (ethanol), workplace chemicals (n-hexane), pest-control agents (aldrin), environmental pollutants (mercury), and substances (methamphetamine) used to induce euphoria. Others are associated with special applications, such as chemical warfare in military and civilian settings (sarin). Direct-acting substances with neurotoxic potential are supplemented by other agents that initiate neurological change as a consequence of effects on another organ system on which the brain depends for normal function. Substances that target the liver, kidneys, or lungs fall into this category, as do agents that interfere with the continuous supply of oxygen (cyanide, azide) and glucose (6-chloro-6-deoxyglucose) required by the nervous system for normal function. Chronic liver failure and manganese intoxication are both associated with high signal abnormalities in the basal ganglia on T1-weighted magnetic resonance images, suggesting that the metal accumulates because it cannot be cleared normally by the liver. s0020 Neurotoxic Effects p0035 The nervous system has a vast repertoire of functional reactions to chemical perturbation, and these responses give rise in the aggregate to a plethora of neurological and psychiatric phenomena, many of which recapitulate the clinical manifestations of disease of nontoxic origins. Large single doses of certain substances, such as organic solvents (ethanol, toluene) that intoxicate, induce functional changes in the organism that appear and disappear rapidly. Other agents, such as the anticholinesterase nerve agents, induce a subset of functional changes (e.g., parasympathomimetic effects) that reverse when the inhibited target protein (acetylcholinesterase) is reactivated or replaced. Sometimes, as in the case of methanol, the latent period (hours) between exposure and effect is associated with the production and action of a toxic metabolite (formate). Single exposures to large amounts of other substances (arsenic, t0010 Table 1 Naturally occurring substances with mammalian neurotoxic potential mercury, thallium) may be followed by a latent period of days or weeks before structural and functional changes become evident. While certain substances (acrylamide) can induce neurological damage after single large exposures, smaller doses over a long period of time are also effective, but the pattern of neurological deficit may be distinct in the two dosing scenarios. Neurotoxic disorders typically progress during the period of exposure and immediately following exposure, when the pathological events already in progress may take time to unfold before stabilization or recovery can begin. Prospects for functional recovery depend on the presence or absence of tissue damage, the extent of damage, and whether neuropathological changes have occurred in the central nervous system (CNS) (poor prognosis).

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An unanswered question is whether in some instances disease may progress or recur after chemical exposure has ceased. Certainly, catastrophic and fatal neurodegeneration after a delay period may follow acute carbon monoxide poisoning, but this is an isolated example. Relapses occur in ciguatoxicity presumably because the offending agent is released from fat stores under certain physiological conditions. Progressive visual defects may occur from release of chloroquine, which has been sequestered in the choroid layer of the eye. There is also concern that certain substances (carbon disulfide, organochlorine pesticides) might predispose or accelerate the onset of age-related diseases of the nervous system, such as Parkinson's disease. Finally, research is underway to determine whether certain DNA-damaging agents (methylazoxymethanol (MAM)) may predispose neurons to tardive degeneration because of their low capacity for DNA repair. Studies reported in 2011 suggest that genotoxins such as MAM have biphasic effects depending on the ability of the targeted cells to divide: cycling cells undergo proliferation as a result of mutation arising from DNA damage (O 6 -methylguanine (O 6 -mG)), while noncycling neurons respond through related signal transduction pathways with degeneration. There are many factors that determine the response of the nervous system to chemical exposure. Species, gender, genotype, age, nutritional status, body temperature, and activity are key determinants, as are chemical access, structure, and biotransformation. The time of day has been found to affect the degree of ataxia induced in mice treated with sodium nitroprusside. Metabolic activity of the brain may serve to activate a neurotoxic substance, as in the conversion of methylphenyltetrahydropyridine (MPTP) to the mitochondrial toxin N-methyl-4-phenylpyridinium ion (MPP þ ), which targets substantia nigra neurons and precipitates parkinsonism in humans and other mammals. b-N-Methylamino-L-alanine (L-BMAA) is metabolized t0015 Table 2 Heavy metals and synthetic substances with neurotoxic potential to formaldehyde in rodent brain tissue, thereby transforming an excitant amino acid to a potential genotoxin. Hepatic biotransformation is broadly concerned with the conversion of lipophilic chemicals to less toxic hydrophilic metabolites (Phase I) and their conjugation (Phase II) prior to excretion. Occasionally, Phase I metabolism may increase the neurotoxic potential of an exogenous substance, as in the case of the stepwise conversion of n-hexane to 2,5-hexanedione, a solvent that targets neuroproteins and causes nerve fiber degeneration in the CNS and peripheral nervous system (PNS). Co-exposure to substances such as methyl ethyl ketone or toluene may impact Phase I enzyme function and thereby markedly modify (increase or decrease, respectively) the quantitative neurotoxic response to n-hexane.

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Most mammalian species reproduce the qualitative response of the human nervous system to chemical perturbation, but the sensitivity may differ markedly among species. For example, relative to humans, primates, and cats, rodents are relatively refractory to organophosphate-induced neuropathy. Gender is a factor in risk for tardive dyskinesia (stereotypic behaviors, dystonia, myoclonus, and tics) associated with the dopamine receptor-blocking properties of neuroleptic drugs. Gender as a determinant of biotransformation may be less important in humans than in rats, where marked differences in the metabolism and consequent functional responses to individual chemicals such as parathion may be noted. 3,4-Methylenedioxymethamphetamine (MDMA) may depress serotonin more in female than male rats. Differences in genotype may determine the presence of neurotoxic responses, as in the rare mitochondrial polymorphism that results in hypersensitivity to aminoglycoside-induced deafness. Age in humans is generally associated with increased susceptibility to many chemical substances largely because of reductions in biotransformation, renal clearance, and biliary excretion, as well as factors such as reduced body weight, inanition, and polypharmacy that promotes drug and chemical interactions. In addition, neurons display age-related increases of DNA damage, regional nerve cell loss (e.g., substantia nigra), and axonal pathology (e.g., spinal roots). Nutritional status may predispose to human neurotoxicity as seen in minimally nourished Africans who develop spastic paraparesis from a combination of sulfur amino acid deficiency and exposure to cyanogenic substances, both of which arise from dietary dependence on the root crop cassava (Manihot esculenta). Substances that interfere with vitamin production or utilization, including thiamine (pyrithiamine), riboflavin (quinacrine), niacin (3-acetylpyridine, 6-aminonicotinamide), or cyanocobalamin (nitrous oxide), produce various types of severe neurological deficit, as does excessive exposure to vitamin A. Other types of neurodegeneration are seen with substances that chelate physiologically important metals ions (pyridinethione, 8-hydroxyquinolines, ethambutol), such as zinc. Excessive dietary intake of sulfur and selenium produces neuronal lesions in ruminants and pigs, respectively. Body temperature is an important determinant of the neurotoxic response of rodents, primates, and possibly humans to the psychostimulant methamphetamine: hyperthermia exacerbates and hypothermia attenuates methamphetamine-induced dopamine neurotoxicity. Finally, excessive physical activity has been associated with the acute onset of central motor weakness in cassavism and lathyrism, the latter associated with dietary dependency on grasspea (Lathyrus sativus), a legume that contains the excitant amino acid b-N-oxalylamino-L-alanine (L-BOAA).

