Pope CN

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Full name : Pope Cary N

First name : Cary N

Mail : Department of Physiological Sciences (Dr Pope), Center for Veterinary Sciences, Oklahoma State University, Stillwater.

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Country : USA

Email : cary.pope@okstate.edu

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References (43)

Title : Comparing Longitudinal Measures of Cholinesterase as Biomarkers for Insecticide Exposure Among Latinx Children in Rural Farmworker and Urban Non-Farmworker Communities in North Carolina - Quandt_2023_J.Occup.Environ.Med__
Author(s) : Quandt SA , Smith SA , Arcury TA , Chen H , Hester K , Pope CN , Anderson KA , Laurienti PJ
Ref : J Occup Environ Med , : , 2023
Abstract : OBJECTIVE: In a two-group prospective design, this study compares seasonal cholinesterase levels of Latinx children in rural farmworker families and comparable urban children, to assess the impact of environmental exposure to cholinesterase-inhibiting insecticides. METHODS: Quarterly blood samples and passive dosimeter wristbands were collected over 2 years in 8 year old children (74 rural, 62 urban). Laboratory analysis assessed total cholinesterase (total ChE), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) from blood samples, and insecticides from wristbands. RESULTS: In spring and summer, total ChE and AChE levels were depressed in rural children compared to winter and fall. BChE was depressed in rural children in fall, compared to spring and summer. Adjustment for insecticide exposure did not affect these associations. CONCLUSIONS: Environmental exposures to cholinesterase-inhibiting insecticides have measurable biochemical effects on blood cholinesterases in rural children from farmworker families.
ESTHER : Quandt_2023_J.Occup.Environ.Med__
PubMedSearch : Quandt_2023_J.Occup.Environ.Med__
PubMedID: 37696813

Title : Cholinesterases and the fine line between poison and remedy - Pope_2018_Biochem.Pharmacol_153_205
Author(s) : Pope CN , Brimijoin S
Ref : Biochemical Pharmacology , 153 :205 , 2018
Abstract : Acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8) are related enzymes found across the animal kingdom. The critical role of acetylcholinesterase in neurotransmission has been known for almost a century, but a physiological role for butyrylcholinesterase is just now emerging. The cholinesterases have been deliberately targeted for both therapy and toxicity, with cholinesterase inhibitors being used in the clinic for a variety of disorders and conversely for their toxic potential as pesticides and chemical weapons. Non-catalytic functions of the cholinesterases (ChEs) participate in both neurodevelopment and disease. Manipulating either the catalytic activities or the structure of these enzymes can potentially shift the balance between beneficial and adverse effect in a wide number of physiological processes.
ESTHER : Pope_2018_Biochem.Pharmacol_153_205
PubMedSearch : Pope_2018_Biochem.Pharmacol_153_205
PubMedID: 29409903

Title : The impacts of pesticide and nicotine exposures on functional brain networks in Latino immigrant workers - Bahrami_2017_Neurotoxicol_62_138
Author(s) : Bahrami M , Laurienti PJ , Quandt SA , Talton J , Pope CN , Summers P , Burdette JH , Chen H , Liu J , Howard TD , Arcury TA , Simpson SL
Ref : Neurotoxicology , 62 :138 , 2017
Abstract : Latino immigrants that work on farms experience chronic exposures to potential neurotoxicants, such as pesticides, as part of their work. For tobacco farmworkers there is the additional risk of exposure to moderate to high doses of nicotine. Pesticide and nicotine exposures have been associated with neurological changes in the brain. Long-term exposure to cholinesterase-inhibiting pesticides, such as organophosphates and carbamates, and nicotine place this vulnerable population at risk for developing neurological dysfunction. In this study we examined whole-brain connectivity patterns and brain network properties of Latino immigrant workers. Comparisons were made between farmworkers and non-farmworkers using resting-state functional magnetic resonance imaging data and a mixed-effects modeling framework. We also evaluated how measures of pesticide and nicotine exposures contributed to the findings. Our results indicate that despite having the same functional connectivity density and strength, brain networks in farmworkers had more clustered and modular structures when compared to non-farmworkers. Our findings suggest increased functional specificity and decreased functional integration in farmworkers when compared to non-farmworkers. Cholinesterase activity was associated with population differences in community structure and the strength of brain network functional connections. Urinary cotinine, a marker of nicotine exposure, was associated with the differences in network community structure. Brain network differences between farmworkers and non-farmworkers, as well as pesticide and nicotine exposure effects on brain functional connections in this study, may illuminate underlying mechanisms that cause neurological implications in later life.
ESTHER : Bahrami_2017_Neurotoxicol_62_138
PubMedSearch : Bahrami_2017_Neurotoxicol_62_138
PubMedID: 28583619

