1,721,329 research outputs found
In vitro and in vivo modulation of cholinergic muscarinic receptors in rat lymphocytes and brain by cholinergic agents
No full textA binding site for 3H-quinuclidinyl benzylate (QNB) has been identified in rat lymphocytes which has the characteristics of a cholinergic muscarinic receptor (Costa, L. G., Kaylor, G. & Murphy, S. D. (1988). Muscarinic cholinergic binding sites on rat lymphocytes. Immunopharmacology, 16, 139-149.) Here we show that prolonged exposures to cholinergic compounds in vitro and in vivo modulate muscarinic receptor binding in lymphocytes as well as in brain tissue. Exposure of rat splenic lymphocytes in vitro to oxotremorine caused a time- and concentration-dependent decrease in the density of 3H-QNB binding sites. This decrease occurred only when incubation with oxotremorine was carried out at 37 degrees C and not at 0-4 degrees C, suggesting that it was not an artifact due to residual, unwashed, oxotremorine. The effect of oxotremorine was mimicked by two other cholinergic agonists, acetylcholine and carbachol, and was antagonized by atropine, which, when present alone, caused an increase in 3H-QNB binding. In vivo exposures to oxotremorine or atropine (both at 20 mg/kg/day for 14 days via an ALZA minipump) caused a significant decrease (20-30%) and increase (13-30%), respectively, of 3H-QNB binding in various brain areas as well as circulating lymphocytes. Repeated administrations of the organophosphorus insecticide disulfoton (2 mg/kg/day for 14 days, i.p.) caused significant reductions (59-88%) of acetylcholinesterase activity in brain, lymphocytes, plasma and red blood cells, as well as a 23-39% decrease of 3H-QNB binding in brain areas and circulating lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS
The emerging field of ecogenetics
No full textGenetic differences in biotransformation enzymes and in target proteins can affect the individual susceptibility to drugs and environmental chemicals. The field of ecogenetics has emerged from the older area of pharmacogenetics, and investigates how genetic polymorphisms may represent risk factors for a number of diseases associated with exposure to toxic chemicals. Here, two polymorphisms, aldehyde dehydrogenase and delta-aminolevulinic acid dehydratase, are briefly discussed in relationship to alcohol and lead toxicity, respectively. The role of genetic polymorphisms in neurodegenerative diseases, such as Parkinson's disease, is also discussed. Furthermore, issues related to the functional significance of genetic polymorphisms, their interaction/combination, and ethical and societal considerations, are briefly addressed
Inhibition of gamma-[3H]aminobutyric acid uptake by organotin compounds in vitro
No full textTrimethyltin, its tetra-, di-, and monomethyl analogs, inorganic tin (Sn II and Sn IV), triethyltin, tripropyltin, tributyltin, and triphenyltin were tested for their ability in inhibiting the uptake of gamma-[3H]aminobutyric acid (GABA) into mouse forebrain synaptosomes in vitro. All organotins containing three carbon-tin bonds were potent inhibitors of [3H]GABA uptake with IC50 values ranging from 10(-4) to 10(-6) M. Various thiol and sulfur compounds, particularly sodium sulfide, were capable of antagonizing the inhibitory effect of triphenyltin and, to a minor extent, of other organotins. All triorganotins also inhibited Na+,K+-ATPase, measured by binding of [3H]ouabain and by hydrolysis of ATP. Although a correlation between inhibition of ouabain binding and GABA uptake by organotins could be found, inhibition of [3H]GABA uptake by the specific inhibitors ouabain and strophantidin was qualitatively and quantitatively different from organotins. These results suggest that all triorganotins are capable of inhibiting synaptosomal [3H]GABA uptake in vitro by a mechanism involving, but not exclusively, inhibition of Na+,K+-ATPase. The role of [3H]GABA uptake inhibition in the neurotoxicity of organotins remains to be determined
Signal transduction in environmental neurotoxicity
No full textSignal transduction is the process by which specific information is transferred from the cell surface to the cytosol and ultimately to the nucleus, leading to changes in gene expression. Since these chains of biochemical and molecular steps control the normal function of each cell, disruption of these processes would have a significant impact on cell physiology. Some of the major signal transduction pathways are briefly reviewed. The interactions of four chemicals (lead, ethanol, polychlorinated biphenyls, and trimethyltin) with different cell signaling systems, particularly the phospholipid hydrolysis/protein kinase C pathway, are discussed. The possible causal relationship of such cellular and molecular interactions with known signs and symptoms of neurotoxicity are highlighted
Biomarker research in neurotoxicology: the role of mechanistic studies to bridge the gap between the laboratory and epidemiological investigations
