Chambers JE


Full name : Chambers Janice E

First name : Janice E

Mail : Mississippi State University\; College of Veterinary Medicine\; Dept of Basic Sciences\; PO Box 6100\; College of Vet. Medicine\; 240 Wise Center Dr.\; Mississippi State University\; Mississippi\; 39762

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Country : USA

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Phone : +16623251255

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References (55)

Title : Pharmacokinetics of three novel pyridinium aldoxime acetylcholinesterase reactivators in female rats - Backer_2022_Toxicol.Appl.Pharmacol_446_116046
Author(s) : Backer BS , Meek EC , Ross MK , Chambers JE
Ref : Toxicol Appl Pharmacol , 446 :116046 , 2022
Abstract : A platform of novel lipophilic substituted phenoxyalkyl pyridinium oximes was invented to reactivate organophosphate-inhibited acetylcholinesterase. This platform has provided superior efficacy in rats to the current standard of care, 2-PAM, for survival of lethal doses of nerve agent surrogates as well as evidence of brain penetration and neuroprotection. The pharmacokinetics of three of these novel oximes in female rats was studied for comparison to previous data in male rats. Compared to the published half-life of 2-PAM (less than 2 h), the lead novel oxime, Oxime 20, displayed a plasma half-life of about 5 h in both sexes of rats following intramuscular administration. Very few sex differences in pharmacokinetic parameters were apparent. Oxime 20 displayed an increase in brain concentration to plasma concentration over the initial 2 h following intramuscular administration in male rats, with a plateau at 1 h; there were no differences in brain concentrations between the sexes at 2 h. Hepatic metabolism of Oxime 20 was higher in rat microsomes than in human microsomes. The relatively long plasma half-life is likely an important factor in both the enhanced survival and the neuroprotection previously observed for Oxime 20. The metabolism data suggest that the clearance of Oxime 20 could be slower in humans than was observed in rats, which might allow less frequent administration than 2-PAM for therapy of organophosphate acute toxicity. Therefore, the pharmacokinetic data combined with our earlier efficacy data suggest that Oxime 20 has potential as a superior therapeutic for nerve agent poisoning.
ESTHER : Backer_2022_Toxicol.Appl.Pharmacol_446_116046
PubMedSearch : Backer_2022_Toxicol.Appl.Pharmacol_446_116046
PubMedID: 35550885

Title : Effect of high fat diet on the toxicokinetics and toxicodynamics of chlorpyrifos following acute exposure in male C57BL\/6J mice - Kondakala_2022_J.Biochem.Mol.Toxicol__e23028
Author(s) : Kondakala S , Ross MK , Chambers JE , Howell GE, 3rd
Ref : J Biochem Mol Toxicol , :e23028 , 2022
Abstract : Chlorpyrifos (CPS) is one of the most widely used organophosphate (OP) insecticides. The acute neurotoxicity of OPs results from the inhibition of acetylcholinesterase (AChE). However, some OPs also inhibit noncholinergic targets including monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH), and carboxylesterase (CES). Data have shown that highly lipophilic OPs, including CPS, have a persistent toxic effect in obese patients. Therefore, the present study was designed to determine the effect of high fat diet (HFD) induced obesity on the disposition of CPS and its detoxified metabolite 3,5,6-trichloro-2-pyridinol (TCP) following acute exposure as well as effects on cholinergic and noncholinergic CPS targets. Male C57BL/6J mice were fed a standard diet (STD) or HFD for 4 weeks, then treated with vehicle or CPS (25 mg/kg) via oral gavage and euthanized postdosing at 0, 3, 6, and 12 h. Following exposure, CPS levels in adipose tissue of HFD fed animals were increased to a greater extent than in STD fed animals, whereas overall hepatic TCP levels were decreased in HFD fed animals. Red blood cell (RBC) AChE and plasma cholinesterase activities were inhibited regardless of diet intake, but inhibition of RBC AChE activity was significantly lower after 3 h in HFD animals. Hepatic CES and FAAH activities were also significantly decreased following CPS exposure regardless of diet. In conclusion, increased time-integrated CPS levels in adipose tissue indicate CPS may possibly form a depot there and may be retained longer in obese animals than in normal animals.
ESTHER : Kondakala_2022_J.Biochem.Mol.Toxicol__e23028
PubMedSearch : Kondakala_2022_J.Biochem.Mol.Toxicol__e23028
PubMedID: 35225412

Title : Reactivation of Organophosphate-inhibited Serum Butyrylcholinesterase by Novel Substituted Phenoxyalkyl Pyridinium Oximes and Traditional Oximes - Nichols_2021_Toxicology__152719
Author(s) : Nichols RH , Chambers JE
Ref : Toxicology , :152719 , 2021
Abstract : Organophosphorus compounds (OPs) include nerve agents and insecticides that potently inhibit acetylcholinesterase (AChE), an essential enzyme found throughout the nervous system. High exposure levels to OPs lead to seizures, cardiac arrest, and death if left untreated. Oximes are a critical piece to the therapeutic regimen which remove the OP from the inhibited AChE and restore normal cholinergic function. The current oximes 2-PAM, MMB-4, TMB-4, HI-6, and obidoxime (OBD) have two drawbacks: lack of broad spectrum protection against multiple OP structures and poor brain penetration to protect against OP central neurotoxicity. An alternative strategy to enhance therapy is reactivation of serum butyrylcholinesterase (BChE). BChE is stoichiometrically inhibited by OPs with no apparent toxic result. Inhibition of BChE in the serum followed by reactivation could create a pseudo-catalytic scavenger allowing numerous regenerations of BChE to detoxify circulating OP molecules before they can reach target AChE. BChE in serum from rats, guinea pigs or humans was screened for the reactivation potential of our novel substituted phenoxyalkyl pyridinium oximes, plus 2-PAM, MMB-4, TMB-4, HI-6, and OBD (100microM) in vitro after inhibition by highly relevant surrogates of sarin, VX, and cyclosarin, and also DFP, and the insecticidal active metabolites paraoxon, phorate-oxon, and phorate-oxon sulfoxide. Novel oxime 15 demonstrated significant broad spectrum reactivation of OP-inhibited rat serum BChE while novel oxime 20 demonstrated significant broad spectrum reactivation of OP-inhibited human serum BChE. All tested oximes were poor reactivators of OP-inhibited guinea pig serum BChE. The bis-pyridinium oximes were poor BChE reactivators overall. BChE reactivation may be an additional mechanism to attenuate OP toxicity and contribute to therapeutic efficacy.
ESTHER : Nichols_2021_Toxicology__152719
PubMedSearch : Nichols_2021_Toxicology__152719
PubMedID: 33592259

Title : Inhibition Kinetics of 16 Organophosphorus Pesticides or Their Active Metabolites on Erythrocyte Acetylcholinesterase from Humans and Rats - Meek_2021_Toxicol.Sci__
Author(s) : Meek EC , Reiss R , Crow JA , Chambers JE
Ref : Toxicol Sci , : , 2021
Abstract : Inhibition kinetics assays were conducted with 16 commercial organophosphate (OP) pesticides or their metabolites on acetylcholinesterase (AChE) in erythrocyte "ghost" preparations from 18 individual humans (both sexes; adults, juveniles and cord blood samples; mixed races/ethnicities) and pooled samples from adult rats (both sexes). A well established spectrophotometric assay using acetylthiocholine as substrate and a chromogen was employed. The kinetic parameters bimolecular rate constant (ki), dissociation constant (KI) and phosphorylation constant (kp) were calculated for each compound. As expected, a wide range of potencies were displayed among the tested compounds. Statistical analysis of the resultant data indicated no differences in sex, age or race/ethnicity among the human samples that are unexpected based on chance (4.2% statistically significant out of 48 parameters calculated) and no differences between the sexes in rats. The bimolecular rate constants for 10 of the compounds were not statistically different between rats and humans. The data indicate that, consistent with the high level of conservation of AChE among species and the fact that AChE at different locations within a species arises from the same gene, the inhibition kinetic parameters calculated from rat erythrocyte ghost preparations should be useful in estimating potencies of OP compounds on target AChE in humans. Additionally the data indicate that differences in sensitivities among individual humans were not apparent. Impact Statement: These data are expected to be useful in consideration of the intraspecies and interspecies uncertainty factors in OP pesticide risk assessment.
ESTHER : Meek_2021_Toxicol.Sci__
PubMedSearch : Meek_2021_Toxicol.Sci__
PubMedID: 33720374

Title : In vitro age-related differences in rats to organophosphates - Meek_2021_Toxicol.In.Vitro__105102
Author(s) : Meek EC , Carr RL , Chambers JE
Ref : Toxicol In Vitro , :105102 , 2021
Abstract : The mechanism of toxic action for organophosphates (OPs) is the persistent inhibition of acetylcholinesterase (AChE) resulting in accumulation of acetylcholine and subsequent hyperstimulation of the nervous system. Organophosphates display a wide range of acute toxicities. Differences in the OP's chemistries results in differences in the compound's metabolism and toxicity. Acute toxicities of OPs appear to be principally dependent on compound specific efficiencies of detoxication, and less dependent upon efficiencies of bioactivation and sensitivity of AChE. Serine esterases, such as carboxylesterase (CaE) and butyrylcholinesterase (BChE), play a prominent role in OP detoxication. Organophosphates can stoichiometrically inhibit these enzymes, removing OPs from circulation thus providing protection for the target enzyme, AChE. This in vitro study investigated age-related sensitivity of AChE, BChE and CaE to twelve structurally different OPs in rat tissues. Sensitivity of esterases to these OPs was assessed by inhibitory concentration 50s (IC(50)s). The OPs displayed a wide range of inhibitory potency toward AChE with IC(50)s in the low nM-microM range with no differences among ages; however, the CaE IC(50)s generally increased with age reflecting greater protection in adults. These results suggest age-related differences in acute toxicities of OPs in mammals are primarily a result of their detoxication capacities.
ESTHER : Meek_2021_Toxicol.In.Vitro__105102
PubMedSearch : Meek_2021_Toxicol.In.Vitro__105102
PubMedID: 33497710

Title : Effects of novel brain-penetrating oxime acetylcholinesterase reactivators on sarin surrogate-induced changes in rat brain gene expression - Dail_2021_J.Biochem.Mol.Toxicol__e22755
Author(s) : Dail ME , Brino MLM , Chambers JE
Ref : J Biochem Mol Toxicol , :e22755 , 2021
Abstract : Past assassinations and terrorist attacks demonstrate the need for a more effective antidote against nerve agents and other organophosphates (OP) that cause brain damage through inhibition of acetylcholinesterase (AChE). Our lab has invented a platform of phenoxyalkyl pyridinium oximes (US patent 9,277,937) that demonstrate the ability to cross the blood-brain barrier in in vivo rat tests with a sarin surrogate nitrophenyl isopropyl methylphosphonate (NIMP) and provide evidence of brain penetration by reducing cessation time of seizure-like behaviors, accumulation of glial fibrillary acidic protein (GFAP), and hippocampal neuropathology, as opposed to the currently approved oxime, 2-pyridine aldoxime methyl chloride (2-PAM). Using two of the novel oximes (Oximes 1 and 20), this project examined whether gene expression changes might help explain this protection. Expression changes in the piriform cortex were examined using polymerase chain reaction arrays for inflammatory cytokines and receptors. The hippocampus was examined via quantitative polymerase chain reaction for the expression of immediate-early genes involved in brain repair (Bdnf), increasing neurotoxicity (Fos), and apoptosis control (Jdp2, Bcl2l1, Bcl2l11). In the piriform cortex, NIMP significantly stimulated expression for the macrophage inflammatory proteins CCL4, IL-1A, and IL-1B. Oxime 20 by itself elicited the most changes. When it was given therapeutically post-NIMP, the largest change occurred: a 310-fold repression of the inflammatory cytokine, CCL12. In the hippocampus, NIMP increased the expression of the neurotoxicity marker Fos and decreased the expression of neuroprotective Bdnf and antiapoptotic Bcl2l1. Compared with 2-PAM, Oxime 20 stimulated Bcl2l1 expression more and returned expression closer to the vehicle control values.
ESTHER : Dail_2021_J.Biochem.Mol.Toxicol__e22755
PubMedSearch : Dail_2021_J.Biochem.Mol.Toxicol__e22755
PubMedID: 33682265