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The structure of chemicals and their differential access to the nervous system are of cardinal importance in determining the presence and nature of the neurotoxic response. While access to nervous tissue dictates the possibility of a direct neurotoxic effect, neurotoxicity ultimately depends on the ability of the substance to bind to neural tissue targets and interfere with functional or structural integrity. Structure-activity relationships are therefore of critical importance. For example, 1,2-diacetylbenzene but not 1,3-diacetylbenzene induces leg weakness in rodents because only the former binds to and cross-links neuroproteins, interferes with anterograde transport of neurofilaments, and causes giant proximal axonal swellings that disrupt nerve conduction. Triethyltin targets the myelin sheath and trimethyltin damages neurons, but tributyltin lacks neurotoxic propertiesanother illustration of the critical importance of chemical structure in determining the presence and nature of the neurotoxic response. Even stereological properties of molecules can dictate the presence or absence of neurotoxic properties: L-BOAA (but not D-BOAA) is a potent agonist of neuronal DL-a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Only levo-naloxone displays opioid receptor antagonistic activity, and studies published in 2011 indicate enantioselective neurotoxicity of chiral polychlorinated biphenyls (PCBs).

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The large majority of the nervous system is protected from direct exposure to chemicals in the bloodstream and the cerebrospinal fluid (CSF) by blood-brain/nerve/CSF regulatory interfaces. These cell-based molecular separate the microenvironment of the brain parenchyma from changes in circulating ion and metabolite concentrations. Regulation of blood-brain/nerve interchange is a key function of capillaries coursing through nervous tissue. Structural specializations of capillary walls in the form of tight junctions between adjacent endothelial cells constitute a diffusion barrier. This allows the endothelium to regulate the selective transport and metabolism of substances from blood to brain and vice versa. While gases (oxygen, carbon monoxide, nitrous oxide) cross capillary walls with ease, many substances are excluded or their access to nervous tissue impeded by the presence of the capillary barrier. Lipophilicity and size are key elements in regulating the passage of macromolecules across the blood-brain barrier. Key nutrients and macromolecules required by the brain cross via facilitated diffusion or specific carriers. The epithelial junctions that constitute the blood-CSF barrier at the choroid plexus are somewhat more permeable and allow greater passage of drugs and toxicants into the interstitial fluid that bathes brain tissue. Many metals are required for normal CNS function and are thus transported across the bloodbrain and blood-CSF barriers. However, excess metal may accumulate in their endothelial cells and give rise to toxic damage of the cellular barrier. Several metals are known to accumulate in both barriers, including substances with neurotoxic potential such as lead, mercury, arsenic, and manganese. Lead accumulates in the choroid plexus and alters key functions, including transthyretin, the binding protein for thyroid hormone. High concentrations of lead damage the blood-brain barrier cause vascular leakage and may result in brain swelling accompanied by herniation, ventricular compression, and petechial hemorrhages.

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p0070 Some regions of the brain (e.g., hypothalamus) and PNS (spinal and autonomic ganglia) lack capillary barriers and are thus directly exposed to chemicals circulating in the bloodstream. Damage to the hypothalamus can have far reaching effects on somatic metabolism, reproductive function, and growth. The adult obesity of rats treated postnatally with monosodium glutamate (MSG) exemplifies the effect and raises important questions for human health in regard to past exposure to glutamate-rich foods during postnatal development. In the PNS, the selective loss of sensory neurons in rats treated with doxorubicin arises because spinal ganglia lack a protective capillary-nerve barrier. Certain other substances (tetanus toxin) reach nerve cell bodies directly via distal axonal entry and retrograde axonal transport. Tetanus toxin is transported to the spinal anterior horn cell, subsequently translocates and binds to inhibitory presynaptic inhibitory (glycinergic) nerve terminals impinging on the motor nerve cell, and thereby suppresses the inhibition of motor neuron activity leading to hyperexcitation. Violent and sustained muscle contraction (tetany) in response to external stimulation results. Another example of peripheral entry to the CNS is the transport and delivery of metals (manganese, aluminum) from the nose along olfactory neurons to the brain of laboratory animals. The mammalian nervous system has functional design features that predispose it to chemical perturbation. Consequently, neurological dysfunction is among the most common of the toxic responses of humans to chemical substances. Some neurotoxic agents perturb energy generation by interfering with glycolysis (arsenic), while others (3-nitroprionic acid, cyanide, rotenone) disrupt sites in the electron transport chain. Some agents (metronidazole, misonidazole) damage brain regions such as the brainstem nuclei that seem to have a high requirement for glucose.

