Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of chronic exposure to corticosterone in drinking water on corticosterone kinetics, blood chemistry, and concentrations of catecholamines in parts of brain were studied in Long-Evans rats. Rats were randomly grouped into 3 x 2 treatments (n=4), with three treatments of drinking water (tap water, or 2.5% ethanol, or 400 microg/mL of corticosterone in 2.5% ethanol) for 28 days and two treatments of gavage with a single dose of either corn oil or corticosterone 20 mg/kg on day 28. Blood samples were collected at 0, 15, 30, 60, 120, 240, 480, and 720 min after dosing to determine plasma corticosterone concentrations. Blood samples were collected for clinical pathology on day 42. Hippocampus, cerebral cortex, caudate-putamen, and pons were examined to determine concentrations of catecholamines and activities of esterases. Concentrations of plasma corticosterone before gavage of the corticosterone-drinking rats (47.61 +/- 1.13 ng/mL) were lower than the water (418.47 +/- 1.13 ng/mL) or the ethanol rats (383.71 +/- 1.13 ng/mL, P < 0.0001). Plasma corticosterone rose to peak concentrations by 15 min after gavage in all three groups of drinking rats. Corticosterone-drinking rats had concentrations of plasma corticosterone that returned to basal levels slower than water- and ethanol-drinking rats. Plasma sodium and chloride concentrations were lower in the corticosterone-drinking rats than the water-drinking rats (P < 0.01). Plasma albumin, globulin, and total protein were highest in the corticosterone-drinking rats when compared to the other groups of drinking rats (P < 0.001, P < 0.05, and P < 0.001, respectively). Corticosterone in drinking water did not affect activities of brain neurotoxic esterase, carboxylesterase, acetylcholinesterase, or concentrations of monoamines and their metabolites. A single oral dose of corticosterone reduced neurotoxic esterase activity in the cerebral cortex (P < 0.05) and increased norepinephrine concentrations in the hippocampus (P < 0.05).
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PMID:Corticosterone in drinking water: altered kinetics of a single oral dose of corticosterone and concentrations of plasma sodium, albumin, globulin, and total protein. 1574 78

Environmental exposures generally involve chemical mixtures instead of single chemicals. Statistical models such as the fixed-ratio ray design, wherein the mixing ratio (proportions) of the chemicals is fixed across increasing mixture doses, allows for the detection and characterization of interactions among the chemicals. In this study, we tested for interaction(s) in a mixture of five organophosphorus (OP) pesticides (chlorpyrifos, diazinon, dimethoate, acephate, and malathion). The ratio of the five pesticides (full ray) reflected the relative dietary exposure estimates of the general population as projected by the US EPA Dietary Exposure Evaluation Model (DEEM). A second mixture was tested using the same dose levels of all pesticides, but excluding malathion (reduced ray). The experimental approach first required characterization of dose-response curves for the individual OPs to build a dose-additivity model. A series of behavioral measures were evaluated in adult male Long-Evans rats at the time of peak effect following a single oral dose, and then tissues were collected for measurement of cholinesterase (ChE) activity. Neurochemical (blood and brain cholinesterase [ChE] activity) and behavioral (motor activity, gait score, tail-pinch response score) endpoints were evaluated statistically for evidence of additivity. The additivity model constructed from the single chemical data was used to predict the effects of the pesticide mixture along the full ray (10-450 mg/kg) and the reduced ray (1.75-78.8 mg/kg). The experimental mixture data were also modeled and statistically compared to the additivity models. Analysis of the 5-OP mixture (the full ray) revealed significant deviation from additivity for all endpoints except tail-pinch response. Greater-than-additive responses (synergism) were observed at the lower doses of the 5-OP mixture, which contained non-effective dose levels of each of the components. The predicted effective doses (ED20, ED50) were about half that predicted by additivity, and for brain ChE and motor activity, there was a threshold shift in the dose-response curves. For the brain ChE and motor activity, there was no difference between the full (5-OP mixture) and reduced (4-OP mixture) rays, indicating that malathion did not influence the non-additivity. While the reduced ray for blood ChE showed greater deviation from additivity without malathion in the mixture, the non-additivity observed for the gait score was reversed when malathion was removed. Thus, greater-than-additive interactions were detected for both the full and reduced ray mixtures, and the role of malathion in the interactions varied depending on the endpoint. In all cases, the deviations from additivity occurred at the lower end of the dose-response curves.
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PMID:Neurotoxicological and statistical analyses of a mixture of five organophosphorus pesticides using a ray design. 1580 32