Title : Central neuroprotection demonstrated by novel oxime countermeasures to nerve agent surrogates - Chambers_2020_Ann.N.Y.Acad.Sci__
Author(s) : Chambers JE , Meek EC
Ref : Annals of the New York Academy of Sciences , : , 2020
Abstract : Oximes remain a long-standing element of the therapy for nerve agents, organophosphates (OPs) that poison by inhibiting the enzyme acetylcholinesterase (AChE), resulting in hypercholinergic activity both centrally and peripherally. Oximes, such as the pyridinium oxime pralidoxime (2-PAM) in the United States, can reactivate the inhibited AChE and restore cholinergic function. However, there are several drawbacks to the current oximes; one of them, the inability of these oximes to effectively enter the brain, is the subject of study by several laboratories, including ours. Our laboratory invented a platform of substituted phenoxyalkyl pyridinium oximes that were tested against highly relevant surrogates of the nerve agents, sarin and VX. Using high sublethal dosages of the OPs, the novel oximes were observed to attenuate seizure-like behavior in rats and to reduce the levels of glial fibrillary acidic protein (an indicator of glial scarring) to control levels, in contrast to levels observed with 2-PAM or no oxime therapy. Using lethal levels of surrogates, some novel oximes protected against lethality compared with 2-PAM, shortened the time to cessation of seizure-like behavior (from 8+ to 6 h), and protected the brain neurons. Therefore, some of these novel oximes are showing exceptional promise alone or in combination with 2-PAM as therapeutics against nerve agent toxicity.
ESTHER : Chambers_2020_Ann.N.Y.Acad.Sci__
PubMedSearch : Chambers_2020_Ann.N.Y.Acad.Sci__
PubMedID: 32319115

Title : Oxime-mediated reactivation of organophosphate-inhibited acetylcholinesterase with emphasis on centrally-active oximes - Chambers_2020_Neuropharmacol__108201
Author(s) : Chambers JE , Dail MB , Meek EC
Ref : Neuropharmacology , :108201 , 2020
Abstract : This review provides an overview of the global research leading to the large number of compounds developed as reactivators of acetylcholinesterase inhibited by a variety of organophosphate compounds, most of which are nerve agents but also some insecticides. A number of these organophosphates are highly toxic and effective therapy by reactivators contributes to saving lives. Two major challenges for more effective therapy with reactivators are identification of a broad spectrum reactivator efficacious against a variety of organophosphate structures, and a reactivator that can cross the blood-brain barrier to protect the brain. The most effective of the reactivators developed are the nucleophilic pyridinium oximes, which bear a permanent positive charge from the quaternary nitrogen in the pyridinium ring. The permanent positive charge retards the oximes from crossing the blood-brain barrier and therefore restoration of normal cholinergic function in the brain is unlikely. A number of laboratories have developed nucleophiles, mostly oximes, that are theorized to cross the blood-brain barrier by several strategies. At the present time, no reactivator is optimally broad spectrum across the wide group of organophosphate chemistries. Some oximes, including the substituted phenoxyalkyl pyridinium oximes invented by our laboratories, have the potential to provide neuroprotection in the brain and show evidence of efficacy against both nerve agent and insecticidal chemistries, so these novel oximes have promise for future development.
ESTHER : Chambers_2020_Neuropharmacol__108201
PubMedSearch : Chambers_2020_Neuropharmacol__108201
PubMedID: 32544483

Title : Novel centrally active oxime reactivators of acetylcholinesterase inhibited by surrogates of sarin and VX - Chambers_2019_Neurobiol.Dis__104487
Author(s) : Chambers JE , Meek EC
Ref : Neurobiol Dis , :104487 , 2019
Abstract : A novel oxime platform, the substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937), was invented at Mississippi State University with an objective of discovering a brain-penetrating antidote to highly potent organophosphate anticholinesterases, such as the nerve agents. The goal was reactivation of inhibited brain acetylcholinesterase to attenuate the organophosphate-induced hypercholinergic activity that results in glutamate-mediated excitotoxicity and neuropathology. The currently approved oxime antidote in the US, 2-PAM, cannot do this. Using highly relevant surrogates of sarin and VX that leave acetylcholinesterase phosphylated with the same chemical moiety as their respective nerve agents, in vitro screens and in vivo tests in rats were conducted to identify the most efficacious members of this platform. The most promising novel oximes provided 24-h survival of lethal level surrogate exposure better than 2-PAM in almost all cases, and two of the oximes shortened the time to cessation of seizure-like behavior while 2-PAM did not. The most promising novel oximes attenuated neuropathology as indicated by immunohistochemical stains for both glia and neurons, while 2-PAM did not protect either glia or neurons. These results strongly suggest that these novel oximes can function within the brain to protect it, and therefore show great promise as potential future nerve agent antidotes.
ESTHER : Chambers_2019_Neurobiol.Dis__104487
PubMedSearch : Chambers_2019_Neurobiol.Dis__104487
PubMedID: 31158460

Title : Novel Brain-Penetrating Oxime Acetylcholinesterase Reactivators Attenuate Organophosphate-Induced Neuropathology in the Rat Hippocampus - Dail_2019_Toxicol.Sci_169_465
Author(s) : Dail MB , Leach CA , Meek EC , Olivier AK , Pringle RB , Green CE , Chambers JE
Ref : Toxicol Sci , 169 :465 , 2019
Abstract : Organophosphate (OP) anticholinesterases cause excess acetylcholine leading to seizures which, if prolonged, result in neuronal damage in the rodent brain. Novel substituted phenoxyalkyl pyridinium oximes have previously shown evidence of penetrating the rat blood-brain barrier (BBB) in in vivo tests with a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the active metabolite of the insecticide parathion, paraoxon (PXN), by reducing the time to cessation of seizure-like behaviors and accumulation of glial fibrillary acidic protein, whereas 2-PAM did not. The neuroprotective ability of our lead oximes (15, 20, and 55) was tested using NeuN, Nissl, and Fluoro-Jade B staining in the rat hippocampus. Following lethal-level subcutaneous challenge with NIMP or PXN, rats were intramuscularly administered a novel oxime or 2-PAM plus atropine and euthanized at 4 days. There were statistically significant increases in the median damage scores of the NeuN-stained NIMP, NIMP/2-PAM, and NIMP/Oxime 15 groups compared with the control whereas the scores of the NIMP/Oxime 20 and NIMP/Oxime 55 were not significantly different from the control. The same pattern of statistical significance was observed with PXN. Nissl staining provided a similar pattern, but without statistical differences. Fluoro-Jade B indicated neuroprotection from PXN with novel oximes but not with 2-PAM. The longer blood residence times of Oximes 20 and 55 compared with Oxime 15 might have contributed to their greater efficacy. These results suggest that novel oximes 20 and 55 were able to penetrate the BBB and attenuate neuronal damage after NIMP and PXN exposure, indicating potential broad-spectrum usefulness.
ESTHER : Dail_2019_Toxicol.Sci_169_465
PubMedSearch : Dail_2019_Toxicol.Sci_169_465
PubMedID: 30835286

Title : In vitro P-glycoprotein activity does not completely explain in vivo efficacy of novel centrally effective oxime acetylcholinesterase reactivators - Dail_2018_Drug.Chem.Toxicol__1
Author(s) : Dail MB , Meek EC , Chambers HW , Chambers JE
Ref : Drug & Chemical Toxicology , :1 , 2018
Abstract : Novel-substituted phenoxyalkyl pyridinium oxime acetylcholinesterase (AChE) reactivators (US patent 9,227,937) that showed convincing evidence of penetration into the brains of intact rats were developed by our laboratories. The oximes separated into three groups based on their levels of brain AChE reactivation following exposure of rats to the sarin surrogate nitrophenyl isopropyl methylphosphonate (NIMP). P-glycoprotein (P-gp) is a major blood-brain barrier (BBB) transporter and requires ATP for efflux. To determine if P-gp affinity screening could be used to reduce animal use, we measured in vitro oxime-stimulated ATPase activity to see if the in vivo reactivation efficacies related to the oximes' functions as P-gp substrates. High efficacy oximes were expected to be poor P-gp substrates, thus remaining in the brain longer. The high efficacy oximes (24-35% brain AChE reactivation) were worse P-gp substrates than the low efficacy oximes (0-7% brain AChE reactivation). However, the oxime group with medium in vivo reactivation of 10-17% were even worse P-gp substrates than the high efficacy group so their reactivation ability was not reflected by P-gp export. The results suggest that in vitro P-gp ATPase activity can remove the low efficacy oximes from in vivo testing, but is not sufficient to differentiate between the top two tiers.
ESTHER : Dail_2018_Drug.Chem.Toxicol__1
PubMedSearch : Dail_2018_Drug.Chem.Toxicol__1
PubMedID: 29722548

Title : Neuroprotection From Organophosphate-Induced Damage by Novel Phenoxyalkyl Pyridinium Oximes in Rat Brain - Pringle_2018_Toxicol.Sci_166_420
Author(s) : Pringle RB , Meek EC , Chambers HW , Chambers JE
Ref : Toxicol Sci , 166 :420 , 2018
Abstract : The nerve agents are extremely toxic organophosphates which lead to massive inhibition of acetylcholinesterase (AChE) in both the central and peripheral nervous systems. The currently approved pyridinium oxime reactivators of organophosphate-inhibited AChE (eg, 2-PAM in the United States) cannot penetrate the blood-brain barrier because of the permanent positive charge in the pyridinium ring. Therefore these current oximes cannot rescue inhibited AChE in the brain. Our laboratories have invented and patented a platform of substituted phenoxyalkyl pyridinium oximes that have been tested for efficacy as therapy within the brains of adult male rats which were challenged with a high sublethal dosage of highly relevant surrogates of sarin (nitrophenyl isopropyl methylphosphonate, NIMP) and VX (nitrophenyl ethyl methylphosphonate, NEMP). The histochemical astrocyte marker glial fibrillary acidic protein (GFAP) was investigated as an indication of neuropathology in two brain regions, the piriform cortex and the dentate gyrus of the hippocampus, which are regions known to be damaged by nerve agent toxicity. Rats treated with either NIMP or NEMP without therapy or with NIMP or NEMP plus 2-PAM therapy showed similar increases in GFAP compared with vehicle controls. However, the rats challenged with NIMP or NEMP plus therapy with our novel Oxime 20 (either a bromide or a mesylate salt) showed GFAP levels statistically undistinguishable from controls. These data provide highly supportive functional evidence of novel oxime entry into the brain. These novel oximes have the potential to provide central neuroprotection from organophosphate anticholinesterase-induced damage, which is a characteristic not displayed by most pyridinium oximes.
ESTHER : Pringle_2018_Toxicol.Sci_166_420
PubMedSearch : Pringle_2018_Toxicol.Sci_166_420
PubMedID: 30496567

Title : Effects of Chlorpyrifos or Methyl Parathion on Regional Cholinesterase Activity and Muscarinic Receptor Subtype Binding in Juvenile Rat Brain - Guo-Ross_2017_J.Toxicol.Pharmacol_1_
Author(s) : Guo-Ross SX , Meek EC , Chambers JE , Carr RL
Ref : J Toxicol Pharmacol , 1 : , 2017
Abstract : The effects of developmental exposure to two organophosphorus (OP) insecticides, chlorpyrifos (CPF) and methyl parathion (MPS), on cholinesterase (ChE) activity and muscarinic acetylcholine receptor (mAChR) binding were investigated in preweanling rat brain. Animals were orally gavaged daily with low, medium, and high dosages of the insecticides using an incremental dosing regimen from postnatal day 1 (PND1) to PND20. On PND12, PND17 and PND20, the cerebral cortex, corpus striatum, hippocampus, and medulla-pons were collected for determination of ChE activity, total mAChR density, and the density of the individual mAChR subtypes. ChE activity was inhibited by the medium and high dosages of CPF and MPS at equal levels in all four brain regions at all three ages examined. Exposure to both compounds decreased the levels of the M1, M2/M4, and M3 subtypes and the total mAChR level in all brain regions, but the effects varied by dosage group and brain region. On PND12, only the high dosages induced receptor changes while on PND17 and PND20, greater effects became evident. In general, the effects on the M1 subtype and total receptor levels appeared to be greater in the cerebral cortex and hippocampus than in the corpus striatum and medulla-pons. This did not appear to be the case for the M2/M4 and M3 subtypes effects. The differences between CPF and MPS were minimal even though in some cases, CPF exerted statistically greater effects than MPS did. In general, repeated exposure to organophosphorus insecticides can alter the levels of the various mAChR subtypes in various brain regions which could induce perturbation in cholinergic neurochemistry during the maturation of the brain regions.
ESTHER : Guo-Ross_2017_J.Toxicol.Pharmacol_1_
PubMedSearch : Guo-Ross_2017_J.Toxicol.Pharmacol_1_
PubMedID: 30035273

Title : Comparison of inhibition kinetics of several organophosphates, including some nerve agent surrogates, using human erythrocyte and rat and mouse brain acetylcholinesterase - Coban_2016_Toxicol.Lett_248_39
Author(s) : Coban A , Carr RL , Chambers HW , Willeford KO , Chambers JE
Ref : Toxicol Lett , 248 :39 , 2016
Abstract : Because testing of nerve agents is limited to only authorized facilities, our laboratory developed several surrogates that resemble nerve agents because they phosphylate the acetylcholinesterase (AChE) with the same moiety as the actual nerve agents. The inhibition kinetic parameters were determined for AChE by surrogates of cyclosarin (NCMP), sarin (NIMP, PIMP and TIMP) and VX (NEMP and TEMP) and other organophosphorus compounds derived from insecticides. All compounds were tested with rat brain and a subset was tested with mouse brain and purified human erythrocyte AChE. Within the compounds tested on all AChE sources, chlorpyrifos-oxon had the highest molecular rate constant followed by NCMP and NEMP. This was followed by NIMP then paraoxon and DFP with rat and mouse brain AChE but DFP was a more potent inhibitor than NIMP and paraoxon with human AChE. With the additional compounds tested only in rat brain, TEMP was slightly less potent than NEMP but more potent than PIMP which was more potent than NIMP. Methyl paraoxon was slightly less potent than paraoxon but more potent than TIMP which was more potent than DFP. Overall, this study validates that the pattern of inhibitory potencies of our surrogates is comparable to the pattern of inhibitory potencies of actual nerve agents (i.e., cyclosarin>VX>sarin), and that these are more potent than insecticidal organophosphates.
ESTHER : Coban_2016_Toxicol.Lett_248_39
PubMedSearch : Coban_2016_Toxicol.Lett_248_39
PubMedID: 26965078