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Architectural design is another important determinant of vulnerability both at the cellular and organ level. Unlike most organs (liver, kidney, testes), the nervous system is regionally organized; motor function, memory, vision, audition, and olfaction require the function and interaction of different brain regions. Whereas small lesions of the liver and kidney have little functional impact, a chemical that damages the hippocampus (domoic acid), visual cortex (methylmercury), or the peripheral vestibular and auditory system (streptomycin) may have devastating effects on function of the organism. Moreover, whereas tissue repair follows damage to many organs, the CNS recovers from injury poorly. Some recovery may be afforded by neurogenesis and/or reorganization of synaptic connections on surviving nerve cells, but regrowth and reconnection of damaged axons are impeded by postinjury proliferation of astrocytes.
p0090 Cellular architecture is yet another important factor in determining vulnerability to chemical attack. Unlike most types of mammalian cells, mature neurons and myelinating cells in the CNS (oligodendrocytes) and PNS (Schwann cells) possess elongated cellular processes that expose vast surface areas of membrane to chemicals present in extracellular fluid ( Figure 1). Additionally, each of these cells has a segregated anabolic region (cell body) that is responsible for supplying the metabolic needs of proportionately huge volumes of cytoplasm (axons, dendrites, myelin). The unusual architecture of these cells demands the presence of a distribution system that efficiently transports materials from sites of production to sites of utilization. Within neurons, chemicals that disrupt axonal transport (taxol, vincristine) are known to induce axonal degeneration with consequent effects on sensory and motor function. The special vulnerability of the longest and largediameter axons leads clinically to sensory dysfunction and motor weakness in a stocking-and-glove distribution.  Neural cells are highly interconnected and dependent upon each other's presence and physiological activity for normal function. Thus, chemicals that disrupt Schwann cells (diphtheria toxin) or myelin (hexachlorophene) secondarily disturb nerve conduction along the axonal processes of neurons with which they are physically associated. Other agents interfere directly with electrical transmission (pyrethroids) or the orderly conveyance of signals via synapses (certain organophosphates) that connect nerve cells to each other. Similarly, agents (nitrofurantoin) that cause peripheral axons to degenerate thereby sever neuronal connections with muscle cells and cause muscle weakness. p0100 Given the nervous system has built-in redundancy, the loss of neurons or axons must exceed a certain threshold for clinical effects to become apparent. That redundancy of nerve cells may be substantially reduced with the advance of age, such that regional loss of CNS striatal dopaminergic neurons is thought to be a factor in dictating susceptibility to agents (carbon disulfide) that can trigger parkinsonism. Similarly, age-related spinal nerve root demyelination and distal axonal degeneration of long and large-diameter axons may predispose elderly individuals to substances that cause peripheral neuropathy (vide infra).
s0030 Vulnerability of Neurons and Their Processes p0105 Nerve cells are vulnerable to chemical attack at many loci, including protein synthesis, mitochondrial, and nucleic acid function. Somal DNA is predisposed to damage by reactive oxygen species because of the high oxygen consumption and metabolic activity of neurons. The cycad genotoxin MAM, an agent that alkylates DNA with formation of O 6 -mG and other adducts, interferes with neuronal development and has been implicated in a long-latency progressive neurodegenerative disease (O 6 ). Adult neurons have very low levels of the specific DNA repair enzyme, O 6 -methylguanine methyltransferase, such that long-term neuronal effects might occur as a consequence of unrepaired DNA damage. Mitochondrial DNA chain growth is blocked by certain anti-HIV drugs (2',3'-dideoxyinosine, 2',3'-dideoxycytidine) that cause painful axonal neuropathy. Interference with neuronal protein synthesis occurs with agents (ricin) that disrupt polypeptide elongation and trigger axonal degeneration. Chemicals that alter the mitochondrial electron transport chain (cyanide, rotenone) have a propensity to induce basal ganglia damage. Substances (bromothelin, pentachlorophenol) that uncouple electron transport and oxidative phosphorylation elevate temperature and induce tremor and hyperexcitability. Several neuronal enzymes are key sites of chemical attack, including synaptic acetylcholinesterase (organophosphates, carbamates) and neuropathy target esterase (a subset of organophosphates), with resulting neuroexcitation and axonal degeneration, respectively. Lead interferes with oxidative phosphorylation by potently activating protein kinase C. The excitable membrane of neurons is the target of a rich array of neurotoxins that interfere with ion channels required for the proper functioning of neurons, axons, muscle, and glial cells. These agents are often complex structures generated by invertebrate species and plants presumably for purposes of chemical defense. Sodium ion channels are common targets.
Agents that bind to the outer surface of the Na þ channel and prevent ion influx are found in dinoflagellates (saxitoxin), vertebrates, including fish, octopus and salamander (tetrodotoxin), and cone snails (geographutoxin). Lipid-soluble anesthetics (lidocaine, procaine) bind to a hydrophobic site in the channel and interfere with the gating mechanism. Activation of Na þ channels by opening or impeding normal closure is seen with certain plant chemicals (grayanotoxin; pyrethrin), dinoflagellate chemicals (ciguatoxin) stored in fish, amphibian skin toxins (batrachotoxin), scorpion a-toxins, and synthetic pesticides (pyrethroids). Interference with Na þ channel function is usually heralded by abnormal sensation (paresthesias) in the tongue, around the mouth and in the extremities. While usually transient, ciguatoxin is a fat-soluble agent that may cause repeated neurotoxic events after single exposures presumably because of tissue sequestration and periodic release within the affected subject. K þ -channel toxins with selective blocking actions have been identified in the venom of certain scorpions, bees, and snakes. Thallium and bromine ions are transported by K þ and Cl À channels, respectively, with significant neurological and psychiatric consequences for the affected subject. Calcium channel blockers are produced by certain plants, insects, spiders, snails, and snakes. Divalent lead ions interfere with intracellular processes regulated by Ca 2þ ions and accumulate in the same intramitochondrial compartment as calcium. Alternative pre-RNA splicing in the gene (Ca(V)2.2) that codes for N-type Ca 2þ channels in nociceptors modulates opioid channel inhibition and spinal analgesia. Numerous substances target mechanisms involved in neurotransmitter (NT) synthesis, transport, synaptic release, reuptake, the interaction between NT and postsynaptic receptor, or the removal of NT from the synaptic gap. Neurotoxicity occurs when the agent reduces or increases NT release, alters NT concentration or resident time, or acts as an agonist or antagonist at a postsynaptic NT receptor. p0120 Acetylcholine synapses at neuromuscular junctions are targets for a number of biologic and synthetic substances ( Figure 2). Neurotransmission is disrupted by agents that interfere with choline transport (hemicholinium, choline), with acetylcholine synthesis (triethylcholine), or synaptic vesicle uptake (vesamicol). Other agents (b-bungarotoxin, crotoxin) target mechanisms involved in presynaptic NT release. Botulism arises from the action of a zinc-endopeptidase (the light chain of the botulinum toxin dipeptide) in blocking synaptic transmission by cleaving synaptic-vesicle fusion proteins required for NT exocytosis. Botulinum-induced blockade of normal depolarization-induced NT release at the neuromuscular junction leads to flaccid muscle weakness. Conversely, a-latrotoxin in venom of the black widow spider causes massive NT release at vertebrate neuromuscular junctions resulting in a painful disorder featured by dysarthria, tremor, clonic muscle contraction, and paralysis. Numerous chemicals interfere with acetylcholinesterase, the enzyme that terminates NT action at the neuromuscular junction. Certain anticholinesterases (edrophonium) bind directly to the active center of the enzyme and act rather briefly; others (physostigmine) carbamylate the enzyme and have longer lasting actions. The large class of organophosphates, which Neurotoxicity 5