Cognitive and motor impairment often follow acute poisoning with an organophosphorous (OP) pesticide. However, the persistence of these effects and the conditions necessary for their appearance are not clear: two specific concerns are whether symptomatic poisoning is necessary for persistent effects, and whether inhibition of cholinesterase (ChE) activity is a protective metric of OP exposure. This study examined the effects of chronic dietary and repeated high-level acute exposure to the pesticide chlorpyrifos (diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate, CPF) on learning and attention. Beginning at 3 months of age, male Long-Evans rats received dietary CPF at a daily dose of 0, 1, or 5 mg/kg for 1 year. Half of each dietary group also received an acute oral dose of CPF (initial dose at 60 mg/kg, 5 doses at 45 mg/kg) every 2 months. Beginning 2 weeks before the fourth acute dose, behavioral assessments were conducted on the eight rats in each of the six exposure groups (0-Oil, 0-CPF, 1-Oil, 1-CPF, 5-Oil, and 5-CPF). Using an auto-shaping procedure, the groups learned to press a lever for food in the following order: 5-Oil, 5-CPF, 1-Oil, and 0-Oil. The 0-CPF and 1-CPF groups did not learn the response in three 50-trial sessions. Chronic CPF did not affect acquisition of other behaviors required by a signal detection task (SDT) designed to assess sustained attention. The sixth acute CPF dose significantly disrupted the SDT in all dosed groups. Two months after the end of dosing, performance of the SDT was impaired in the 5-CPF group. These data suggest that learning the contingency between an action and reward may be accelerated by chronic exposure to CPF and inhibited by previous symptomatic exposure to CPF, and that persistent cognitive impairment may follow if CPF exposure inhibits brain ChE activity and is accompanied by acute doses sufficient to induce signs of toxicity.
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PMID:Effects of chronic dietary and repeated acute exposure to chlorpyrifos on learning and sustained attention in rats. 1603 91

Most toxicity data are based on studies using single compounds. This study assessed if there is an interaction between mixtures of the anticholinesterase insecticides chlorpyrifos (CHP) and carbaryl (CAR) using hypothermia and cholinesterase (ChE) inhibition as toxicological endpoints. Core temperature (T(c)) was continuously monitored by radiotelemetry in adult Long-Evans rats administered CHP at doses ranging from 0 to 50mg/kg and CAR doses of 0-150 mg/kg. The temperature index (TI), an integration of the change in T(c) over a 12h period, was quantified. Effects of mixtures of CHP and CAR in 2:1 and 1:1 ratios on the TI were examined and the data analyzed using a statistical model designed to assess significant departures from additivity for chemical mixtures. CHP and CAR elicited a marked hypothermia and dose-related decrease in the TI. The TI response to a 2:1 ratio of CHP:CAR was significantly less than that predicted by additivity. The TI response to a 1:1 ratio of CHP and CAR was not significantly different from the predicted additivity. Plasma and brain ChE activity were measured 4h after dosing with CHP, CAR, and mixtures in separate groups of rats. There was a dose-additive interaction for the inhibition of brain ChE for the 2:1 ratio, but an antagonistic effect for the 1:1 ratio. The 2:1 and 1:1 mixtures had an antagonistic interaction on plasma ChE. Overall, the departures from additivity for the physiological (i.e., temperature) and biochemical (i.e., ChE inhibition) endpoints for the 2:1 and 1:1 mixtures studies did not coincide as expected. An interaction between CHP and CAR appears to depend on the ratio of compounds in the mixture as well as the biological endpoint.
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PMID:Thermoregulatory response to an organophosphate and carbamate insecticide mixture: testing the assumption of dose-additivity. 1618 29