Title : Novel brain-penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates - Chambers_2016_Ann.N.Y.Acad.Sci_1374_52
Author(s) : Chambers JE , Meek EC , Chambers HW
Ref : Annals of the New York Academy of Sciences , 1374 :52 , 2016
Abstract : Current oxime reactivators for organophosphate-inhibited cholinesterase (ChE) do not effectively cross the blood-brain barrier and therefore cannot restore brain ChE activity in vivo. Our laboratories have studied highly relevant sarin and VX surrogates, which differ from their respective nerve agents only in the leaving group and thereby leave ChE phosphylated with the same chemical moiety as sarin and VX. Our laboratories have developed novel substituted phenoxyalkyl pyridinium oximes that lead to reduced ChE inhibition in the brains of rats challenged with a high sublethal dosage of the sarin surrogate, whereas 2-PAM did not, using a paradigm designed to demonstrate brain penetration. In addition, treatment of rats with these novel oximes is associated with attenuation of seizure-like behavior compared to rats treated with 2-PAM, providing additional evidence that the oximes penetrate the blood-brain barrier. Further, some of the oximes provided 24-h survival superior to 2-PAM, and shortened the duration of seizure-like behavior when rats were challenged with lethal dosages of the sarin and VX surrogates, providing additional support for the conclusion that these oximes penetrate the brain.
ESTHER : Chambers_2016_Ann.N.Y.Acad.Sci_1374_52
PubMedSearch : Chambers_2016_Ann.N.Y.Acad.Sci_1374_52
PubMedID: 27153507

Title : Efficacy of novel phenoxyalkyl pyridinium oximes as brain-penetrating reactivators of cholinesterase inhibited by surrogates of sarin and VX - Chambers_2016_Chem.Biol.Interact_259_154
Author(s) : Chambers JE , Chambers HW , Funck KE , Meek EC , Pringle RB , Ross MK
Ref : Chemico-Biological Interactions , 259 :154 , 2016
Abstract : Pyridinium oximes are strong nucleophiles and many are effective reactivators of organophosphate-inhibited cholinesterase (ChE). However, the current oxime reactivators are ineffective at crossing the blood-brain barrier and reactivating brain ChE in the intact organism. Our laboratories have developed a series of substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937 B2) with the goal of identifying reactivators effective in crossing the blood-brain barrier. The first 35 of the series were found to have similar in vitro efficacy as reactivators of ChE inhibited by a sarin surrogate (phthalimidyl isopropyl methylphosphonate, PIMP) or a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP) in bovine brain preparations as previously observed in rat brain preparations. A number of these novel oximes have shown the ability to decrease the level of ChE inhibition in the brains of rats treated with a high sublethal dosage of either a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the VX surrogate NEMP. Levels of reactivation at 2 h after oxime administration were up to 35% while the currently approved therapeutic, 2-PAM, yielded no reduction in brain ChE inhibition. In addition, there was evidence of attenuation of seizure-like behavior with several of the more effective novel oximes, but not 2-PAM. Therefore these novel oximes have demonstrated an ability to reactivate inhibited ChE in brain preparations from two species and in vivo data support their ability to enter the brain and provide a therapeutic action. These novel oximes have the potential to be developed into improved antidotes for nerve agent therapy.
ESTHER : Chambers_2016_Chem.Biol.Interact_259_154
PubMedSearch : Chambers_2016_Chem.Biol.Interact_259_154
PubMedID: 27387540

Title : In vitro characterization of pralidoxime transport and acetylcholinesterase reactivation across MDCK cells and stem cell-derived human brain microvascular endothelial cells (BC1-hBMECs) - Gallagher_2016_Fluids.Barriers.CNS_13_10
Author(s) : Gallagher E , Minn I , Chambers JE , Searson PC
Ref : Fluids Barriers CNS , 13 :10 , 2016
Abstract : BACKGROUND: Current therapies for organophosphate poisoning involve administration of oximes, such as pralidoxime (2-PAM), that reactivate the enzyme acetylcholinesterase. Studies in animal models have shown a low concentration in the brain following systemic injection.
METHODS: To assess 2-PAM transport, we studied transwell permeability in three Madin-Darby canine kidney (MDCKII) cell lines and stem cell-derived human brain microvascular endothelial cells (BC1-hBMECs). To determine whether 2-PAM is a substrate for common brain efflux pumps, experiments were performed in the MDCKII-MDR1 cell line, transfected to overexpress the P-gp efflux pump, and the MDCKII-FLuc-ABCG2 cell line, transfected to overexpress the BCRP efflux pump. To determine how transcellular transport influences enzyme reactivation, we developed a modified transwell assay where the inhibited acetylcholinesterase enzyme, substrate, and reporter are introduced into the basolateral chamber. Enzymatic activity was inhibited using paraoxon and parathion.
RESULTS: The permeability of 2-PAM is about 2 x 10(-6) cm s(-1) in MDCK cells and about 1 x 10(-6) cm s(-1) in BC1-hBMECs. Permeability is not influenced by pre-treatment with atropine. In addition, 2-PAM is not a substrate for the P-gp or BCRP efflux pumps.
CONCLUSIONS: The low permeability explains poor brain penetration of 2-PAM and therefore the slow enzyme reactivation. This elucidates one of the reasons for the necessity of sustained intravascular (IV) infusion in response to organophosphate poisoning.
ESTHER : Gallagher_2016_Fluids.Barriers.CNS_13_10
PubMedSearch : Gallagher_2016_Fluids.Barriers.CNS_13_10
PubMedID: 27396356

Title : The effect of PON1 enhancers on reducing acetylcholinesterase inhibition following organophosphate anticholinesterase exposure in rats - Meek_2015_Toxicology_336_79
Author(s) : Meek EC , Chambers HW , Pringle RB , Chambers JE
Ref : Toxicology , 336 :79 , 2015
Abstract : Novel nucleophiles, a series of substituted phenoxyalkyl pyridinium oximes, have been previously shown by our laboratories to enhance in vitro paraoxonase 1 (PON1)-mediated degradation of a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) and a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP). Five of the most efficacious of these nucleophiles were tested in rats for their ability to reduce the level of acetylcholinesterase (AChE) inhibition in brain and peripheral tissues following exposure to NIMP or NEMP. Following simultaneous administration of a nucleophile plus surrogate (at 3 dosages yielding about 10-50% AChE inhibition in the brain at 15min), all five nucleophiles reduced the AChE inhibition in the brain at all 3 dosages, and reduced peripheral AChE inhibition at the lowest dosage. Protective effects were seen for only a short period of time, i.e., 15min. Even though these nucleophiles are oximes, they are not effective AChE reactivators so it is unlikely that the resultant decreases in AChE inhibition are from appreciable AChE reactivation. It is likely that the protective effects seen are, at least in part, the result of enhancement of PON1-mediated surrogate degradation, an unprecedented mechanism of therapy that has the potential to be developed into a nerve agent countermeasure.
ESTHER : Meek_2015_Toxicology_336_79
PubMedSearch : Meek_2015_Toxicology_336_79
PubMedID: 26275814

Title : Novel substituted phenoxyalkyl pyridinium oximes enhance survival and attenuate seizure-like behavior of rats receiving lethal levels of nerve agent surrogates - Chambers_2015_Toxicology_339_51
Author(s) : Chambers JE , Meek EC , Bennett JP , Bennett WS , Chambers HW , Leach CA , Pringle RB , Wills RW
Ref : Toxicology , 339 :51 , 2015
Abstract : Novel substituted phenoxyalkyl pyridinium oximes, previously shown to reactivate brain cholinesterase in rats treated with high sublethal dosages of surrogates of sarin and VX, were tested for their ability to prevent mortality from lethal doses of these two surrogates. Rats were treated subcutaneously with 0.6mg/kg nitrophenyl isopropyl methylphosphonate (NIMP; sarin surrogate) or 0.65mg/kg nitrophenyl ethyl methylphosphonate (NEMP; VX surrogate), dosages that were lethal within 24h to all tested rats when they received only 0.65mg/kg atropine at the time of initiation of seizure-like behavior (about 30min). If 146mmol/kg 2-PAM (human equivalent dosage) was also administered, 40% and 33% survival was obtained with NIMP and NEMP, respectively, while the novel Oximes 1 and 20 provided 65% and 55% survival for NIMP and 75 and 65% for NEMP, respectively. In addition, both novel oximes resulted in a highly significant decrease in time to cessation of seizure-like behavior compared to 2-PAM during the first 8h of observation. Brain cholinesterase inhibition was slightly less in novel oxime treated rats compared to 2-PAM in the 24h survivors. The lethality data indicate that 24h survival is improved by two of the novel oximes compared to 2-PAM. The cessation of seizure-like behavior data strongly suggest that these novel oximes are able to penetrate the blood-brain barrier and can combat the hypercholinergic activity that results in seizures. Therefore this oxime platform has exceptional promise as therapy that could both prevent nerve agent-induced lethality and attenuate nerve agent-induced seizures.
ESTHER : Chambers_2015_Toxicology_339_51
PubMedSearch : Chambers_2015_Toxicology_339_51
PubMedID: 26705700

Title : Novel nucleophiles enhance the human serum paraoxonase 1 (PON1)-mediated detoxication of organophosphates - Chambers_2015_Toxicol.Sci_143_46
Author(s) : Chambers JE , Chambers HW , Meek EC , Funck KE , Bhavaraju MH , Gwaltney SR , Pringle RB
Ref : Toxicol Sci , 143 :46 , 2015
Abstract : Paraoxonase 1 (PON1) is a calcium-dependent hydrolase associated with serum high-density lipoprotein particles. PON1 hydrolyzes some organophosphates (OPs), including some nerve agents, through nucleophilic attack of hydroxide ion (from water) in the active site. Most OPs are hydrolyzed inefficiently. This project seeks to identify nucleophiles that can enhance PON1-mediated OP degradation. A series of novel nucleophiles, substituted phenoxyalkyl pyridinium oximes, has been synthesized which enhance the degradation of surrogates of sarin (nitrophenyl isopropyl methylphosphonate; NIMP) and VX (nitrophenyl ethyl methylphosphonate; NEMP). Two types of in vitro assays have been conducted, a direct assay using millimolar concentrations of substrate with direct spectrophotometric quantitation of a hydrolysis product (4-nitrophenol) and an indirect assay using submicromolar concentrations of substrate with quantitation by the level of inhibition of an exogenous source of acetylcholinesterase from non-hydrolyzed substrate. Neither NIMP nor NEMP is hydrolyzed effectively by PON1 if one of these novel oximes is absent. However, in the presence of eight novel oximes, PON1-mediated degradation of both surrogates occurs. Computational modeling has created a model of PON1 embedded in phospholipid and has indicated general agreement of the binding enthalpies with the relative efficacy as PON1 enhancers. PON1 enhancement of degradation of OPs could be a unique and unprecedented mechanism of antidotal action.
ESTHER : Chambers_2015_Toxicol.Sci_143_46
PubMedSearch : Chambers_2015_Toxicol.Sci_143_46
PubMedID: 25304213

Title : Testing of novel brain-penetrating oxime reactivators of acetylcholinesterase inhibited by nerve agent surrogates - Chambers_2013_Chem.Biol.Interact_203_135
Author(s) : Chambers JE , Chambers HW , Meek EC , Pringle RB
Ref : Chemico-Biological Interactions , 203 :135 , 2013
Abstract : A critical need for combating the effects of organophosphate (OP) anticholinesterases, such as nerve agents, is the current lack of an effective oxime reactivator which can penetrate the blood-brain barrier (BBB), and therefore reactivate inhibited acetylcholinesterase (AChE) in the brain. Our laboratories have synthesized and have initiated testing of novel phenoxyalkyl pyridinium oximes (patent pending) that are more lipophilic than currently approved oximes. This is a preliminary report on these novel oximes which have been tested in vitro in rat brain homogenates with highly relevant surrogates for sarin (phthalimidyl isopropyl methylphosphonate; PIMP) and VX (nitrophenyl ethyl methylphosphonate; NEMP). The oximes demonstrated a range of 14-76% reactivation of rat brain AChE in vitro. An in vivo testing paradigm was developed in which the novel oxime was administered at the time of maximal brain AChE inhibition (about 80%) (1h) elicited by nitrophenyl isopropyl methylphosphonate (NIMP; sarin surrogate). This paradigm, with delayed administration of oxime to a time when brain AChE was starting to recover, was designed to minimize reactivation/reinhibition of peripheral AChE during the reactivation period which would decrease the availability of the surrogate for entry into the brain; this paradigm will allow proof of concept of BBB penetrability. The initial studies of these oximes in vivo with the sarin surrogate NIMP have indicated reactivation of up to about 25% at 30min after oxime administration and substantial attenuation of seizure behavior from some of the oximes. Therefore these novel oximes have considerable potential as brain-protecting therapeutics for anticholinesterases.
ESTHER : Chambers_2013_Chem.Biol.Interact_203_135
PubMedSearch : Chambers_2013_Chem.Biol.Interact_203_135
PubMedID: 23123249