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include high-potency agents used in chemical warfare and less hazardous materials employed as agricultural pesticides, interact with the anionic and/or esteratic sites in the active center of acetylcholinesterase to form complexes; the stability of the phosphorylated enzyme is further enhanced by the loss of one of the alkyl groups, a phenomenon known as (chemical) aging. Biological anticholinesterases include the product of a cyanobacterium (anatoxin-a(s)) and certain snake toxins (fasciculins).

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Acetylcholine receptors provide another target for chemicals with neurotoxic potential; most of these act as antagonists. D-Tubocurarine is the classical nicotinic receptor antagonist, and curare-like substances are found in elapid and hydrophid snakes (a-neurotoxins), such as cobra (a-cobratoxin) and krait (a-bungarotoxin), molluscs (a-conotoxin), corals (lophotoxin), and certain plants, such as the delphinium (methyllcaconitine). Anatoxin-a is a potent agonist at neuromuscular, autonomic, and brain nicotinic receptors. Muscarinic receptor antagonists include atropine, scopolamine, and the synthetic warfare agent quinuclidinyl benzilate, which induces dryness of the mouth, blurred vision, confusion, delirium, and coma.

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Glutamate receptors, which mediate most excitatory synaptic traffic in the CNS, are another important target of chemical substances linked to human disease. Fast synaptic transmission is mediated by AMPA-type glutamate receptors, a target of L-BOAA that causes pyramidal tract degeneration and spastic paraparesis (lathyrism). Seaweed (kainic acid) and dinoflagellate (domoic acid) toxins act as agonists at the kainate subclass of glutamate receptors, the latter causing significant CNS neuronal excitotoxicity and CNS degeneration in humans. Glutamate receptors that respond to N-methyl-D-aspartate (NMDA) have numerous antagonists, including the anesthetic agent ketamine and phencylidine (angel dust). Termination of excitatory neurotransmission by removal of synaptic glutamate is perturbed by dithiocarbamate pesticides. Ionotropic glutamate receptors also play an important role in mediating neuronal death secondary to energy deficits induced by hypoxia. p0135 g-Aminobutyric acid (GABA), which is synthesized from glutamic acid decarboxylase (GAD), is the major inhibitory NT in the mammalian brain. GAD inhibition (2-amino-4-pentenoic acid) induces convulsions. Numerous compounds bind to and act as antagonists (picrotoxin) or agonists (muscimol) at GABA A receptors, which employ chloride (Cl À ) channels to mediate fast inhibitory postsynaptic potentials. Enhanced GABAergic transmission occurs under the action of benzodiazepine and barbiturate drugs, while organochlorine insecticides (lindane, aldrin) exert convulsant effects mediated through picrotoxinbinding sites.  Glycine receptors, which mediate inhibitory neurotransmission in the brainstem and spinal cord, have a number of plantderived antagonists (strychnine, hydrastine) that elicit hyperreflexia and tetanic muscle contraction among other signs. Tetanus toxin from Clostridium tetanii triggers generalized muscle rigidity by binding to glycinergic nerve terminals (and inhibiting glycine NT release) after crossing from anterior horn cells that retrogradely transport the agent from a peripheral wound site.
p0145 Several other NT systems and pathways are impacted by chemicals that exhibit neurotoxicity. Dopamine mediates communication in a number of important pathways, including the nigrostriatal tract (a key component of basal ganglia mechanisms for control of the quality of motor movement) that degenerates in Parkinson disease and MPP þ -induced toxicity. Extrapyramidal movement disorders occur as a side effect of a number of therapeutic drugs acting on dopaminergic pathways. Chemicals that perturb adrenergic function may interfere with NT synthesis (a-methyltyrosine), serve as false NTs (methyl-dopa), block vesicular uptake (reserpine), inhibit the cleavage enzyme catechol-O-methyltransferase (pyrogallol), or promote NT release (amphetamine). Substituted amphetamines (MDMA) damage axons derived from the dorsal raphe serotonergic projection system of rodents and primates. Natural substances in plants interfere with substance P neurotransmission (capsaicin), cannabinoid receptors (cannabis), purinoceptors, and adenosine receptors (caffeine). Caffeine intoxication is characterized by anxiety, sleep disturbance, and mood changes, while caffeine withdrawal in sensitive subjects leads to vascular headache, drowsiness, and fatigue.
s0040 Axonal Transport p0150 Disruption of the transport of materials along axons is another method by which chemicals perturb neural function and induce changes, including focal axonal pathology and axonal degeneration (axonopathy). Some agents interfere with the anterograde transport of materials from sites of synthesis (cell body) to sites of utilization (axon and terminal) (b-b'-iminodipropionitrile, 1,2diacetylbenzene), some with retrograde axon transport (acrylamide), and others with the return of materials from nerve terminals (zinc pyridinethione). Certain plant-derived chemicals (colchicine, vinca alkaloids) bind to tubulin, inhibit microtubulebased function, and thereby block bidirectional axonal transport. Taxol, originally isolated from the Pacific yew tree, interferes with axonal transport by promoting microtubule assembly and stabilization. Retrograde axonal transport may also serve to ferry foreign substances (ricin, tetanospasmin, certain metals) to targets in neuronal somata.
s0045 Neuroglia and Myelin p0155 Neuroglia include (1) ependymal cells lining the ventricles of the brain and the central canal of the spinal cord; (2) cells of the PNS (Schwann cell) and CNS (oligodendrocyte) that wrap around axons to form compacted plasma membranes (myelin) that provide electrical insulation to speed nerve conduction; (3) cells (astrocytes) that interface between nerve cells and capillaries in the CNS, regulate interstitial water content, K þ concentration, remove and metabolize certain NT molecules, and proliferate following injury; and (4) microglia, which are phagocytic cells that function as endogenous immune cells in the brain.