Reports from Japan and India and data submissions to the US EPA indicate that exposure to cholinesterase (ChE)-inhibiting organophosphorous insecticides (OP) can produce ocular toxicity, in particular long-lasting changes in retinal physiology and anatomy. We have examined the effects of a 1 year dietary exposure to the OP chlorpyrifos (CPF) on retinal structure and function. Adult male Long-Evans rats were fed CPF in their diet at the rate of 0, 1 (low), or 5 (high) mg/kg body weight/day. In addition, half of each feeding group received an oral (spike) dose of CPF in corn oil (45 mg/kg) or corn oil (VEH) alone every 2 months, resulting in six exposure groups: Control-VEH, Control-CPF, Low-VEH, Low-CPF, High-VEH, and High-CPF. Dark-adapted electroretinograms (ERG) were measured 3-5 months (n= 15-18/group) after the completion of dosing. There were no significant differences between dose or spike groups in a-wave, b-wave, or oscillatory potential amplitudes or implicit times. In addition, the time course of dark adaptation were measured in a subset of these rats (6-8/group) eight months after the completion of dosing by determining the flash intensity needed to elicit a 40 microV b-wave at selected intervals after bleaching 90% of the photopigment. Rats receiving the episodic oral spike of CPF showed a slowed recovery of dark-adapted sensitivity compared to rats receiving the corn oil VEH across chronic dosing conditions. No effects were seen on retinal morphology. This result suggests that episodic high dose exposures to CPF may result in altered retinal function. This effect, akin to effects seen in aging humans and humans exposed to other ChE-inhibiting compounds, may reflect alterations in the photoreceptors and retinal pigment epithelium (RPE) complex necessary for regenerating photopigment.
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PMID:Repeated spike exposure to the insecticide chlorpyrifos interferes with the recovery of visual sensitivity in rats. 1624 59

Repeated stress has been reported to cause reversible impairment in the central nervous system (CNS). It was proposed that alterations in glutamatergic, cholinergic, and monoamine neurotransmitter systems after exposure to stress are initial CNS events contributing to this impairment and that exacerbation could occur with concurrent exposure to cholinesterase inhibitors. Effects of concurrent exposure to repeated stress and chlorpyrifos on activities of acetylcholinesterase (AChE), carboxylesterase, and choline acetyltransferase (ChAT); concentrations of excitatory amino acids, monoamines, and their metabolites; and maximum binding densities (B(max)) and equilibrium dissociation rate constants (K(d)) of glutamatergic N-methyl-d-aspartate (NMDA) and total muscarinic cholinergic receptors were studied in the blood, hippocampus, cerebral cortex, or hypothalamus of adult Long-Evans rats. Stress treatments extended over 28 days included (1) control rats handled 5 days/week; (2) rats restrained 1 h/day for 5 days/week; (3) rats swum 30 min for 1 day/week; or (4) rats restrained 4 days/week and swum for 1 day/week. On day 24, each stress treatment group was randomly divided and injected either with corn oil or chlorpyrifos, 160 mg/kg subcutaneously (sc) (60% of the maximum tolerated dose), 4 h after restraint. Blood and brain tisssues were collected on day 28. Rats restrained and swum had a statistical trend toward increasing concentrations of glutamate in the hippocampus when compared to rats only swum (p = .064). Chlorpyrifos administration decreased restraint-induced elevated aspartate in the hippocampus, and decreased B(max) of total muscarinic receptors in the cerebral cortex. In addition, chlorpyrifos decreased B(max) and K(d) of total muscarinic receptors in the cerebral cortex of swum rats. Results demonstrated that chlorpyrifos inhibited AChE activity in blood, cerebral cortex, and hippocampus, but stress did not affect AChE activity. Carboxylesterase activity was inhibited by chlorpyrifos and by repeated restraint with swim. Swim stress decreased concentrations of norepinephrine in the hippocampus and hypothalamus, and increased concentrations of dopamine and its metabolite, DOPAC, in the hypothalamus. Both stress and chlorpyrifos altered serotonin concentrations, and the interactions of repeated stress and chlorpyrifos on serotonin approached significance in the hippocampus (p = .06) and hypothalamus (p = .08). Therefore, stress models were demonstrated to alter glutamatergic and monoamine responses, whereas chlorpyrifos alone had effects on cholinergic and monoamine systems in the rat CNS. However, the interactions between stress and chlorpyrifos significant at p < 0.05 were restricted to attenuation of elevated aspartate in the hippocampus of restrained with swim rats and decreased K(d) of acetylcholine receptors in the cerebral cortex of swum rats and restrained rats.
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PMID:Examination of concurrent exposure to repeated stress and chlorpyrifos on cholinergic, glutamatergic, and monoamine neurotransmitter systems in rat forebrain regions. 1651 Mar 59