Title : Synthesis and in vitro and in vivo inhibition potencies of highly relevant nerve agent surrogates - Meek_2012_Toxicol.Sci_126_525
Author(s) : Meek EC , Chambers HW , Coban A , Funck KE , Pringle RB , Ross MK , Chambers JE
Ref : Toxicol Sci , 126 :525 , 2012
Abstract : Four nonvolatile nerve agent surrogates, 4-nitrophenyl ethyl dimethylphosphoramidate (NEDPA, a tabun surrogate), 4-nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate), and two sarin surrogates, phthalimidyl isopropyl methylphosphonate (PIMP) and 4-nitrophenyl isopropyl methylphosphonate (NIMP), were synthesized and tested as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. These surrogates were designed to phosphorylate cholinesterases with the same moiety as their respective nerve agents, making them highly relevant for the study of cholinesterase reactivators. Surrogates were characterized by liquid chromatography-mass spectrometry and nuclear magnetic resonance. NEMP, PIMP, and NIMP were potent inhibitors of rat brain, skeletal muscle, diaphragm, and serum AChE as well as human erythrocyte AChE and serum BuChE in vitro. PIMP was determined to degrade quickly in aqueous solution, making it useful for in vitro assays only, and NEDPA was not a potent inhibitor of AChE or BuChE in vitro; therefore, these two surrogates were not tested in subsequent in vivo studies. Sublethal dosages (yielding about 80% brain AChE inhibition) were determined for both the stable sarin surrogate, NIMP (0.325 mg/kg ip), and the VX surrogate, NEMP (0.4 mg/kg ip), in adult male rats. Time course studies indicated the time to peak brain AChE inhibition for both NIMP and NEMP to be 1 h postexposure. Both surrogates yielded severe cholinergic signs. These dosages did not require the addition of atropine to prevent lethality, and the rate of AChE aging was slow, making these surrogates useful for reactivation studies both in vitro and in vivo. The surrogates synthesized in this study are potent yet safer to test than nerve agents and are useful tools for initial screening of nerve agent oxime therapeutics.
ESTHER : Meek_2012_Toxicol.Sci_126_525
PubMedSearch : Meek_2012_Toxicol.Sci_126_525
PubMedID: 22247004

Title : Developmental chlorpyrifos and methyl parathion exposure alters radial-arm maze performance in juvenile and adult rats - Johnson_2009_Toxicol.Sci_109_132
Author(s) : Johnson FO , Chambers JE , Nail CA , Givaruangsawat S , Carr RL
Ref : Toxicol Sci , 109 :132 , 2009
Abstract : Although the use of organophosphate (OP) insecticides has been restricted, sufficient exposure can occur to induce detrimental neurobehavioral effects. In this study, we measured physical and reflex development and spatial learning and memory in rats repeatedly exposed to incremental doses of chlorpyrifos (CPS) and methyl parathion (MPS) from postnatal day (PND) 1 to PND21. Other than decreased body weight in the higher dosage groups, no effects on physical or reflex development were observed. Significant hippocampal cholinesterase inhibition was induced in all treatment groups for up to 19 days following exposure. Beginning on PND36, working and reference memory was tested using a 12-arm radial maze, with subject animals trained and tested 4 days a week for 4 weeks. In males, working memory was decreased with the medium and high dosage of MPS but only the high dosage of CPS; while in females, no deficits were observed. For reference memory, errors were significantly increased in males exposed to the high dosage of CPS and all dosages of MPS. In females, enhanced performance was observed within the medium and high dosages of CPS but not with MPS. These data show that repeated developmental exposure to OP insecticides can induce sex-selective alterations and long-lasting changes in spatial learning and memory formation when measured using a radial arm maze and that MPS and CPS induce different neurobehavioral outcomes.
ESTHER : Johnson_2009_Toxicol.Sci_109_132
PubMedSearch : Johnson_2009_Toxicol.Sci_109_132
PubMedID: 19293373

Title : Assessing intermittent pesticide exposure from flea control collars containing the organophosphorus insecticide tetrachlorvinphos - Davis_2008_J.Expo.Sci.Environ.Epidemiol_18_564
Author(s) : Davis MK , Boone JS , Moran JE , Tyler JW , Chambers JE
Ref : J Expo Sci Environ Epidemiol , 18 :564 , 2008
Abstract : Fleas are a persistent problem for pets that require implementation of control measures. Consequently, pesticide use by homeowners for flea control is common and may increase pesticide exposure for adults and children. Fifty-five pet dogs (23 in study 1; 22 in study 2) of different breeds and weights were treated with over-the-counter flea collars containing tetrachlorvinphos (TCVP). During study 1, fur of treated dogs was monitored for transferable TCVP residues using cotton gloves to pet the dogs during 5-min rubbings post-collar application. Plasma cholinesterase (ChE) activity was also measured in treated dogs. Average amounts of TCVP transferred from the fur of the neck (rubbing over the collar) and from the back to gloves at 3 days post-collar application were 23,700+/-2100 and 260+/-50 microg/glove, respectively. No inhibition of plasma ChE was observed. During study 2, transferable TCVP residues to cotton gloves were monitored during 5-min rubbings post-collar application. Transferable residues were also monitored on cotton tee shirts worn by children and in the first morning urine samples obtained from adults and children. Average amounts of TCVP transferred to gloves at 5 days post-collar application from the neck (over the collar) and from the back were 22,400+/-2900 and 80+/-20 microg/glove, respectively. Tee shirts worn by children on days 7-11 contained 1.8+/-0.8 microg TCVP/g shirt. No significant differences were observed between adults and children in urinary 2,4,5-trichloromandelic acid (TCMA) levels; however, all TCMA residues (adults and children) were significantly greater than pretreatment concentrations (alpha=0.05). The lack of ChE inhibition in dogs and the low acute toxicity level of TCVP (rat oral LD(50) of 4-5 g/kg) strongly suggest that TCVP is rapidly detoxified and excreted and therefore poses a very low toxicological risk, despite these high residues.
ESTHER : Davis_2008_J.Expo.Sci.Environ.Epidemiol_18_564
PubMedSearch : Davis_2008_J.Expo.Sci.Environ.Epidemiol_18_564
PubMedID: 18167506

Title : Assessing transferable residues from intermittent exposure to flea control collars containing the organophosphate insecticide chlorpyrifos - Chambers_2007_J.Expo.Sci.Environ.Epidemiol_17_656
Author(s) : Chambers JE , Boone JS , Davis MK , Moran JE , Tyler JW
Ref : J Expo Sci Environ Epidemiol , 17 :656 , 2007
Abstract : Children can be exposed to pesticides from numerous residential sources such as carpet, house dust, toys and clothing from treated homes, and flea control remedies on pets. In the present studies, 48 pet dogs (24 in each of two studies) of different breeds and weights were treated with over-the-counter flea collars containing chlorpyrifos (CP), an organophosphorus insecticide. Transferable insecticide residues were quantified on cotton gloves used to rub the dogs for 5 min and on cotton tee shirts worn by a child (Study 2 only). First morning urine samples were also obtained from adults and children in both studies for metabolite (3,5,6-trichloro-2-pyridinol) quantification. Blood samples were obtained from treated dogs in Study 1 and plasma cholinesterase (ChE) activity was monitored. Transferable residues on gloves for all compounds were highest near the neck of the dogs and were lowest in areas most distant from the neck. Rubbing samples (over the collar) at two weeks post-collar application contained 447+/-57 microg CP/glove while samples from the fur of the back contained 8+/-2 microg CP/glove. In Study 2, cotton tee shirts worn by children at 15 days post-collar application for 4 h showed CP levels of 134+/-66 ng/g shirt. There were significant differences between adults and children in the levels of urinary metabolites with children generally having higher urinary levels of metabolites than adults (grand mean+/-SE; 11.6+/-1.1 and 7.9+/-0.74 ng/mg creatinine for children and adults, respectively, compared to 9.4+/-0.8 and 6.9+/-0.5 ng/mg creatinine before collar placement). Therefore, there was little evidence that the use of this flea collar contributed to enhanced CP exposure of either children or adults.
ESTHER : Chambers_2007_J.Expo.Sci.Environ.Epidemiol_17_656
PubMedSearch : Chambers_2007_J.Expo.Sci.Environ.Epidemiol_17_656
PubMedID: 17392689

Title : Altered muscarinic acetylcholine receptor subtype binding in neonatal rat brain following exposure to chlorpyrifos or methyl parathion - Guo-Ross_2007_Toxicol.Sci_100_118
Author(s) : Guo-Ross SX , Chambers JE , Meek EC , Carr RL
Ref : Toxicol Sci , 100 :118 , 2007
Abstract : The neurodevelopmental effects of two organophosphorus (OP) insecticides, chlorpyrifos (CPS) and methyl parathion (MPS), on cholinesterase (ChE) activity and muscarinic acetylcholine receptor (mAChR) binding were investigated in neonatal rat brain. Animals were orally gavaged using an incremental dosing regimen from postnatal day 1 (PND1) until PND8 with a low, medium, and high dosage for both CPS and MPS. On PND4 and PND8, ChE activity was measured in whole brain while the total and subtype densities of mAChRs were measured in three brain sections: area anterior to optic chiasma (anterior forebrain), area from the optic chiasma to the medulla/pons (posterior forebrain); and the medulla/pons excluding the cerebellum. The ligands 3H-pirenzepine, 3H-AF-DX 384, 3H-4-DAMP, and 3H-QNB were used to measure the maximal binding of the M1, M2/M4, and M3 subtypes and total mAChR receptors, respectively. In the anterior and the posterior forebrain, the levels of all mAChRs nearly doubled from PND4 to PND8, while in the medulla/pons, M1- and M3-subtype mAChR densities were low and did not increase and M2/M4 subtype and total mAChR slightly increased from PND4 to PND8. Reduction of ChE activity and mAChR binding by CPS or MPS was more evident in rats at PND8 than at PND4. With respect to mAChR binding, the greatest effects were observed in the medulla/pons and the least effects were observed in the posterior region of the forebrain. These results demonstrate that OPs exert adverse effects on rat central nervous system development through the cholinergic system in an age- and region-dependent manner.
ESTHER : Guo-Ross_2007_Toxicol.Sci_100_118
PubMedSearch : Guo-Ross_2007_Toxicol.Sci_100_118
PubMedID: 17666426

Title : Effects of topical phosmet on fur residue and cholinesterase activity of dogs - Boone_2006_Toxicol.Mech.Methods_16_275
Author(s) : Boone JS , Tyler JW , Davis MK , Chambers JE
Ref : Toxicol Mech Methods , 16 :275 , 2006
Abstract : Fleas, ticks, and mites are a major problem in many areas of the country for pet owners, and one treatment option involves the use of dips that contain pesticides. In the present study, dogs were dipped with a commercial phosmet (Imidan(R)) flea dip using the recommended guidelines for four consecutive treatments to determine the residues available for transfer to humans from the fur of the dogs. Twenty-four dogs of various breeds and weights were dipped, and each animal's fur was sampled with cotton gloves by petting for 5 minutes in a 10'' x 4'' area along the upper back before dipping and at 4 hours, and 1, 3, 7, and 14 days after dipping. Over the 4 dippings the 4-hour samples had a geometric mean of 2653 mug, and the 1-, 3-, 7-, and 14- day samples had geometric means of 877, 316, 84, and 20 mug, respectively. The samples ranged (in mug) from 80 to 16,794 at 4 hours, 44 to 7028 at 1 day, 1 to 4897 at 3 days, 1 to 2691 at 7 days, and 0.3 to 835 at 14 days. The residues removed by the petting did increase with the subsequent dips, but this was probably due to handler experience. The increase is not attributed to accumulation since there was less than 2% of transferable residue on the dog at 14 days post application. There was no significant inhibition of the plasma cholinesterase in the dogs over the study, suggesting that there was either a very low level of dermal absorption of phosmet or there was rapid detoxication (supported by EPA R 825170-01-0).
ESTHER : Boone_2006_Toxicol.Mech.Methods_16_275
PubMedSearch : Boone_2006_Toxicol.Mech.Methods_16_275
PubMedID: 20021025