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Ependymal cells are susceptible to agents (amosconate) present in CSF. Astrocyte foot processes investing cerebral capillaries undergo marked swelling in water intoxication, lead encephalopathy and in hypercapnia, and after the experimental administration of 6-aminonicotinamide, isoniazid, misonidazole, or ouabain. Astrocytes increase their glycogen content in a variety of insults (methionine sulfoxamine), form intranuclear inclusion bodies in lead intoxication, and greatly increase the relative size of the nuclear compartment in hepatic encephalopathy, which is thought to be triggered by hyperammonemia. The food-associated mycotoxin ochratoxin A inhibits glutamate uptake by astrocytes, which has been proposed to increase extracellular glutamate, excitotoxicity, and neuronal loss. Myelinating cells are susceptible to substances that disrupt the synthesis of myelin components, the best example of which is diphtheria toxin, which has access to peripheral nerves where it inhibits Schwann cell protein synthesis and causes primary demyelination. Oligodendrocyte demyelination can be induced experimentally by diphtheria toxin and by other protein synthesis inhibitors, such as ethidium bromide and actinomycin D. The latter induces widespread status spongiosus of white matter, with edema fluid in the periaxonal space and between myelin membranes split open at the intraperiod line. Cuprizone (biscyclohexanone oxalylhydrazone) induces oligodendrocyte degeneration with intramyelinic edema. Several other agents (cycloleucine, hexachlorophene, triethyltin) trigger reversible changes in CNS and/ or PNS myelin without apparent damage or loss of the myelinforming cells. The dominant host factor influencing response of the nervous system to exogenous chemicals is developmental age. The intrinsic neural factors that determine or influence response to chemicals differ in development, at maturity, and in late life. Thus, physiological differences between developing and adult organisms underlie potentially significant differences in distribution, metabolism, and excretion of neurotoxic agents. As a result, neurotoxic effects observed following developmental exposure differ both quantitatively and qualitatively from those seen following adult exposure. Quantitatively, the developing nervous system is generally more sensitive to neurotoxic agents. Studies of both humans and rodents indicate that intrauterine exposure to lead or to PCBs is more damaging to the nervous system than exposure later in life. Neurotoxic effects may also differ qualitatively as a function of developmental age. For example, infants of mothers treated with the anticonvulsant drug sodium valproate may display congenital malformations, including neural tube defects, whereas neurotoxicity in the adult is manifest as tremor, a confusional state and, in rare cases, parkinsonism. The influence of developmental age on the response to neurotoxic agents largely reflects the susceptibility of developmental processes occurring in the developing brain. Neurodevelopment is a complex process that is precisely regulated in time and space, with the basic framework of the nervous system Neurotoxicity 7

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laid down in a step-by-step process in which each step is dependent upon the proper completion of the previous one. In both humans and rodents, normal neurodevelopment begins very early in the fetus and is not complete until puberty. Active organogenesis, which occurs during the period from implantation through mid-gestation, requires the concomitant and coordinated ontogeny of cell proliferation, differentiation, and migration. During late gestation and the early neonatal period, the processes of synaptogenesis, apoptosis, and myelination are predominant. These processes continue throughout later stages of neurodevelopment, and together with elimination of extraneous synapses via axon and dendrite retraction function to refine patterns of neuronal connectivity. Experimental and clinical data suggest that errors in timing, spatial resolution, or magnitude of any of these developmental events can have functional consequences. For example, magnetic resonance imaging studies of patients with schizophrenia reveal excessive pruning of axons and dendrites in the cerebral cortex during late adolescence, coincident with the onset of symptoms. Importantly, substances have been identified that interfere with each of these processes in animal models and, in some instances, humans. The outcome of such interactions ranges from death to gross structural abnormalities to subtle defects in structure or function: early gestational exposure to substances such as fumonisins can produce neural tube defects; exposure to ionizing radiation produces altered brain morphology and mental retardation; exposure to high concentrations of ethanol causes mental retardation, while moderate levels of alcohol exposure can delay motor development; intrauterine exposure to cocaine causes excessive outgrowth of dendrites; and exposure of infants and children to relatively low levels of lead is linked to reduced scores on tests of cognitive development and to increased aggressive tendencies.