Title : Brain Anatomy in Latino Farmworkers Exposed to Pesticides and Nicotine - Laurienti_2016_J.Occup.Environ.Med_58_436
Author(s) : Laurienti PJ , Burdette JH , Talton J , Pope CN , Summers P , Walker FO , Quandt SA , Lyday RG , Chen H , Howard TD , Arcury TA
Ref : J Occup Environ Med , 58 :436 , 2016
Abstract : OBJECTIVE: Migrant tobacco farmworkers experience regular occupational exposure to pesticides and nicotine. The present study was designed to determine whether there are differences in brain anatomy between Latino farmworkers and non-farmworkers.
METHODS: Magnetic resonance brain images were compared between farmworkers and non-farmworkers. In addition, blood cholinesterase activity and urinary cotinine levels were also used to identify associations with pesticide and nicotine exposure.
RESULTS: Farmworkers had greater gray matter signal in putamen and cerebellum, and lower gray matter signal in frontal and temporal lobes. Urinary cotinine was associated with the observed differences in brain anatomy, but blood cholinesterase activity was not.
CONCLUSIONS: Nicotine exposure was associated with neuroanatomical differences between Latino farmworkers and non-farmworkers. Future studies are needed to differentiate iron deposition from brain atrophy and to further assess the potential role of nicotine and pesticide exposure.
ESTHER : Laurienti_2016_J.Occup.Environ.Med_58_436
PubMedSearch : Laurienti_2016_J.Occup.Environ.Med_58_436
PubMedID: 27158949

Title : Longitudinal Assessment of Blood Cholinesterase Activities Over 2 Consecutive Years Among Latino Nonfarmworkers and Pesticide-Exposed Farmworkers in North Carolina - Quandt_2015_J.Occup.Environ.Med_57_851
Author(s) : Quandt SA , Pope CN , Chen H , Summers P , Arcury TA
Ref : J Occup Environ Med , 57 :851 , 2015
Abstract : OBJECTIVE: This study (1) describes patterns of whole blood total cholinesterase, acetylcholinesterase, and butyrylcholinesterase activities across the agricultural season, comparing farmworkers and nonfarmworkers; and (2) explores differences between farmworkers' and non-farmworkers' likelihood of cholinesterase depression.
METHODS: Blood samples from 210 Latino male farmworkers and 163 Latino workers with no occupational pesticide exposure collected 8 times across 2 agricultural seasons were analyzed. Mean cholinesterase activity levels and depressions 15% or more were compared by month.
RESULTS: Farmworkers had significantly lower total cholinesterase and butyrylcholinesterase activities in July and August and lower acetylcholinesterase activity in August. Farmworkers had significantly greater likelihood of cholinesterase depression for each cholinesterase measure across the agricultural season. SIGNIFICANCE: A repeated-measures design across 2 years with a nonexposed control group demonstrated anticholinesterase effects in farmworkers. Current regulations designed to prevent pesticide exposure are not effective.
ESTHER : Quandt_2015_J.Occup.Environ.Med_57_851
PubMedSearch : Quandt_2015_J.Occup.Environ.Med_57_851
PubMedID: 26247638