Title : Effects of Piperonyl Butoxide on the Metabolism of DEF S,S,S-Tributyl Phosphorotrithioate) in Fingerling Channel Catfish - Straus_2006_Toxicol.Mech.Methods_16_235
Author(s) : Straus DL , Chambers JE
Ref : Toxicol Mech Methods , 16 :235 , 2006
Abstract : The present study was undertaken to investigate the significance of monooxygenases in bioactivation of DEF to a more effective anticholinesterase in fish. Channel catfish were exposed via the water column for 20 h to piperonyl butoxide (PBO) followed by a 4-h exposure to the organophosphate defolient DEF (concurrent with the PBO). Acetylcholinesterase (AChE) and aliesterases (ALiEs) activities were determined at 0 and 12 h after the exposure period. Inhibition of brain, liver, and plasma AChE activity by DEF was antagonized by PBO; muscle AChE was not inhibited by DEF. Piperonyl butoxide did not antagonize the inhibition of liver or plasma ALiEs by DEF. These results suggest that PBO retards the formation of the metabolite(s) of DEF that inhibit AChE, and that DEF is an effective inhibitor of ALiEs without metabolic activation.
ESTHER : Straus_2006_Toxicol.Mech.Methods_16_235
PubMedSearch : Straus_2006_Toxicol.Mech.Methods_16_235
PubMedID: 20021048

Title : Effects of repeated oral postnatal exposure to chlorpyrifos on cholinergic neurochemistry in developing rats - Richardson_2005_Toxicol.Sci_84_352
Author(s) : Richardson JR , Chambers JE
Ref : Toxicol Sci , 84 :352 , 2005
Abstract : The neurochemical effects of repeated postnatal exposure to chlorpyrifos (CPS) were studied in developing rats. Rats were gavaged daily from postnatal day (PND) 1-21 with CPS in corn oil starting at 1.5 mg/kg (low dosage group) and increasing gradually to 3 mg/kg and then to 6 mg/kg (high dosage group). Brain cholinesterase (ChE) activity was significantly inhibited on PND 6, 12, 22, and 30, with maximum inhibition on PND 6 of 49 and 59% and recovering to 18 and 33% on PND 30 in the low and high dosage groups, respectively. On PND 22 and 30, 94% or greater of the inhibited ChE could not be reactivated by the oxime TMB-4(Trimedoxime) in both treatment groups, indicating aging of the phosphorylated ChE. Total muscarinic acetylcholine receptors (mAChR) were reduced in a dose-related manner on PND 12 and 22, with substantial recovery by PND 30. M1/M3 mAChR were significantly reduced on PND 6 and 12 only in the high dosage group, and on PND 22 in both groups, while M2/M4 mAChR were reduced in the high dosage group on PND 22 and 30. On PND 30 choline acetyltransferase activity and vesicular acetylcholine transporter levels were decreased by 12 and 22%, respectively, only in the high dosage group. High-affinity choline transporter levels were decreased at all time points in the high dosage group and on PND 6, 22, and 30 in the low dosage group. The results presented here demonstrate that repeated postnatal exposures to CPS result in transient reductions of mAChR and more persistent alterations of presynaptic cholinergic neurons. In addition, the long-term reduction of brain ChE activity observed following repeated postnatal exposure to CPS is attributable to permanent inactivation or "aging" of the enzyme.
ESTHER : Richardson_2005_Toxicol.Sci_84_352
PubMedSearch : Richardson_2005_Toxicol.Sci_84_352
PubMedID: 15647600

Title : Neurochemical effects of repeated gestational exposure to chlorpyrifos in developing rats - Richardson_2004_Toxicol.Sci_77_83
Author(s) : Richardson JR , Chambers JE
Ref : Toxicol Sci , 77 :83 , 2004
Abstract : The neurochemical effects in developing rats exposed during gestation to the anticholinesterase organophosphorus insecticide chlorpyrifos (CPS) were determined. Pregnant rats were dosed daily with CPS (0, 3, or 7 mg/kg) in corn oil from gestation days (GD) 6-20. Pups were euthanized on postnatal days (PND) 1, 3, 6, 9, 12, and 30 for the determination of brain cholinesterase (ChE) and choline acetyltransferase (ChAT) activities, along with muscarinic receptor (mAChR) densities, the levels of the high-affinity choline uptake (HACU) system, and the vesicular acetylcholine transporter (VAChT). ChE activities were inhibited about 15 and 30% on PND 1, in the low- and high-dosage groups, respectively, and were not different from control values by PND 6. mAChR densities on PND 1 were reduced in the high-dosage group by about 18, 21, and 17%, using 3H-N-methylscopolamine, 3H-quinuclidinyl benzilate, and 3H-4-DAMP, respectively, as ligands, and were not different from control levels by PND 6. ChAT activity was decreased by approximately 12% in the high-dosage group on PND 9, 12, and 30. HACU levels, using 3H-hemicholinium-3 as the ligand, were reduced by approximately 25% on PND 6 in the low- and high-dosage groups, and by approximately 14 and 21% on PND 12 and 30, only in the high-dosage group. Levels of the VAChT were reduced by a range of 13-31% on PND 3 through 30 in the high-dosage group, using 3H-AH5183 (vesamicol) as the ligand. These data suggest that gestational exposure to 7 mg/kg/day CPS results in long-term alterations of presynaptic cholinergic neurochemistry.
ESTHER : Richardson_2004_Toxicol.Sci_77_83
PubMedSearch : Richardson_2004_Toxicol.Sci_77_83
PubMedID: 14600274

Title : The effects of repeated oral exposures to methyl parathion on rat brain cholinesterase and muscarinic receptors during postnatal development - Tang_2003_Toxicol.Sci_76_400
Author(s) : Tang J , Carr RL , Chambers JE
Ref : Toxicol Sci , 76 :400 , 2003
Abstract : Dimethyl phosphorylated cholinesterase (ChE) is known to be more rapidly reactivated, spontaneously, and have a higher aging rate than diethyl phosphorylated ChE. This may result in differences in toxic signs and tolerance development after treatment of juvenile rats with methyl parathion (MPS), a dimethyl phosphorothionate, than after treatment with chlorpyrifos (CPS), a diethyl phosphorothionate. The effects of repeated MPS exposures on brain ChE activity and surface and total muscarinic acetylcholine receptor (mAChR) density were studied in postnatal rats gavaged daily from postnatal day 1 (PND1) through PND 21. Results of this study were compared to our recent report with CPS (Tang et al., 1999, Toxicol. Sci. 51, 265-272). Rats received MPS daily starting at 0.3 mg/kg and increasing gradually to 0.6 mg/kg (for the medium-dosage groups) and then to 0.9 mg/kg (for the high-dosage group). ChE activity was assayed in brain homogenates. Synaptosomal mAChR densities, surface, and total were assayed using 3H-N-methylscopolamine (NMS) and 3H-quinuclidinyl benzilate (QNB), respectively, as ligands. Developmental increases in brain ChE activities and mAChR densities were observed from PND 6 through PND 22. On PND 22, inhibition of ChE activity was observed in the low (26%)-, medium (42%)-, and high (55%)-dosage groups. Significant inhibition was still present on PND 30 (16-24%) and PND 40 (12-14%), which were 9 and 19 days after the last treatment, respectively. Densities of 3H-NMS and 3H-QNB binding sites in treated groups were significantly reduced by PND 22, 1 day following cessation of treatment, and were significantly increased during the recovery period. After MPS exposure, the initial recovery of phosphorylated ChE was more rapid and the density of 3H-NMS binding sites was less readily reduced than following CPS exposure. The lesser effects on surface mAChR may explain why more severe signs appeared after each treatment with the high dosage of MPS than were observed previously with CPS, indicating little or no tolerance had developed to MPS.
ESTHER : Tang_2003_Toxicol.Sci_76_400
PubMedSearch : Tang_2003_Toxicol.Sci_76_400
PubMedID: 14514956

Title : Effects of gestational exposure to chlorpyrifos on postnatal central and peripheral cholinergic neurochemistry - Richardson_2003_J.Toxicol.Environ.Health.A_66_275
Author(s) : Richardson J , Chambers JE
Ref : J Toxicol Environ Health A , 66 :275 , 2003
Abstract : The effects of gestational exposure to the commonly used organophosphorus insecticide chlorpyrifos (O,O-diethyl O-[3,5,6-trichloro-2-pyridinyl]phosphorothioate) on postnatal central and peripheral cholinergic neurochemistry were investigated. Pregnant rats were orally dosed daily with chlorpyrifos (0, 3, 5, or 7 mg/kg) in corn oil from gestation day 6 to 20. Pups were sacrificed on postnatal days 1, 3, 6, 9, and 12 for the determination of brain, heart, lung, and serum cholinesterase, and brain choline acetyltransferase activities, along with liver carboxylesterase activity. Exposure to chlorpyrifos did not produce signs of overt toxicity to the dams or developing offspring. Cholinesterase activities were inhibited in a dose-related manner, with brain cholin-esterase inhibition of about 26%, 32%, and 45% on postnatal day 1. Inhibition of brain cholineste-rase persisted in all treatment groups until postnatal day 6 and in the medium and high-dosage groups through postnatal day 9. Liver carboxylesterase activity was also inhibited in a dose-related manner, with a recovery profile parallel to that of brain cholinesterase. Choline acetyltransferase activity was decreased by about 13% in the high-dosage group on postnatal days 9 and 12. These results indicate that gestational exposure to chlorpyrifos results in relatively persistent inhibition of brain cholinesterase and a delayed depression of choline acetyltransferase at a time when brain cholinesterase activity had returned to control levels in the high-dosage group.
ESTHER : Richardson_2003_J.Toxicol.Environ.Health.A_66_275
PubMedSearch : Richardson_2003_J.Toxicol.Environ.Health.A_66_275
PubMedID: 12521672

Title : Effects of PCB exposure on the toxic impact of organophosphorus insecticides - Carr_2002_Toxicol.Sci_67_311
Author(s) : Carr RL , Richardson JR , Guarisco JA , Kachroo A , Chambers JE , Couch TA , Durunna GC , Meek EC
Ref : Toxicol Sci , 67 :311 , 2002
Abstract : Exposure to polychlorinated biphenyls (PCBs) can alter the metabolism of organophosphorus (OP) insecticides. Female rats were fed vanilla wafers containing either 4 mg/kg/day of Aroclor 1254 (PCB-treated) or safflower oil (oil-treated) for 50 days. Rats were then injected, ip, with corn oil, parathion (P=S), methyl parathion (MP=S), chlorpyrifos (C=S), paraoxon (P=O), methyl paraoxon (MP=O), or chlorpyrifos-oxon (C=O). In the livers of rats treated with PCBs but not OP compounds, there was induction of desulfuration (activation) of P=S, MP=S, and C=S, but dearylation (detoxication) was induced only with P=S and MP=S. Hepatic A-esterase hydrolysis of all three oxons was induced. Cholinesterase (ChE) activity was determined in the medulla-pons, hippocampus, corpus striatum, cerebral cortex, skeletal muscle, lung, and heart at 2 and 24 h post exposure. With C=S, P=S, and MP=S, differences in brain ChE inhibition were observed at 2 h (MP=S > P=S > C=S) but few differences were observed between oil- and PCB-treated rats. By 24 h, the level of brain ChE inhibition had increased with P=S and C=S but had decreased with MP=S. In rats exposed to P=S and C=S but not MP=S, ChE inhibition was lower in PCB-treated rats than in oil-treated rats. This suggests that pre-exposure to PCBs has a protective effect against the acute toxicity of P=S and C=S, but not MP=S. This protective effect does not appear to be related to the alteration of the metabolism of these compounds. The slower rate of ChE inhibition following P=S and C=S compared to MP=S suggests that the protection may be mediated by the PCB-induced increase in A-esterase activity. This protection appears to be related to the time between exposure and inhibition of ChE. With the oxons at 2 h, inhibition of ChE was substantial and no differences were present between the PCB- and oil-treated rats. Thus, the rapid rate of inhibition of ChE by the oxons does not afford time for the increase in A-esterase hydrolysis to effectively provide protection against inhibition of ChE. However, while no differences between oil- and PCB-treated rats were observed with MP=O by 24 h, PCB-treated rats exposed to P=O and C=O had lower ChE inhibition than did oil-treated rats with greater differences observed with P=O than C=O.
ESTHER : Carr_2002_Toxicol.Sci_67_311
PubMedSearch : Carr_2002_Toxicol.Sci_67_311
PubMedID: 12011491

Title : Effects of repeated oral postnatal exposure to chlorpyrifos on open-field behavior in juvenile rats - Carr_2001_Toxicol.Sci_59_260
Author(s) : Carr RL , Chambers HW , Guarisco JA , Richardson JR , Tang J , Chambers JE
Ref : Toxicol Sci , 59 :260 , 2001
Abstract : Organophosphorus (OP) insecticides have the potential to cause behavioral effects in children. This study was designed to determine if repeated oral exposure of preweanling rats to chlorpyrifos would produce behavioral changes at both pre- and postweanling ages. Treatment occurred every second day beginning on post-natal day (PND) 1, and continued through PND 21. The rats received one of the following regimens: a low-dosage (3 mg/kg) from PND 1-21; a medium dosage (mg/kg from PND 1-5, and then 6 mg/kg from PND 7-21; or a high-dosage schedule of 3 mg/kg on PND 1-5, then 6 mg/kg from PND 7-13, and 12 mg/kg from PND 15-21. There were no differences in body weights among the control-, low-, and medium-dosage groups but the high-dosage group had significantly lower body weights on PND 13-21. An open field was used to measure locomotor activity on PND 10, 12, 14, 16, 18, 20, 25, and 30. There were no differences in locomotor activity levels or treatment effects between males and females. On PND 10, 12, 14, 16, 18, and 20 there was no effect on locomotor activity with any dosage. On days 25 and 30, locomotor activity was significantly decreased with the medium- and high-dosage groups. Brain cholinesterase (ChE) inhibition was about 25-38% on PND 25 and 14-34% on PND 30. On PND 25 but not 30, lung and diaphragm ChE and serum butyrylcholinesterase (BChE), with the high-dosage animals, and heart ChE with the medium- and high-dosage groups were significantly inhibited. There was no significant inhibition of skeletal muscle ChE or serum acetylcholinesterase (AChE) on PND 25 and 30. These data suggest that early postnatal chlorpyrifos exposures will depress locomotor activity in juvenile rats, with the effects most pronounced after brain ChE activity has substantially recovered.
ESTHER : Carr_2001_Toxicol.Sci_59_260
PubMedSearch : Carr_2001_Toxicol.Sci_59_260
PubMedID: 11158719