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A critical determinant of the pattern of damage induced by neurotoxic agents is the timing of exposure relative to ongoing ontogenetic events. For example, vitamin A and other retinoic acid derivatives cause marked and irreversible abnormalities, including anencephaly and spina bifida, when exposure occurs during gestation days 5-10 in rats. In contrast, administration of retinoic acid on gestational day 12 fails to perturb brain development. There are at least four scenarios to explain how timing of exposure influences neurotoxic outcome. First, later stages of neurodevelopment depend on successful completion of early stages; therefore, even relatively minor disturbances early in neurodevelopment may cause significantly more damage than perturbations occurring at later stages. For example, inhibition of cellular proliferation by agents, such as MAM, lead, mercury, or ethanol, can subsequently impact migration, differentiation, and ultimately neuronal connectivity. Second, individual neurodevelopmental events may be differentially vulnerable to specific substances. It has been clearly demonstrated that specific brain regions are vulnerable to antimitotic agents during the developmental period when cells in these region are actively proliferating. The DNAdamaging agent MAM disrupts regional mouse brain development in an O 6 -mG-dependent manner, with little change from normal in MAM-treated animals that overexpress the specific DNA-repair enzyme O 6 -mG methyltransferase. Third, since different brain regions develop on different time lines during prenatal and postnatal life, a chemical may produce impairment in different functional domains depending on the time of exposure. Changing the time at which neonatal rats are exposed to ethanol can trigger neuronal cell loss via apoptosis in different brain regions, thereby giving rise to different profiles of functional deficits. Fourth, the expression and/or function of target proteins can vary in the developing versus adult brain. The alpha subunit of the glycine receptor exists in several isoforms that are transcriptionally regulated during development. The adult isoforms of the alpha subunit have a higher affinity for strychnine than the neonatal isoforms; thus, the developing nervous system is less vulnerable to strychnine than the adult. Another important example includes NTs and enzymes that metabolize NTs, such as acetylcholinesterase. In the adult nervous system, these proteins function in neurotransmission; however, during development, NTs and acetylcholinesterase act as morphogenic factors that modulate patterns of neuronal connectivity. Therefore, substances that target NT systems (chlorpyrifos) may have quite different effects on the developing fetus or child compared to the adult, and this has been demonstrated in animal models.

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The potential for chemical exposure to the fetus begins before conception in that prior parental exposure to toxicants can have a major impact on the developing fetus. Parental exposures threaten fetal health by either altering maternal or paternal reproductive organs directly or via release of stored neurotoxic agents from maternal tissues during pregnancy. Yusho disease is a tragic example of preconception exposure to polychlorobiphenyl compounds (PCBs) influencing fetal neurodevelopment. Women in the Japanese town of Yusho who consumed cooking oil contaminated with PCBs up to a year prior to conception gave birth to infants exhibiting a constellation of symptoms including dysmorphism, skin lesions, hepatic dysfunction, and cognitive abnormalities. PCBs stored in maternal tissues were mobilized during pregnancy. Similarly, lead can be mobilized from storage depots in bone during pregnancy. Once in the maternal blood supply, chemicals may diffuse across the placenta and enter the fetal circulation. Some agents (organoarsenicals) accumulate in the placenta, which shields the offspring from exposure. However, the placenta does not block small molecular weight compounds (carbon monoxide), lipophilic compounds (PCBs, ethanol, methylmercury), or compounds using active transport mechanisms (lead). Once in the fetal circulation, the developing brain is protected by the same brain barrier mechanisms that protect the adult brain. Contrary to a long-standing belief, functional brain barrier mechanisms are in place after neural tube closure. The vulnerability of the developing brain may be enhanced, however, by inward transport mechanisms for nutrients such as amino acids, glucose, and trace metals, which are more active than in the adult brain and thus may facilitate the entry of neurotoxins such as mercury, lead, and manganese. The lower concentration of proteins in fetal and neonatal plasma may allow their binding capacity for drugs and toxicants (heavy metals) to be exceeded more easily than in the adult. In addition, the presence of transport mechanisms that are unique to the developing brain may similarly increase the vulnerability of the developing brain. Prior to keratinization of the human fetal epidermis, beginning at 20 weeks of gestation, exogenous chemicals may also diffuse from the amniotic fluid into the developing fetus. After birth, exposure to potential toxicants may occur via breastfeeding and consumption of other contaminated foodstuffs, oral contact via hand-tomouth activity, dermal contact, or inhalation. Compared with adults, children in all postnatal developmental stages have higher rates of respiration and energy consumption per kilogram of body weight, which increases their exposure rates. In addition, skin is highly permeable during the newborn period and several epidemics of developmental neurotoxicity have been described involving percutaneous absorption of chemicals. These include hypothyroidism from iodine in povidone iodine (Betadine) scrub solutions and myelin disorders consequent to bathing infants in hexachlorophene. The expression of Phase I and Phase II metabolic enzymes is also developmentally regulated, resulting in altered abilities of developing organisms to detoxify and excrete chemicals relative to adults. This difference may confer increased resistance when a substance must be metabolized to an active metabolite. But, more frequently, the metabolic differences manifest as a decreased capacity of children to excrete toxins as compared to adults, and thus they are more vulnerable to certain neurotoxic agents. The lack of functional paroxonase, the enzyme that detoxifies many organophosphates, contributes to the increased vulnerability of the developing nervous system to the neurotoxic effects of these agents. Many chemicals are recognized teratogens in animals; a significantly smaller subset of these is known or suspected to cause toxic effects in the developing human nervous system. Some of the more significant human developmental neurotoxicants include ethanol, which causes a constellation of effects ranging from fetal alcohol syndrome to alcohol-related neurodevelopmental disorder; maternal tobacco use (fetal tobacco syndrome); excess vitamins A and D; metals, particularly inorganic and organic mercury, lead, arsenic, magnesium, and cadmium; anticonvulsants, such as phenytoin, valproate, phenobarbital, carbamazepine, and primidone; drugs of abuse, including cocaine, cannabis, and mescaline; persistent aromatic hydrocarbons, especially PCBs; and both organochlorine and organophosphate pesticides.

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Detecting effects in the human population is difficult because they may be subtle (small shifts in IQ scores, slight changes in behavior) or because neurotoxicity does not become manifest until a significant period of time after the developmental exposure. Delayed neurotoxicity may arise via two different mechanisms. One of these involves a developmental insult in which anatomical and/or functional effects may be masked or attenuated initially because of compensatory mechanisms or plasticity. However, these developmental perturbations predispose the individual to neural deficits following subsequent insults, such as chemical exposure, disease, or aging because of decreased reserve capacity. This phenomenon has been demonstrated in animal models for organochlorine pesticides, and in both animal models and humans following developmental exposures to methyl mercury. The second mechanism involves the occurrence of a toxic insult early in neurodevelopment, but with manifestation of the pathological change much later in neurodevelopment when function of the affected cells is normally activated. An agent that causes this type of delayed neurotoxicity experimentally is the food additive monosodium glutamate (MSG). Developmental exposure to MSG causes excessive apoptosis of neurons via activation of NMDA glutamate receptors in the developing hypothalamus. However, the fetal loss of these hypothalamic neurons becomes evident (as hypogonadism and infertility) only in adolescence when the neuroendocrine function of these neurons is normally activated.