Title : Behavioral sequelae following acute diisopropylfluorophosphate intoxication in rats: comparative effects of atropine and cannabinomimetics - Wright_2010_Neurotoxicol.Teratol_32_329
Author(s) : Wright LK , Liu J , Nallapaneni A , Pope CN
Ref : Neurotoxicology & Teratology , 32 :329 , 2010
Abstract : The comparative effects of atropine and the indirect cannabinomimetics URB597 (a fatty acid amide hydrolase inhibitor) and URB602 (a monoacylglycerol lipase inhibitor) on functional and neurobehavioral endpoints following acute diisopropylfluorophosphate intoxication were studied. Male Sprague-Dawley rats were treated with vehicle or DFP (2.5mg/kg, sc), immediately post-treated with either vehicle, atropine (16mg/kg), URB597 (3mg/kg), URB602 (10mg/kg) or a combination of URB597 and URB602, and functional signs of toxicity as well as nocturnal motor activity were measured daily for seven consecutive days. Performance in the elevated plus maze (for anxiety-like behavior) and the forced swimming test (for depression-like behavior) was measured at days 6-8 and 27-29 after dosing. Twenty-four hours after dosing, DFP markedly reduced cholinesterase activity in selected brain regions and peripheral tissues (diaphragm and plasma). Substantial recovery of cholinesterase activity was noted at both 8 and 29days after dosing but significant inhibition was still noted in some brain regions at the latest time-point. DFP elicited body weight reductions and typical signs of cholinergic toxicity, and reduced nocturnal ambulation and rearing. Atropine and the cannabinomimetics (alone and in combination) partially attenuated DFP-induced functional signs of toxicity. None of the post-treatments reversed the DFP-induced reduction in ambulation or rearing, however. No significant treatment-related effects on elevated plus maze performance were noted. DFP-treated rats exhibited decreased swimming and increased immobility in the forced swimming test at both time-points. None of the post-treatments had any effect on DFP-induced changes in immobility or swimming at day 8. At day 29, atropine and the combination of URB597/URB602 significantly blocked DFP-induced changes in immobility, while URB597 and the combination reversed DFP-induced changes in swimming. The results suggest that early blockade of muscarinic receptors and enhancement of eCB signaling can attenuate both acute and delayed effects elicited by DFP.
ESTHER : Wright_2010_Neurotoxicol.Teratol_32_329
PubMedSearch : Wright_2010_Neurotoxicol.Teratol_32_329
PubMedID: 20034559

Title : Selective inhibition of butyrylcholinesterase in vivo in horses by the feed-through larvacide Equitrol - Karanth_2008_Regul.Toxicol.Pharmacol_50_200
Author(s) : Karanth S , Holbrook T , MacAllister C , Pope CN
Ref : Regul Toxicol Pharmacol , 50 :200 , 2008
Abstract : The organophosphate insecticide tetrachlorvinphos (TCVP, Rabon) is the active ingredient in "feed-through" larvacides (e.g., Equitrol) for fly control around horse stables. As with other organophosphates, TCVP elicits toxicity by inhibiting acetylcholinesterase, leading to accumulation of the neurotransmitter acetylcholine and cholinergic signs. Relatively little is known, however, on the effects of TCVP-containing larvacides on acetylcholinesterase or other esterases in horses. Previous in vitro studies indicated that horse plasma cholinesterase activity was substantially (>10,000-fold) more sensitive than erythrocyte cholinesterase activity to inhibition by TCVP. In the current study, we examined the relative proportion of acetylcholinesterase and butyrylcholinesterase activities in horse plasma and muscle, and evaluated the in vivo effects of Equitrol on target and non-target esterases following oral feeding in horses. In vitro inhibition studies suggested that essentially all cholinesterase activity in horse plasma was butyrylcholinesterase, while muscle contained >90% acetylcholinesterase activity. For in vivo studies, adult, male horses (364-590kg; n=3/treatment group) were given either sweet feed alone or sweet feed supplemented with Equitrol daily for 21 consecutive days at the recommended rate. Clinical signs (vital signs, abdominal auscultation, ophthalmic exam, body temperature) were recorded on a daily basis. Heparinized blood samples were taken at days -1, 1, 3, 7, 21, 28, and 42 while muscle (semimembranosus) biopsies were taken under aseptic conditions on days -1 and 21. No signs of overt toxicity were noted at any time during the study. Plasma cholinesterase activity was significantly inhibited (33%) in larvacide-treated horses as early as one day after treatment and peak inhibition (69-71%) was noted at days 7 and 21. Following cessation of dosing, plasma cholinesterase activity recovered (46% and 83% of control on days 28 and 42, respectively). Neither erythrocyte cholinesterase activity nor plasma carboxylesterase activity was affected by larvacide treatment in vivo. Muscle cholinesterase activity was highly variable among individual horses (pre-treatment range: 0.50-4.92nmole/min/mg protein), but there was no suggestion of a treatment-related reduction in muscle cholinesterase activity. These in vivo results confirm our previous in vitro studies indicating marked differential sensitivity of horse plasma and erythrocyte cholinesterase to inhibition by TCVP. Furthermore, the results suggest that recommended dosing levels of the TCVP-containing larvacide in horses are unlikely to affect acetylcholinesterase activities or disrupt cholinergic neurotransmission in target tissues.
ESTHER : Karanth_2008_Regul.Toxicol.Pharmacol_50_200
PubMedSearch : Karanth_2008_Regul.Toxicol.Pharmacol_50_200
PubMedID: 18166255