Title : Analysis of the additivity of in vitro inhibition of cholinesterase by mixtures of chlorpyrifos-oxon and azinphos-methyl-oxon - Richardson_2001_Toxicol.Appl.Pharmacol_172_128
Author(s) : Richardson JR , Chambers HW , Chambers JE
Ref : Toxicol Appl Pharmacol , 172 :128 , 2001
Abstract : Organophosphorus (OP) insecticides or their active metabolites act through a common mechanism of toxicity, the inhibition of cholinesterase (ChE). The effects of in vitro exposure of brain (target) and serum (biomarker) ChE to chlorpyrifos-oxon (C horizontal lineO) and azinphos-methyl-oxon (AZM horizontal lineO), the active metabolites of the insecticides chlorpyrifos and azinphos-methyl, respectively, were investigated to determine if simultaneous or sequential exposure to these two OP compounds results in purely additive effects. Additive was defined by the theoretical calculated percent inhibition (dose additivity), which takes into account the fraction of ChE molecules assumed to be available for inhibition by the second compound following inhibition by the first compound, not simple mathematical summation of percent inhibition (response additivity). Brain ChE simultaneously exposed to the two compounds resulted in additive effects, which were less than the simple mathematical summation of percent inhibition. However, serum ChE simultaneously exposed to the two compounds resulted in a nonlinear response, presumably due in part to the presence of detoxifying enzymes in the serum. Sequential exposure of both brain and serum ChE to the two compounds resulted in greater than additive effects at the higher concentrations of each compound. There was no departure from additivity at the lower concentrations of the two compounds. These data suggest that simple mathematical summation of percent inhibitions, i.e., response additivity, is not the appropriate method for describing the combined effects of C horizontal lineO and AZM horizontal lineO on ChE in vitro. In addition, there are other mechanisms involved, such as the presence of detoxication enzymes, that must be taken into account when analyzing the effects of combined exposure of ChE to these two compounds.
ESTHER : Richardson_2001_Toxicol.Appl.Pharmacol_172_128
PubMedSearch : Richardson_2001_Toxicol.Appl.Pharmacol_172_128
PubMedID: 11298499

Title : Transferable Residues From Dog Fur and Plasma Cholinesterase Inhibition in Dogs Treated with a Flea Control Dip Containing Chlorpyrifos - Boone_2001_Environ.Health.Perspect_109_1109
Author(s) : Boone JS , Tyler JW , Chambers JE
Ref : Environmental Health Perspectives , 109 :1109 , 2001
Abstract : We studied chlorpyrifos, an insecticide present in a commercial dip for treating ectoparasites in dogs, to estimate the amount of transferable residues that children could obtain from their treated pets. Although the chlorpyrifos dip is no longer supported by the manufacturer, the methodology described herein can help determine transferable residues from other flea control insecticide formulations. Twelve dogs of different breeds and weights were dipped using the recommended guidelines with a commercial, nonprescription chlorpyrifos flea dip for 4 consecutive treatments at 3-week intervals (nonshampoo protocol) and another 12 dogs were dipped with shampooing between dips (shampoo protocol). The samples collected at 4 hr and 7, 14, and 21 days after treatment in the nonshampoo protocol averaged 971, 157, 70, and 26 microg chlorpyrifos, respectively; in the shampoo protocol the samples averaged 459, 49, 15, and 10 microg, respectively. The highest single sample was about 7,000 microg collected at 4 hr. The pretreatment specific activities in the plasma of the dogs were about 75 nmol/min/mg protein for butyrylcholinesterase (BChE), and 9 nmol/min/mg protein for acetylcholinesterase (AChE). BChE was inhibited 50-75% throughout the study, and AChE was inhibited 11-18% in the nonshampoo protocol; inhibition was not as great in the shampoo protocol. There was no correlation (p
ESTHER : Boone_2001_Environ.Health.Perspect_109_1109
PubMedSearch : Boone_2001_Environ.Health.Perspect_109_1109
PubMedID: 11712994

Title : Detoxication of paraoxon by rat liver homogenate and serum carboxylesterases and A-esterases - Tang_1999_J.Biochem.Mol.Toxicol_13_261
Author(s) : Tang J , Chambers JE
Ref : J Biochem Mol Toxicol , 13 :261 , 1999
Abstract : Paraoxon, the active metabolite of parathion, can be detoxified through a noncatalytic pathway by carboxylesterases and a catalytic pathway by calcium-dependent A-esterases, producing p-nitrophenol as a common metabolite. The detoxication patterns of carboxylesterases and A-esterases were investigated in vitro in the present study with a high tissue concentration (75 mg/mL rat liver homogenate or 50% rat serum solution) to more closely reflect enzyme concentrations in intact tissues. A final paraoxon concentration of 3.75 microM was used to incubate with liver homogenates or serum solutions for 5 seconds or 3, 5, 15, or 25 minutes; also 0.625, 1.25, 2.5, 3.125, 3.75, or 5.0 microM paraoxon (final concentration) was incubated with liver homogenates or serum solutions for 15 minutes. Phenyl saligenin cyclic phosphate and EDTA were used to inhibit carboxylesterases and A-esterases, respectively. Significant amounts of p-nitrophenol were generated with or without either inhibitor during a 15 minute incubation with paraoxon from low (0.625 microM) to high (5.0 microM) concentrations. The amount of p-nitrophenol generated via carboxylesterase phosphorylation was greater than via A-esterase-mediated hydrolysis in the initial period of incubation or when incubating with a low concentration of paraoxon. Plateau shape curves of p-nitrophenol concentration versus time or paraoxon concentration indicated that carboxylesterase phosphorylation was saturable. When incubated for long time intervals or with high concentrations of paraoxon, more p-nitrophenol was generated via A-esterase-mediated hydrolysis than from carboxylesterase phosphorylation. The ratio of paraoxon concentration to tissue amount used in in vitro assays of this study was equivalent to dosing a rat with toxicologically relevant dosages. These in vitro data suggest that both carboxylesterases and A-esterases detoxify paraoxon in vivo; carboxylesterases may be an important mode of paraoxon detoxication in initial exposures to paraoxon or parathion before they become saturated, whereas A-esterases may contribute to paraoxon detoxication in repeated exposures to paraoxon or parathion because they will not become inhibited and will remain catalytically active unlike the carboxylesterases. The importance of carboxylesterases in detoxication of paraoxon was verified by an in vivo study. In rats pretreated with tri-o-tolyl phosphate, an in vivo carboxylesterase inhibitor, brain acetylcholinesterase was significantly inhibited after intravenous exposure to parathion. No significant inhibition of brain acetylcholinesterase was observed in rats pretreated with corn oil.
ESTHER : Tang_1999_J.Biochem.Mol.Toxicol_13_261
PubMedSearch : Tang_1999_J.Biochem.Mol.Toxicol_13_261
PubMedID: 10402560

Title : Changes in rat brain cholinesterase activity and muscarinic receptor density during and after repeated oral exposure to chlorpyrifos in early postnatal development - Tang_1999_Toxicol.Sci_51_265
Author(s) : Tang J , Carr RL , Chambers JE
Ref : Toxicol Sci , 51 :265 , 1999
Abstract : The effects of repeated oral exposures to the organophosphorus insecticide chlorpyrifos (CPS) on brain muscarinic receptor densities, together with cholinesterase (ChE) activity, were studied in early postnatal rats. Initially, the effects on esterases from lactational exposure to CPS were investigated in young rats by administering CPS (100, 150, or 200 mg/kg subcutaneously in corn oil) to dams 1 day postpartum, yielding a significant body burden of CPS in the dams for possible excretion in the milk. Brain ChE inhibition in pups was less severe than in dams, whereas liver carboxylesterase (CbxE) inhibition in pups was at the same level as in dams. Because of the limited brain ChE inhibition obtained following lactation, pups were exposed to CPS directly by gavage, using 3 dosing regimens to yield a dose response. The rats were gavaged with CPS in corn oil on alternate days from postnatal day (PND) 1 through PND 21. Rats in the low-dosage group received 11 treatments at 3 mg/kg, those in the medium-dosage group received 3 treatments at 3 mg/kg and 8 at 6 mg/kg, and those in the high dosage group received 3 treatments at 3 mg/kg, 4 at 6 mg/kg, and 4 at 12 mg/kg. ChE activity in brain homogenates were inhibited significantly by 29% and 63% in the low- and high-dosage groups, respectively, on PND 22 and by 17% in the high dosage group on PND 40. Muscarinic receptor densities in brain synaptosomes were reduced using 3H-N-methylscopolamine (NMS) and 3H-quinuclidinyl benzilate (QNB) as ligands, with the effects more prominent from 3H-NMS. Densities of both ligands recovered to the control level several days after terminating treatment. The results indicate that pups are apparently exposed to only limited amounts of chlorpyrifos and/or its oxon through the milk when dams are exposed to extremely high chlorpyrifos levels. In addition, repeated direct oral exposures of early postnatal rats to CPS will result in persistent brain ChE inhibition and will transiently reduce muscarinic receptor density.
ESTHER : Tang_1999_Toxicol.Sci_51_265
PubMedSearch : Tang_1999_Toxicol.Sci_51_265
PubMedID: 10543028

Title : Common mechanism of toxicity: a case study of organophosphorus pesticides - Mileson_1998_Toxicol.Sci_41_8
Author(s) : Mileson BE , Chambers JE , Chen WL , Dettbarn W , Ehrich M , Eldefrawi AT , Gaylor DW , Hamernik K , Hodgson E , Karczmar AG , Padilla S , Pope CN , Richardson RJ , Saunders DR , Sheets LP , Sultatos LG , Wallace KB
Ref : Toxicol Sci , 41 :8 , 1998
Abstract : The Food Quality Protection Act of 1996 (FQPA) requires the EPA to consider "available information concerning the cumulative effects of such residues and other substances that have a common mechanism of toxicity ... in establishing, modifying, leaving in effect, or revoking a tolerance for a pesticide chemical residue." This directive raises a number of scientific questions to be answered before the FQPA can be implemented. Among these questions is: What constitutes a common mechanism of toxicity? The ILSI Risk Science Institute (RSI) convened a group of experts to examine this and other scientific questions using the organophosphorus (OP) pesticides as the case study. OP pesticides share some characteristics attributed to compounds that act by a common mechanism, but produce a variety of clinical signs of toxicity not identical for all OP pesticides. The Working Group generated a testable hypothesis, anticholinesterase OP pesticides act by a common mechanism of toxicity, and generated alternative hypotheses that, if true, would cause rejection of the initial hypothesis and provide criteria for subgrouping OP compounds. Some of the alternative hypotheses were rejected outright and the rest were not supported by adequate data. The Working Group concluded that OP pesticides act by a common mechanism of toxicity if they inhibit acetylcholinesterase by phosphorylation and elicit any spectrum of cholinergic effects. An approach similar to that developed for OP pesticides could be used to determine if other classes or groups of pesticides that share structural and toxicological characteristics act by a common mechanism of toxicity or by distinct mechanisms.
ESTHER : Mileson_1998_Toxicol.Sci_41_8
PubMedSearch : Mileson_1998_Toxicol.Sci_41_8
PubMedID: 9520337