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The identification of the food additive MSG as a potential developmental neurotoxicant triggered studies of other substances that modulate excitatory and/or inhibitory neurotransmission in the developing brain. The culmination of this work is the recognition that neuroactive compounds that either block NMDA glutamate receptors or promote inhibitory neurotransmission at GABA A receptors can also trigger neuronal apoptosis in the immature rodent brain. Ethanol, which has both NMDA antagonist and GABA mimetic properties, causes enhanced neuronal apoptosis relative to compounds with only one of these activities. The period of peak vulnerability for this toxic effect coincides with the developmental period of rapid synaptogenesis, also known as the brain growth spurt, which occurs in the early postnatal period in mice and rats, and from the third trimester to several years after birth in humans. These studies have generated significant concern in the clinical setting because a number of anesthetics used in pregnant women and infants function by blocking NMDA receptors (ketamine) or promoting GABA neurotransmission (midazolam, diazepam, propofol). These anesthetic drugs have been shown to cause widespread developmental neurodegeneration via apoptosis and persistent cognitive deficits in rodents exposed to clinically relevant levels, and similar effects have been demonstrated for ketamine in nonhuman primates. Recent epidemiological studies support a link between brief anesthesia exposure during early infancy and poor neurodevelopmental outcome; however, interpretation is confounded by the potential impact of the surgical procedure, concurrent illness, or coexisting pathology. This case study is an illustration of some of the issues associated with confirming developmental neurotoxicity in humans, even for compounds with known mechanisms of action.

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Additional emerging issues in developmental neurotoxicology that merit mention include endocrine disruption as a mechanism of developmental neurotoxicity and geneenvironment interactions as determinants of risk and/or severity of neurodevelopmental disorders. With respect to the former, sex steroids, thyroid hormones, and neuropeptides are known to modulate key neurodevelopmental processes including neuronal differentiation, migration, survival and apoptosis, neuronal connectivity, and synaptic plasticity. Alteration of hormonal status during brain development can cause functional deficits in adolescence and adulthood, as illustrated by cognitive dysfunction associated with fetal hypothyroidism. While a number of chemicals with known endocrine disrupting activity have been shown to interfere with neurodevelopment (PCBs, bisphenol A), it remains to be established whether the developmental neurotoxicity of these compounds is mediated by endocrine disruption and whether endocrine disruption alters neurodevelopment in humans.

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The second emerging issue in developmental neurotoxicology reflects a growing consensus that environmental factors, potentially including environmental pollutants, Gene-environment interactions have been proposed (e.g., organophosphorus pesticides and genetic mutations in the gene encoding paraoxonase-1, the enzyme that detoxifies these pesticides that have been linked to ASD) but as yet, there is no definitive evidence of a specific gene-environment interaction that confers susceptibility to a neurodevelopmental disorder. However, examples of environmentally triggered diseases associated with mutations in RYR, the gene that encodes the ryanodine receptor, provide support for this hypothesis. Humans who are heterozygous for these mutations are fully viable and asymptomatic, but they respond adversely to halogenated hydrocarbon anesthetics with a fulminant malignant hyperthermic episode. Interestingly, it has been reported that the nondioxin-like PCB 95 is significantly more potent and efficacious in disrupting cation regulation by ryanodine receptors expressing mutations associated with malignant hyperthermia than by wild-type ryanodine receptors.
s0060 Adult Nervous System p0220 Chemicals generally perturb neurological function of the adult by interfering differentially with the structure and function of specific neural pathways, circuits, and systems. Vulnerable circuits within the brain include those that modulate and effect efferent output. Most commonly affected, however, are the peripheral neurons in pathways that relay information to and from the brain.