The estimation of risk following exposure to mixtures is an important feature of pesticide risk assessment. Also of concern is the potential for increased sensitivity of the young to pesticide toxicity. We have conducted interaction studies using a mixture of five organophosphorus (OP) pesticides (chlorpyrifos, diazinon, dimethoate, acephate, and malathion) in both adult (published previously) and preweanling rats using a fixed-ratio ray design. In the present study, cholinesterase inhibition and behavioral changes (motor activity, gait, and tail-pinch response) were measured in 17-day-old Long-Evans male rats following acute exposure to the OPs. The ratio of pesticides in the mixture reflected the relative dietary exposure estimates projected by the U.S. Environmental Protection Agency Dietary Exposure Evaluation Model. Dose-response data were collected for each OP alone, which were used (alone or in conjunction with the mixture data) to build an additivity model to predict the effects of the pesticide mixture along a ray of increasing total doses, using the same fixed ratio of components. The mixture data (full ray) were similarly modeled and statistically compared to the additivity model along the ray. Since malathion has been shown to produce synergistic interactions with certain OPs, it was of interest to evaluate the influence of malathion in this study. A second pesticide mixture, without malathion (reduced ray), was tested using the same dose levels of the remaining four OPs. Analysis of the full ray revealed significant greater-than-additive responses for all endpoints. The magnitude of this shift ranged from two- to threefold for estimates of the ED(20) and ED(50). The deviation from additivity was also detected in the reduced ray for all but two endpoints (motor activity and tail-pinch response); however, for all endpoints, the reduced ray was significantly different from the full ray. Thus, greater-than-additive responses were detected in preweanling rats with this OP mixture, and this effect can only partially be attributed to the malathion in the mixture.
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PMID:Neurotoxicological interactions of a five-pesticide mixture in preweanling rats. 1661 28

To compare the toxicity of seven N-methyl carbamates, time course profiles for brain and red blood cell (RBC) cholinesterase (ChE) inhibition were established for each. Adult, male, Long Evans rats (n=4-5 dose group) were dosed orally with either carbaryl (30 mg/kg in corn oil); carbofuran (0.5 mg/kg in corn oil); formetanate HCl (10 mg/kg in water); methomyl (3 mg/kg in water); methiocarb (25 mg/kg in corn oil); oxamyl (1 mg/kg in water); or propoxur (20 mg/kg in corn oil). This level of dosing produced at least 40% brain ChE inhibition. Brain and blood were taken from 0.5 to 24 h after dosing for analysis of ChE activity using two different methods: (1) a radiometric method which limits the amount of reactivation of ChE activity, and (2) a spectrophotometric method (Ellman method using traditional, unmodified conditions) which may encourage reactivation. The time of peak ChE inhibition was similar for all seven N-methyl carbamate pesticides: 0.5-1.0 h after dosing. By 24 h, brain and RBC ChE activity in all animals returned to normal. The spectrophotometric method underestimated ChE inhibition. Moreover, there was a strong, direct correlation between brain and RBC ChE activity (radiometric assay) for all seven compounds combined (r(2)=0.73, slope 1.1), while the spectrophotometric analysis of the same samples showed a poor correlation (r(2)=0.09). For formetanate, propoxur, methomyl, and methiocarb, brain and RBC ChE inhibitions were not different over time, but for carbaryl, carbofuran and oxamyl, the RBC ChE was slightly more inhibited than brain ChE. These data indicate (1) the radiometric method is superior for analyses of ChE activity in tissues from carbamate-treated animals (2) that animals treated with these N-methyl carbamate pesticides are affected rapidly, and recover rapidly, and (3) generally, assessment of RBC ChE is an accurate predictor of brain ChE inhibition for these seven pesticides.
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PMID:Time course of cholinesterase inhibition in adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl or propoxur. 1719 7