Title : Age-related differences in parathion and chlorpyrifos toxicity in male rats: target and nontarget esterase sensitivity and cytochrome P450- mediated metabolism - Atterberry_1997_Toxicol.Appl.Pharmacol_147_411
Author(s) : Atterberry TT , Burnett WT , Chambers JE
Ref : Toxicol Appl Pharmacol , 147 :411 , 1997
Abstract : Juvenile rats are more susceptible to the acute toxicity of the phosphorothionate insecticides parathion and chlorpyrifos than are adult rats. Developmental changes in brain acetylcholinesterase and hepatic aliesterase (carboxylesterase), cytochrome P450, and the P450-mediated metabolism of these two phosphorothionate insecticides were investigated in male Sprague-Dawley rats. Specific activities of acetylcholinesterase in cerebral cortex, but not medulla oblongata, and of liver aliesterases increased with age, indicating the presence of both more target esterases and more protective esterases, respectively, in the adult compared to the juvenile animal. Sensitivity of the brain acetylcholinesterase to inhibition by paraoxon and chlorpyrifosoxon, as measured by IC50 values, did not change significantly with age, whereas the hepatic aliesterase sensitivity to inhibition decreased with age. Progressive increases in activities of P450-mediated activation (desulfuration) (6- to 14-fold) and detoxication (dearylation) (2- to 4-fold), as well as concentrations of P450 (7-fold) and protein (2-fold), were observed between neonate and adult hepatic microsomes. Microsomal pentoxyresorufin O-dealkylase activity followed a developmental pattern similar to desulfuration and dearylation, displaying a 16-fold increase between neonates and adults. However, microsomal ethoxyresorufin O-deethylase activity increased until 21 days of age, displaying a 16-fold increase, then decreased in adulthood to a level 10-fold higher than neonates. These results indicate that target enzyme sensitivity is not responsible for age-related toxicity differences, nor is the potential for hepatic bioactivation, whereas lower levels of hepatic aliesterase-mediated protection and P450-mediated dearylation probably contribute significantly to the greater sensitivity of juveniles to phosphorothionate toxicity.
ESTHER : Atterberry_1997_Toxicol.Appl.Pharmacol_147_411
PubMedSearch : Atterberry_1997_Toxicol.Appl.Pharmacol_147_411
PubMedID: 9439736

Title : Time course of inhibition of cholinesterase and aliesterase activities, and nonprotein sulfhydryl levels following exposure to organophosphorus insecticides in mosquitofish (Gambusia affinis) - Boone_1996_Fundam.Appl.Toxicol_29_202
Author(s) : Boone JS , Chambers JE
Ref : Fundamental & Applied Toxicology , 29 :202 , 1996
Abstract : Cholinesterase (ChE) in brain and muscle was quickly inhibited during a 48-hr in vivo exposure to chlorpyrifos (0.1 ppm), parathion (0.15 ppm), and methyl parathion (8 ppm) in mosquitofish (Gambusia affinis). ChE remained inhibited during a 96-hr nonexposure period. Brain ChE reached peak inhibition by 12 hr after exposure to parathion and chlorpyrifos and by 4 hr after exposure to methyl parathion. All insecticides caused greater than 70% ChE inhibition by 4 hr in muscle. There was no recovery of ChE after 4 days of nonexposure in either brain or muscle. Hepatic aliesterases (AliE) were quickly and greatly inhibited (> 70% by 4 hr) after exposure to parathion and chlorpyrifos but not after exposure to methyl parathion. Exposure to methyl parathion required 24-36 hr to inhibit hepatic AliE to the same level as that following parathion and chlorpyrifos exposures at 4 hr. Exposure to all insecticides eventually resulted in greater than 80% inhibition of AliE. None of the test groups treated with insecticides showed any signs of significant recovery of AliE during the 4 days of nonexposure. Nonprotein sulfhydryl (NPSH) concentrations were lower than controls after 24 hr of exposure and 96 hr after recovery for all compounds. Exposure to methyl parathion lowered NPSH concentrations greater than the other compounds. Hepatic AliE appear capable of affording some protection of ChE from inhibition following parathion or chlorpyrifos exposures, but considerably less protection against methyl parathion.
ESTHER : Boone_1996_Fundam.Appl.Toxicol_29_202
PubMedSearch : Boone_1996_Fundam.Appl.Toxicol_29_202
PubMedID: 8742317

Title : Kinetic analysis of the in vitro inhibition, aging, and reactivation of brain acetylcholinesterase from rat and channel catfish by paraoxon and chlorpyrifos-oxon - Carr_1996_Toxicol.Appl.Pharmacol_139_365
Author(s) : Carr RL , Chambers JE
Ref : Toxicology & Applied Pharmacology , 139 :365 , 1996
Abstract : In rats, the phosphorothionate insecticide parathion exhibits greater toxicity than chlorpyrifos, while in catfish the toxicities are reversed. The in vitro inhibition of brain acetylcholinesterase (AChE) by the active metabolites of the insecticides and the rates at which these inhibitor-enzyme complexes undergo reactivation/ aging were investigated in both species. Rat AChE was more sensitive to inhibition than catfish AChE as demonstrated by greater bimolecular rate constants (ki) in rats than in catfish. In both species, chlorpyrifos-oxon yielded higher ki's than paraoxon. The higher association constant (KA) of chlorpyrifos-oxon than paraoxon in both species and the lack of significant differences in the phosphorylation constants (kp) suggest that association of the inhibitor with AChE is the principal factor in the different potencies between these two inhibitors. In catfish, the ki of chlorpyrifos-oxon was 22-fold greater than that of paraoxon, while in rats it was 9-fold greater, suggesting that target site sensitivity is an important factor in the higher toxicity of chlorpyrifos to catfish but not in the higher toxicity of parathion to rats. No spontaneous reactivation of phosphorylated catfish AChE occurred and there were no differences in the first oder aging constants (ka) between compounds. For phosphorylated rat AChE, there were no differences in the first order reactivation constants (kr) but the ka for chlorpyrifos-oxon was significantly greater than that for paraoxon. This difference suggests that the steric positioning of the diethyl phosphate in the esteratic site is not the same between the two compounds, leading to differences in aging.
ESTHER : Carr_1996_Toxicol.Appl.Pharmacol_139_365
PubMedSearch : Carr_1996_Toxicol.Appl.Pharmacol_139_365
PubMedID: 8806854

Title : The effect of high and low dosages of paraoxon in beta-naphthoflavone-treated rats - Watson_1996_J.Biochem.Toxicol_11_263
Author(s) : Watson AM , Chambers JE
Ref : Journal of Biochemical Toxicology , 11 :263 , 1996
Abstract : Aliesterases (carboxylesterases) are serine esterases that can serve a protective role for the target acetylcholinesterase (AChE) during organophosphorus insecticide intoxication because the former esterases are alternate phosphorylation sites. The levels of aliesterase activity in liver and plasma and AChE activity in brain regions were investigated after the intravenous administration of paraoxon (P = O) into female rats. The rats were pretreated intraperitoneally with beta-napthoflavone (BNF), which decreases hepatic aliesterase activity following a 3 day in vivo treatment, and/or tri-o-tolyl phosphate (TOTP) to inhibit aliesterases. The liver aliesterases were inhibited less by P = O in BNF-treated rats than in control rats, which suggests that either BNF exposure may have resulted in aliesterases that are less sensitive to P = O inhibition or BNF may have altered P = O's availability. The BNF treatment did not seem to alter the degree of inhibition of the brain AChE activity following the low dosage of paraoxon (0.04 mg/kg). However, the brain AChE activity in the P = O/TOTP/BNF-treated rats was lower than that in the P = O/TOTP-treated rats, suggesting that BNF also caused changes in systems affecting the disposition of P = O in addition to the changes in the hepatic aliesterases. At the high dosage of paraoxon (0.12 mg/kg), the AChE and aliesterase activities showed a pattern similar to that of the low dosage. This suggests that the aliesterases, as altered by BNF exposure, even when nearly completely inhibited, did not alter the response of the target enzyme, AChE, and, therefore, the magnitude of the toxic response.
ESTHER : Watson_1996_J.Biochem.Toxicol_11_263
PubMedSearch : Watson_1996_J.Biochem.Toxicol_11_263
PubMedID: 9176738

Title : Identification and isolation of two rat serum proteins with A-esterase activity toward paraoxon and chlorpyrifos-oxon - Pond_1996_Biochem.Pharmacol_52_363
Author(s) : Pond AL , Coyne CP , Chambers HW , Chambers JE
Ref : Biochemical Pharmacology , 52 :363 , 1996
Abstract : The active metabolites (oxons) of phosphorothionate insecticides can be detoxified via A-esterase hydrolysis. Two enzymes with A-esterase activity have been isolated from rat serum. Whole serum was applied to anion exchange gel (DEAE Sepharose Fast Flow) and incubated (1 hr). Tris-HCl buffer (0.05 M; pH 7.7, at 5 degrees) containing 0.25 M NaCl was added to the slurry and incubated. The decant, containing low A-esterase activity but a high protein concentration, was discarded. Further displacement of A-esterase from DEAE gel was achieved with 1.0 M NaCl in 0.05 M Tris-HCl buffer (Ph 7.7 at 5 degrees). Following desalting and concentration, further separation was achieved by gel filtration (Sephacryl S-100 HR) and two sequential preparative scale isoelectric focusings. Final fractions contained two proteins of high molecular mass (one about 200 kDa and one between 137 and 200 kDa). The apparent range of isoelectric points for the two enzymes was 4.5 to 5.6. Following native-PAGE analysis, activity stains with beta-naphthyl acetate and Fast Garnet GBC in the presence of paraoxon (10-5 M) verified that A-esterase activity was associated with both proteins. Spectropho-tometric assay detected A-esterase activity toward paraoxon, chlorpyrifos-oxon, and phenyl acetate in the final preparation.
ESTHER : Pond_1996_Biochem.Pharmacol_52_363
PubMedSearch : Pond_1996_Biochem.Pharmacol_52_363
PubMedID: 8694862

Title : Inhibition and aging of channel catfish brain acetylcholinesterase following exposure to two phosphorothionate insecticides and their active metabolites - Carr_1995_J.Toxicol.Env.Health_45_325
Author(s) : Carr RL , Straus DL , Chambers JE
Ref : Journal of Toxicology & Environmental Health , 45 :325 , 1995
Abstract : The inhibition and aging of acetylcholinesterase (AChE) in fingerling channel catfish (lctalurus punctatus) brain tissue was studied after single in vivo exposures to high levels of chlorpyrifos (0.25 mg/L), chlorpyrifos-oxon (7 micrograms/L), parathion (2.5 mg/L), or paraoxon (30 micrograms/L). Exposure to both parent compounds produced identical initial inhibition (95%), but in the later sampling times there was significantly more inhibited AChE in the chlorpyrifos-treated fish than in the parathion-treated fish (47% and 28%, respectively, on d 16). There were higher levels of aged AChE following chlorpyrifos exposure than following parathion exposure, but differences were not significant. Exposure to both oxons produced initial inhibition greater than 90%, and patterns of recovery and aging were statistically similar between both compounds; no significant inhibition was observed after d 11. The similar patterns of inhibition, recovery, and aging between the two oxon treatments, which have similar lipophilicities, suggest that the greater amount of AChE inhibition and aging observed in the chlorpyrifos-treated fish compared with the parathion-treated fish probably results from the higher lipophilicity of chlorpyrifos than of parathion. Overall, the prolonged brain AChE inhibition exhibited in catfish exposed to phosphorothionates is not the result of aging of the inhibited enzyme but is the result of either a slow rate or a lack of spontaneous reactivation.
ESTHER : Carr_1995_J.Toxicol.Env.Health_45_325
PubMedSearch : Carr_1995_J.Toxicol.Env.Health_45_325
PubMedID: 7541841

Title : Role of detoxication pathways in acute toxicity levels of phosphorothionate insecticides in the rat - Chambers_1994_Life.Sci_54_1357
Author(s) : Chambers JE , Ma T , Boone JS , Chambers HW
Ref : Life Sciences , 54 :1357 , 1994
Abstract : Phosphorothionate insecticides and their active oxon metabolites can be detoxified by a variety of hepatic mechanisms. Cytochrome P450-mediated dearylation activity was higher in males than in females. While dearylation was induced by phenobarbital in both sexes, it was induced by beta-naphthoflavone in females only. Detoxication of oxons in the presence of EDTA was inducible by phenobarbital, was higher in males than in females, and paralleled aliesterase activity. In vitro Ca(++)-dependent A-esterase-mediated hydrolysis of chlorpyrifos-oxon but not of paraoxon occurred at biologically relevant nM concentrations. This hydrolysis was also inducible by phenobarbital. Glutathione-mediated conjugation did not appear to be relevant to the disposition of the phosphorothionates studied here. Hepatic detoxication via dearylation, aliesterase phosphorylation and A-esterase-mediated hydrolysis (for some organophosphates) all appear to be relevant reactions in the attenuation of acute toxicity.
ESTHER : Chambers_1994_Life.Sci_54_1357
PubMedSearch : Chambers_1994_Life.Sci_54_1357
PubMedID: 7514706