No full textThere is an increasing interest in the development and validation of biomarkers for use in biochemical/molecular epidemiological studies. Though the area of neurotoxicology has received much attention in the past several years, it still lags behind with regard to the development of biomarkers, particularly those of health effects and susceptibility. This review discusses several aspects of biomarker research as it relates to neurotoxic compounds and focuses on selected agents (organophosphorus insecticides, styrene, n-hexane, carbon disulfide, acrylamide), which have been the subject of a number of investigations in animals and humans. While traditional biomonitoring approaches and novel techniques (e.g., hemoglobin adducts) provide several measurements for monitoring exposure to neurotoxic chemicals, potential markers of genetic susceptibility have been seldom investigated in a neurotoxicology context. Furthermore, the complexity of the nervous system, together with the multiplicity of end points and the limited knowledge of the exact mechanism(s) of action of neurotoxicants, has led to only limited advancements in the development of biomarkers for neurotoxic effects. Significant progress in this area will depend upon an increased understanding of the cellular, biochemical, and molecular targets directly involved in neurotoxicity
Inhibition of γ-[3H]aminobutyric acid uptake by organotin compounds in vitro
No full textTrimethyltin, its tetra-, di-, and monomethyl analogs, inorganic tin (Sn II and Sn IV), triethyltin, tripropyltin, tributyltin, and triphenyltin were tested for their ability in inhibiting the uptake of γ-[3H]aminobutyric acid (GABA) into mouse forebrain synaptosomes in vitro. All organotins containing three carbontin bonds were potent inhibitors of [3H]GABA uptake with IC50 values ranging from 10-4 to 10-6m. Various thiol and sulfur compounds, particularly sodium sulfide, were capable of antagonizing the inhibitory effect of triphenyltin and, to a minor extent, of other organotins. All triorganotins also inhibited Na+,K+-ATPase, measured by binding of [3H]ouabain and by hydrolysis of ATP. Although a correlation between inhibition of ouabain binding and GABA uptake by organotins could be found, inhibition of [3H]GABA uptake by the specific inhibitors ouabain and strophantidin was qualitatively and quantitatively different from organotins. These results suggest that all triorganotins are capable of inhibiting synaptosomal [3H]GABA uptake in vitro by a mechanism involving, but not exclusively, inhibition of Na+,K+-ATPase. The role of [3H]GABA uptake inhibition in the neurotoxicity of organotins remains to be determined. © 1985
Interactions of neurotoxicants with neurotransmitter systems
No full textMany neurotoxic compounds have been shown to interfere with neurotransmission both in vitro and following acute and chronic administration. Various parameters of neurotransmission can be directly affected by neurotoxicants; these include the enzyme(s) synthesizing a neurotransmitter, the release and uptake processes, the enzyme(s) which metabolize the neurotransmitter, the receptors, and post-synaptic events associated with receptor activation. Some neurotoxicants can interfere with neurotransmission indirectly, by interacting for example with energy metabolism, sodium channels or ATPases. Furthermore, measured alterations of any parameter of neurotransmission can be the result of neuronal death, due to a cytotoxic effect of the neurotoxicants. Chemicals which have been shown to alter neurotransmission include solvents (e.g. carbon disulfide), metals and organometals (e.g. lead, mercury, trimethyltin) and pesticides (e.g. organophosphates, pyrethroids, organochlorines, formamidines). An example of the various alterations in neurotransmitter parameters, which can occur following acute or chronic administration, is represented by the organophosphates. Organophosphorus insecticides owe their acute toxicity to inhibition of acetylcholinesterase and accumulation of acetylcholine at cholinergic receptors. Chronic exposure to these compounds results in the development of tolerance to their toxicity which is associated with a decrease in the density of muscarinic and nicotinic receptors in both the central and peripheral nervous system. Other examples of the interactions of neurotoxicants with neurotransmitters are also described
Signal transduction mechanisms in developmental neurotoxicity: the phosphoinositide pathway
No full textThe importance of activation of second messenger systems which follows the interaction of neurotransmitters, hormones and growth factors with their receptors is increasingly recognized. The phosphoinositide/protein kinase C pathway has received particular attention in the past decade, particularly for its involvement in the control of intracellular calcium levels. Though new functions of this metabolic pathway in the nervous system are continuously discovered, little is still known about the possible role of phosphoinositide metabolism in mediating various aspects of neurotoxicity. Limited information also exists on various aspects of inositol metabolism during brain development and, as a consequence, on its possible role in developmental neurotoxicity. In this brief review, some of the current concepts of receptor--activated phosphoinositide metabolism, particularly during brain development, are summarized. Two examples are presented to indicate its possible involvement in developmental neurotoxicity. The acetylcholine muscarinic receptor--stimulated inositol metabolism is discussed as a potential target for the developmental neurotoxicity of ethanol. The possible contribution of the glutamate metabotropic receptors in the neurotoxicity of excitatory amino acid in the immature brain is also discussed
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