Title : In vitro sensitivity of cholinesterases and [3H]oxotremorine-M binding in heart and brain of adult and aging rats to organophosphorus anticholinesterases - Mirajkar_2008_Biochem.Pharmacol_76_1047
Author(s) : Mirajkar N , Pope CN
Ref : Biochemical Pharmacology , 76 :1047 , 2008
Abstract : Organophosphorus (OP) insecticides elicit toxicity via acetylcholinesterase inhibition, allowing acetylcholine accumulation and excessive stimulation of cholinergic receptors. Some OP insecticides bind to additional macromolecules including butyrylcholinesterase and cholinergic receptors. While neurotoxicity from OP anticholinesterases has been extensively studied, effects on cardiac function have received less attention. We compared the in vitro sensitivity of acetylcholinesterase, butyrylcholinesterase and [(3)H]oxotremorine-M binding to muscarinic receptors in the cortex and heart of adult (3 months) and aging (18 months) rats to chlorpyrifos, methyl parathion and their active metabolites chlorpyrifos oxon and methyl paraoxon. Using selective inhibitors, the great majority of cholinesterase in brain was defined as acetylcholinesterase, while butyrylcholinesterase was the major cholinesterase in heart, regardless of age. In the heart, butyrylcholinesterase was markedly more sensitive than acetylcholinesterase to inhibition by chlorpyrifos oxon, and butyrylcholinesterase in tissues from aging rats was more sensitive than enzyme from adults, possibly due to differences in A-esterase mediated detoxification. Relatively similar differences were noted in brain. In contrast, acetylcholinesterase was more sensitive than butyrylcholinesterase to methyl paraoxon in both heart and brain, but no age-related differences were noted. Both oxons displaced [(3)H]oxotremorine-M binding in heart and brain of both age groups in a concentration-dependent manner. Chlorpyrifos had no effect but methyl parathion was a potent displacer of binding in heart and brain of both age groups. Such OP and age-related differences in interactions with cholinergic macromolecules may be important because of potential for environmental exposures to insecticides as well as the use of anticholinesterases in age-related neurological disorders.
ESTHER : Mirajkar_2008_Biochem.Pharmacol_76_1047
PubMedSearch : Mirajkar_2008_Biochem.Pharmacol_76_1047
PubMedID: 18761328