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The special senses of vision, audition, balance, gustation, and olfaction depend on neural pathways that originate in peripheral receptors and terminate in the brainstem or cerebral cortex. Afferent pathways for taste, smell, hearing, and balance employ sensory neurons in ganglia that lack a bloodnerve barrier. However, chemicals that perturb the special senses seem most commonly to interfere with the structure or function of the peripheral sensory receptors. Olfaction and gustation are subserved by cilia-bearing sensory neurons that are continuously generated from stem cells, a process of cellular replacement that is disrupted by antiproliferative drugs such as vincristine and doxorubicin. For vision, the function of retinal cells is perturbed by a large number of substances, some of which produce reversible change (cardiac glycosides and trimethadone), while others (aminophenoxyalkanes) elicit morphological damage. For retinal ganglion cells, the nerve fibers that form the optic pathway are sites of vulnerability to toxic attack. Substances that impair energy metabolism (thallium, cyanide) tend to damage proximal regions of axons projecting into the optic nerve from the papillomacular bundle, while distal axonal degeneration, with damage to the optic tracts, is seen with drugs such as clioquinol and ethambutol. Vestibular and auditory function may be affected concurrently by agents that target receptor cells in the inner ear of rodents (2-butenenitrile, 2-pentenenitrile) and humans (streptomycin). Other potentially ototoxic substances include cisplatin, furosemide, and imipramine. Noise may exacerbate the neurotoxic effects of some ototoxic agents. Disturbance of human oculomotor function may take the form of nystagmus (carbon monoxide) or opsoclonus (chlordecone), two types of abnormal eye movement. Certain neurotoxic substances produce lesions of vestibular and cochlear nuclei in rodents (6-chloro-6-deoxyglucose) and primates (1-amino-6-chloropropane).
p0230 Sensorimotor function is altered by a number of chemicals that act at different sites in the neuraxis. Most affect the axons or somata of lower motor neurons in the anterior horn of the spinal cord or primary sensory neurons in dorsal root ganglia. Some substances target the nerve cell body of sensory neurons that detect touch and vibration (methylmercury), position sense (pyridoxine), or pain (capsaicin), or of neurons that regulate cardiac muscle (doxorubicin) or voluntary muscle function (domoic acid, b-N-methylamino-L-alanine). Others target motor nerve terminals (botulinum toxin, a-latrotoxin) or the enzyme that targets acetylcholine NT (anticholinesterases), both of which produced acute alterations of neurotransmission associated with reduced or enhanced synaptic transmission. Temporary disruption of electrical impulse conduction is another neurotoxic effect. Agents (pyrethroids, ciguatoxin, tetrodotoxin) that perturb electrical activity in the excitable membrane (axolemma) of the nerve cell produce rapidly reversible sensory abnormalities (paresthesias) in the distribution of trigeminal and elongate peripheral nerves. Those substances (hexachlorophene, ethidium bromide) that attack the myelin sheath or myelinating cell precipitate focal demyelination and remyelination, with consequent disruption and restoration of nerve conduction and associated sensory motor phenomena over a period of several weeks. Focal demyelination and remyelination may also result from exposure to chemicals that block neurofilament transport and cause focal axonal swellings to develop proximally (1,2-diacetylbenzene, 3,4-dimethyl-2,5-hexanedione) or distally (2,5-hexanedione, carbon disulfide, acrylamide). Chemicals that produce distal (acrylamide), but not proximal (b-b'-iminodipropionitrile), giant axonal neurofilamentous swellings trigger retrograde distal axonal degeneration (distal axonopathy). Long and large-diameter myelinated axons in the PNS and CNS are vulnerable to distal axonopathy caused by a number of compounds (organophosphates, isoniazid, thalidomide), the resulting clinical picture being one of symmetrical sensory loss and muscle weakness in the distal extremities (stocking-and-glove polyneuropathy). Shorter and thinner nerve fibers, including postganglionic nerves of the autonomic nervous system, may become involved in distal axonopathies. This common type of neurodegeneration usually occurs after repeated exposure, evolves during and shortly after the period of intoxication, and then reverses as regenerating axons reestablish functional contact with denervated sensory terminals and muscle. Significant atrophy may result from prolonged skeletal muscle denervation, and recovery of sensory-motor function may be slow, progressive, and incomplete. When central motor pathways are heavily impacted by distal axonopathy (leptophos, clioquinol), those affected may display permanent residual spasticity. The motor pathway from brain to muscle is modulated by two other CNS structures that are vulnerable to substances with neurotoxic potential, namely the basal ganglia and cerebellum. Damage to the cerebellum may result in loss of coordination of limb and eye movement and in an ataxic gait (methylmercury, 3-acetylpyridine). Sida carpinifolia and Ipomea carnea are rich in swainsonine, a toxin that inhibits the enzyme alpha mannosidase and induces a cerebellar syndrome. The cerebellum and basal ganglia are both sensitive to hypoxia and related states induced by agents that impair energy metabolism (cyanide) and promote glutamate-mediated excitotoxicity. Other energy-disrupting agents elicit neuronal damage in the putamen (3-nitropropionic acid, methanol), pallidum (carbon monoxide), substantia nigra (MPTP, paraquat), or other parts of the basal ganglia (manganese). These types of neurotoxicity may find clinical expression as parkinsonism, tremor, dystonia, and other clinical signs of extrapyramidal dysfunction. Movement disorders of various types may result from the side effects of several therapeutic agents (amphetamines, anticonvulsants, anticholinergics, neuroleptics, dopamine agonists, lithium, tricyclic antidepressants). Atypical parkinsonism has been linked to ingestion of fruit of the Annonaceae family (corossol, soursop), which contain isoquinolinic alkaloids and acetogenins. A large component of aspartate, together with glutamate, is found in water-soluble component of the Yellow Star thistle (Centaurea solstitialis), which together with Russian knapweed (Acroptilon repens), induces a degenerative extrapyramidal disorder in horses known as equine nigropallidal encephalomalacia. Autonomic regulation of the pupil, lacrimal and salivary glands, airway, heart, gut, bladder, genitalia, and blood vessels involves sympathetic, parasympathetic, and enteric neurons. Unlike their somatic counterparts in the spinal cord, efferent neurons of the autonomic nervous system are housed in peripheral ganglia with permeant blood vessels. Autonomic function is disrupted by agents that target synapses that utilize acetylcholine since this is the principal NT for all preganglionic autonomic fibers, all postganglionic parasympathetic fibers, and some postganglionic sympathetic fibers. Drugs that selectively block nicotinic receptors (curare) curtail ganglionic output, while muscarinic agents (atropine) block transmission to effector cells. Anticholinesterase agents (fasciculins, organophosphates) stimulate sympathetic and parasympathetic activity, sometimes with the dramatic clinical consequences of a cholinergic crisis (nerve agents). Direct contact of anticholinesterase nerve agents (sarin, O-ethyl S-2-diisopropylaminoethyl methylphosphonothioate, or VX) with the eye, nasal passages, and bronchi leads to pupillary constriction (miosis), blurred vision, rhinorrhea, bronchoconstriction, and increased secretions. Systemic exposure results in creased salivation, bradycardia, enhanced lacrimation, urination, and defecation. Attendant muscle fasciculation, weakness, and seizures arise from peripheral somatic and CNS actions of anticholinesterase nerve agents.

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The autonomic nervous system and endocrine function are regulated by the hypothalamus and associated limbic structures of the brain. Hypothalamic functions, including the regulation of temperature, heart rate, blood pressure, blood osmolarity, circadian control, and water and food intake, may be impacted by a range of chemicals. Parts of the hypothalamus lack a blood-brain barrier: Infant mice treated with excitotoxic agents (glutamate, aspartate, cysteic acid) display extensive damage of the arcuate nucleus and develop a syndrome of obesity, skeletal stunting, reproductive failure, and gonadal hypoplasia. The hypothalamus receives major input from the hippocampus, which functions in the storage of declarative memory, uses cellular circuitry that involves glutamatergic synapses vulnerable to excitotoxins (domoic acid) and certain other agents (trimethyltin, trimethyl lead, soman), the latter possibly as a result of seizure-associated hypoxia.