Gene expression profiles in the periaqueductal gray (PAG) of adult Long-Evans rats as a function of a stressful social defeat in inter-male fighting encounters were examined. This social subordination model mimics prototypical behavioral changes that parallel aspects of clinical depression, has been postulated to simulate early changes in the onset of depression in the losers, and has been successfully utilized for the evaluation of antidepressant activity. The 22-kHz ultrasonic vocalizations (USVs) have been shown to reflect negative emotional states akin to anxiety and depression. Social defeat is the most robust and reliable method of eliciting these calls. The PAG has been shown to be a key brain region for the generation of 22-kHz ultrasonic vocalizations, and 22-kHz USVs have been shown to be controlled by the mesolimbic cholinergic system. In this present study, we examined gene expression changes in the PAG of social subordinate rats compared to dominant rats that do not Exhibit 22-kHz USVs. We found that social defeat significantly altered the genes associated with cholinergic synaptic transmission in the PAG. The most robust of these were the increased expression of the beta2 subunit of the nicotinic acetylcholine receptor (CHRNB2) and the T subunit of acetylcholinesterase (ACHE) in the subordinate animals. These changes were corroborated by quantitative real-time polymerase chain reaction (qRT-PCR) and found to be exclusive to the PAG compared to seven other brain regions examined. These data suggest that cholinergic transmission in the PAG is involved in the generation of 22-kHz USVs and provide potential therapeutic targets for the treatment of affective disorders.
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PMID:Social defeat, a paradigm of depression in rats that elicits 22-kHz vocalizations, preferentially activates the cholinergic signaling pathway in the periaqueductal gray. 1745 55

The effects of N-methyl carbamate pesticides on the photic after discharge (PhAD) of flash evoked potentials (FEPs) and the relationship between inhibition of brain cholinesterase (ChE) activity and the PhAD were evaluated. FEPs were recorded in Long Evans rats treated with physostigmine (s.c.) 0, 0.05, 0.1, 0.2 or 0.3mg/kg (free base), in an ascorbic acid/saline vehicle, carbaryl (p.o.) 0, 1, 3, 10, 30, 50 or 75 mg/kg, or propoxur (p.o.) 0, 0.3, 3, 10, 20, 30, or 40 mg/kg in a corn oil vehicle. Physostigmine served as positive control based on literature data. Early (e.g. peak N(36)) and late FEP components (peak N(166) and PhAD) are related to the initial retino-geniculate afferent volley and higher cortical processing of visual information, respectively. Compared to controls, the PhAD duration decreased following treatment with 0.1 and 0.3mg/kg physostigmine, 7 5 mg/kg carbaryl or 30 mg/kg propoxur. Lesser changes were noted in FEP amplitudes or peak latencies. Treatment with 0.2 or 0.3 mg/kg physostigmine increased peak N(36) latency. Peak N(166) latency increased only following exposure to 40 mg/kg propoxur. None of the compounds altered peak N(36) or N(166) amplitudes. Hypothermia was observed at doses greater than 0.05 mg/kg physostigmine, at 30 or 50 mg/kg carbaryl, and after treatment with 10, 20 or 40 mg/kg propoxur. Inhibition of brain ChE activity occurred at dosages greater than 0.05 mg/kg physostigmine, 1mg/kg carbaryl, and 0.3 mg/kg propoxur. Linear regression analysis indicated that the decrease in PhAD duration correlated with decrease in brain ChE activity. The results indicate that at 30 min after treatment, inhibition of brain ChE activity did not affect cortical processing of the input from the retino-geniculate volley (evidenced by unaltered peak N(36) amplitude). However, the data suggest that disruption of cortical processing of visual signals related to FEP late components, as indicated by depression of the PhAD, was related to inhibition of brain ChE activity.
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PMID:Depression of the photic after discharge of flash evoked potentials by physostigmine, carbaryl and propoxur, and the relationship to inhibition of brain cholinesterase. 1795 Aug 90


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