Title : Inhibition patterns of brain acetylcholinesterase and hepatic and plasma aliesterases following exposures to three phosphorothionate insecticides and their oxons in rats - Chambers_1993_Fundam.Appl.Toxicol_21_111
Author(s) : Chambers JE , Carr RL
Ref : Fundamental & Applied Toxicology , 21 :111 , 1993
Abstract : Rats were administered high sublethal intraperitoneal dosages of the phosphorothionate insecticides parathion, methyl parathion, and chlorpyrifos, and their oxons. Acetylcholinesterase activities in cerebral cortex and medulla oblongata and aliesterase activities in liver and plasma were monitored at 2 hr and 1, 2, and 4 days after exposure. The maximal inhibition of brain acetylcholinesterase activity was not immediate with parathion and chlorpyrifos, reflecting the time required for bioactivation of the phosphorothionates as well as the effectiveness of the aliesterases to inactivate much of the hepatically generated oxons. In contrast, brain acetylcholinesterase activities were more quickly inhibited following administration of paraoxon and chlorpyrifos-oxon, which do not require bioactivation. Brain acetylcholinesterase was also rapidly inhibited following administration of methyl parathion and methyl paraoxon, reflecting the low sensitivity of the aliesterases to methyl paraoxon. Aliesterases were inhibited to a greater extent than acetylcholinesterase at each sampling time with parathion and chlorpyrifos and their oxons, whereas the reverse was true with methyl parathion and methyl paraoxon. All of the above patterns correlate with the in vitro sensitivities of acetylcholinesterase and aliesterases to the oxons. The very prolonged inhibition of esterase activities following chlorpyrifos treatment probably results from its substantially greater lipophilicity compared to the other compounds, which would allow it to be stored and released for gradual bioactivation. The data reported indicate that the disposition and effects of different phosphorothionate insecticides will be influenced by the sensitivities of target and nontarget esterases for their oxons and by their lipophilicity, and that predictions of in vivo responses can be made from in vitro data.
ESTHER : Chambers_1993_Fundam.Appl.Toxicol_21_111
PubMedSearch : Chambers_1993_Fundam.Appl.Toxicol_21_111
PubMedID: 7689992

Title : Acute effects of the organophosphate paraoxon on schedule-controlled behavior and esterase activity in rats: dose-response relationships - Carr_1991_Pharmacol.Biochem.Behav_40_929
Author(s) : Carr RL , Chambers JE
Ref : Pharmacol Biochem Behav , 40 :929 , 1991
Abstract : The effects of acute intraperitoneal administration of paraoxon on behavioral and biochemical parameters were studied in male rats. Rats were trained to press a lever under an FR10 schedule of reinforcement. Rats were injected with 3 sublethal doses of paraoxon (0.5, 0.75, and 1.0 mg/kg) and performance was monitored for four days after exposure. Response rates were depressed significantly for days 1 and 2 with 0.75 and 1.0 mg/kg, but not 0.5 mg/kg, even though there was inhibition of brain and plasma cholinesterases at all doses. Performance recovered prior to brain AChE recovery. There was no clear-cut threshold of brain AChE inhibition required to yield performance deficits, nor was there a direct correlation between significant inhibition in peripheral enzymes which could serve as markers (plasma aliesterases, butyrylcholinesterase, non-iso-OMPA-sensitive cholinesterase, and hepatic aliesterases) and performance deficits, suggesting that other noncholinergic targets may play a role in OP-induced behavioral deficits.
ESTHER : Carr_1991_Pharmacol.Biochem.Behav_40_929
PubMedSearch : Carr_1991_Pharmacol.Biochem.Behav_40_929
PubMedID: 1816579

Title : Noncatalytic detoxication of six organophosphorus compounds by rat liver homogenates - Chambers_1990_Pestic.Biochem.Physiol_36_308
Author(s) : Chambers HW , Brown B , Chambers JE
Ref : Pesticide Biochemistry and Physiology , 36 :308 , 1990
Abstract : The ability of rat liver aliesterases to noncatalytically detoxify the oxons of six phosphorothionate insecticides was studied; the insecticides were methyl parathion, parathion, chlorpyrifos-methyl, chlorpyrifos, leptophos, and EPN. All oxons were more potent inhibitors (nM range) of rat liver aliesterases than the target rat brain acetylcholinesterase, with the exception of methyl paraoxon. Rat liver homogenates (including EDTA to eliminate possible A-esterase contributions) increased apparent I50s of the oxons to bovine brain acetylcholinesterase, indicating a detoxication of an appreciable amount of the oxon. Except for EPN-oxon, detoxication ability correlated with aliesterase sensitivity to inhibition. Liver homogenates from rats treated in vivo with the phosphorothionates had a reduced detoxication capability which correlated highly with residual aliesterase activity. With the exception of methyl parathion, animals treated for 90 min with high doses of the phosphorothionates displayed higher liver aliesterase inhibition than brain acetylcholinesterase inhibition. Thus, liver aliesterases represent a significant alternative phosphorylation site for organophosphates, and their efficacy for detoxication is a function of relative affinities of the oxon for the aliesterases and acetylcholinesterase.
ESTHER : Chambers_1990_Pestic.Biochem.Physiol_36_308
PubMedSearch : Chambers_1990_Pestic.Biochem.Physiol_36_308

Title : An investigation of acetylcholinesterase inhibition and aging and choline acetyltransferase activity following a high level acute exposure to paraoxon - Chambers_1989_Pestic.Biochem.Physiol_33_125
Author(s) : Chambers HW , Chambers JE
Ref : Pesticide Biochemistry and Physiology , 33 :125 , 1989
Abstract : Male rats were given a high sublethal dose of the organophosphate paraoxon (the potent anticholinesterase metabolite of the insecticide parathion) or a lethal dose of paraoxon antidoted with atropine to assure survival. These doses yielded a high level persistent inhibition of brain acetylcholinesterase, with 83-94% inhibition in the cerebral cortex, corpus striatum, and medulla oblongata within 2 hr of treatment, and still 25-45% inhibition 4 days after treatment. Recovery was faster in the medulla oblongata than the other two brain parts. Aging, as estimated by the amount of inhibition remaining after in vitro exposure to an oxime reactivator, gradually increased from no aging on the day of treatment to virtually complete aging at 4 days after treatment. Although a change in choline acetyltransferase activity could have helped compensate for the paraoxon-induced hypercholinergic activity to reduce overt symptomology and return other behaviors to normal levels, no paraoxon- or atropine-induced changes were observed in choline acetyltransferase specific activity in the cerebral cortex or corpus striatum at any time after treatment.
ESTHER : Chambers_1989_Pestic.Biochem.Physiol_33_125
PubMedSearch : Chambers_1989_Pestic.Biochem.Physiol_33_125

Title : Short-term effects of paraoxon and atropine on schedule-controlled behavior in rats - Chambers_1989_Neurotoxicol.Teratol_11_427
Author(s) : Chambers JE , Chambers HW
Ref : Neurotoxicology & Teratology , 11 :427 , 1989
Abstract : The effects of lethal (2.0 mg/kg) and high sublethal (1.3 mg/kg) dosages of the organophosphate acetylcholinesterase (AChE) inhibitor paraoxon on FR10 performance rate was determined 1 and 2 days after intoxication. The lethal doses were antidoted with either centrally acting atropine sulfate (AS), or atropine methyl bromide (AMB) or atropine methyl nitrate (AMN), both quaternary salts and not expected to act centrally. AChE inhibition in the brain was about 35-60% on the second day after treatment. AS yielded a small transient depression in performance, while AMB and AMN yielded severe deficits, with incomplete recovery. Performance was depressed by 1.3 mg/kg paraoxon by 52% and 34% on days 1 and 2, respectively, while performance was more greatly depressed by the lethal dose, especially with the noncentrally acting antidotes: AS, 67 and 48%; AMB, 81 and 55%; AMN, 91 and 78%. However, a low dose of AS with 2 mg/kg paraoxon resulted in very severe, nonrecovering deficits. A lethal dose of the nonpersistent anti-AChE eserine sulfate, antidoted with a low dose of AS, yielded no deficits. Thus, a high level, acute intoxication with paraoxon yields behavioral deficits which are attenuated by high levels of a centrally acting muscarinic receptor antagonist. The paraoxon-induced performance deficits or their recovery do not correlate directly with AChE inhibition.
ESTHER : Chambers_1989_Neurotoxicol.Teratol_11_427
PubMedSearch : Chambers_1989_Neurotoxicol.Teratol_11_427
PubMedID: 2593981

Title : Effects of paraoxon, p-nitrophenol, phenyl saligenin cyclic phosphate, and phenol on the rat interleukin 2 system - Pruett_1988_Toxicol.Lett_40_11
Author(s) : Pruett SB , Chambers JE
Ref : Toxicol Lett , 40 :11 , 1988
Abstract : Two organophosphorus compounds, paraoxon and phenyl saligenin cyclic phosphate, as well as p-nitrophenol and phenol which are structurally related to paraoxon, were tested for their effects on interleukin 2 (IL2) production and responsiveness by rat splenocytes in vitro. Three of the four compounds inhibited mitogen-induced lymphocyte proliferation as well as IL2 production and responsiveness. However, phenyl saligenin cyclic phosphate produced maximal inhibition at a much lower concentration (0.5 microM) than p-nitrophenol (200 microM) or paraoxon (200 microM). Phenol was not inhibitory at any concentration tested (up to 250 microM). Since the production of and response to IL2 are key events in immune responses, compounds which suppress these events can be identified as potential suppressors of host resistance to disease.
ESTHER : Pruett_1988_Toxicol.Lett_40_11
PubMedSearch : Pruett_1988_Toxicol.Lett_40_11
PubMedID: 3257593

Title : Inhibition of neurotoxic esterase and acetylcholinesterase by organophosphorus compounds in selected ectothermic vertebrates - Fulton_1985_Pestic.Biochem.Physiol_23_282
Author(s) : Fulton MH , Chambers JE
Ref : Pesticide Biochemistry and Physiology , 23 :282 , 1985
Abstract : The sensitivity of brain acetylcholinesterase and neurotoxic esterase to inhibition by several organophosphorus compounds was studied in selected ectothermic vertebrates. These enzymes are associated with organophosphorus compound acute and delayed toxicity, respectively. In addition, the susceptibility of several of these species to delayed neurotoxicity induced by organophosphorus compounds was studied. Larvae of the gray treefrog, Southern leopard frog, and narrow-mouthed toad were exposed dermally to tri-o-tolyl phosphate or phenyl saliginen cyclic phosphate (PSCP); no symptoms of delayed neurotoxicity were observed in any of these animals up to 2 weeks after metamorphosis. No symptoms of delayed neurotoxicity were seen in juvenile bullfrogs exposed to multiple ip doses of PSCP. The specific activity of neurotoxic esterase was highest in the larval bullfrog, with juvenile channel catfish and adult mosquitofish demonstrating intermediate levels. The larval Southern leopard frog, adult Northern leopard frog, juvenile green treefrog, and adult marine toad exhibited extremely low activities. The specific activity of acetylcholinesterase was highest in the juvenile channel catfish. Neurotoxic esterase in the larval bullfrog was more sensitive to organophosphate inhibition than that in either fish. PSCP was a more potent neurotoxic esterase inhibitor than leptophos-oxon. The juvenile channel catfish had the acetylcholinesterase most sensitive to organophosphate inhibition. Under the conditions tested, no evidence of in vivo sensitivity to the organophosphate-induced delayed neurotoxicity phenomenon was observed.
ESTHER : Fulton_1985_Pestic.Biochem.Physiol_23_282
PubMedSearch : Fulton_1985_Pestic.Biochem.Physiol_23_282

Title : The toxic and teratogenic effects of selected organophosphorus compounds on the embryos of three species of amphibians - Fulton_1985_Toxicol.Lett_26_175
Author(s) : Fulton MH , Chambers JE
Ref : Toxicol Lett , 26 :175 , 1985
Abstract : The toxic and teratogenic effects of 4 organophosphorus compounds (phenyl saliginen cyclic phosphate (PSCP), leptophos-oxon (LPTO), tri-o-tolyl phosphate (TOTP), and paraoxon (PXN] were investigated in the embryos of 3 species of frogs. Developmental abnormalities were observed in surviving embryos of each of the 3 species following exposure to PSCP at concentrations as low as 500 ppb for 24 h. LPTO, while being toxic to gray treefrog embryos at concentrations as low as 2.2 ppm, did not induce developmental abnormalities. TOTP and PXN were neither toxic nor teratogenic at concentrations of 10 ppm and 100 ppm respectively.
ESTHER : Fulton_1985_Toxicol.Lett_26_175
PubMedSearch : Fulton_1985_Toxicol.Lett_26_175
PubMedID: 4035710

Title : Acute toxicities of selected herbicides to fingerling channel catfish, Ictalurus punctatus - McCorkle_1977_Bull.Environ.Contam.Toxicol_18_267
Author(s) : McCorkle FM , Chambers JE , Yarbrough JD
Ref : Bulletin of Environmental Contamination & Toxicology , 18 :267 , 1977
Abstract : A scan of the acute toxicities of eighteen common herbicides to one-year-old channel catfish (Ictalurus punctatus) was conducted. Herbicides causing less than 10% mortality in 48 hr at 10 ppm were: alanap, chloramben, 2,4-D acid, 2,4-D dimethyl amine salt, dalapon, diuron, DSMA, EPTC, fluometuron, metribuzin, monuron, MSMA, nitralin and 2,4,5,-T. The 96-hr LC50 values in pp6 for four nerbicides found toxic were: propanil, 3796; trifluralin, 417; bensulide, 379; and DNBP 118. The toxicity of Dyanap, a mixture of DNBP and alanap, was lower than that of DNBP; there was no apparent synergism between DNBP and alanap in the mixture.
ESTHER : McCorkle_1977_Bull.Environ.Contam.Toxicol_18_267
PubMedSearch : McCorkle_1977_Bull.Environ.Contam.Toxicol_18_267
PubMedID: 907845