Title : Effects of combined, multiple stressors on pyridostigmine-induced acute toxicity in rats - Baireddy_2007_Arch.Toxicol_81_283
Author(s) : Baireddy P , Mirajkar N , Nallapaneni A , Singleton N , Pope CN
Ref : Archives of Toxicology , 81 :283 , 2007
Abstract : A number of studies have evaluated the possibility that stress-induced changes in blood-brain barrier permeability enhanced the central effects of the carbamate acetylcholinesterase inhibitor, pyridostigmine. We previously found relatively little evidence of stress-induced changes in the acute toxicity of pyridostigmine in rats using a variety of restraint, forced running and forced swimming stress conditions. In this study, we evaluated the effects of sequential pre-exposure to multiple stressors on the acute toxicity of pyridostigmine. Rats (n = 8 per treatment group) were either un-stressed or stressed by restraint (60 min), forced running (60 min, 15 m/min, 6 degrees incline) and forced swimming (15 min), and then given either vehicle (saline, 1 ml/kg, po) or pyridostigmine (30 mg/kg, po) immediately after the final stressor. Functional signs of cholinergic toxicity (involuntary movements, autonomic dysfunction) were recorded at 0.5, 1 and 2 h after dosing. Body temperature was measured both before stress and 2 h after dosing. Rats were sacrificed immediately after 2-h functional observations to collect tissues (whole blood, diaphragm, frontal cortex, hippocampus and cerebellum) for measurement of cholinesterase activity. Stressed rats treated with pyridostigmine exhibited higher lethality (2/8) compared to unstressed rats given pyridostigmine (0/8). Pyridostigmine elicited classical signs of cholinergic toxicity, but the rats that died did not show increased cholinergic signs and no significant differences in cholinergic signs were noted between treatment groups. Cholinesterase activity was significantly inhibited in blood (47-50%) and diaphragm (80%) following pyridostigmine exposure regardless of stress conditions. Slight but significant inhibition (11-15%) of cerebellar cholinesterase activity was observed following pyridostigmine exposure, but inhibition was not influenced by stress. We conclude that while acute lethality from pyridostigmine may be increased by combined, multiple stressors, increased lethality does not appear due to enhanced cholinergic toxicity or via increased cholinesterase inhibition in either central or peripheral tissues.
ESTHER : Baireddy_2007_Arch.Toxicol_81_283
PubMedSearch : Baireddy_2007_Arch.Toxicol_81_283
PubMedID: 16944100

Title : Comparative effects of oral chlorpyrifos exposure on cholinesterase activity and muscarinic receptor binding in neonatal and adult rat heart - Howard_2007_Toxicology_238_157
Author(s) : Howard MD , Mirajkar N , Karanth S , Pope CN
Ref : Toxicology , 238 :157 , 2007
Abstract : Organophosphorus (OP) pesticides elicit acute toxicity by inhibiting acetylcholinesterase (AChE), the enzyme responsible for inactivating acetylcholine (ACh) at cholinergic synapses. A number of OP toxicants have also been reported to interact directly with muscarinic receptors, in particular the M(2) muscarinic subtype. Parasympathetic innervation to the heart primarily regulates cardiac function by activating M(2) receptors in the sinus node, atrial-ventricular node and conducting tissues. Thus, OP insecticides can potentially influence cardiac function in a receptor-mediated manner indirectly by inhibiting acetylcholinesterase and directly by binding to muscarinic M(2) receptors. Young animals are generally more sensitive than adults to the acute toxicity of OP insecticides and age-related differences in potency of direct binding to muscarinic receptors by some OP toxicants have been reported. We thus compared the effects of the common OP insecticide chlorpyrifos (CPF) on functional signs of toxicity and cardiac cholinesterase (ChE) activity and muscarinic receptor binding in neonatal and adult rats. Dosages were based on acute lethality (i.e., 0.5 and 1x LD(10): neonates, 7.5 and 15 mg/kg; adults, 68 and 136 mg/kg). Dose- and time-related changes in body weight and cholinergic signs of toxicity (involuntary movements) were noted in both age groups. With 1x LD(10), relatively similar maximal reductions in ChE activity (95%) and muscarinic receptor binding (approximately 30%) were noted, but receptor binding reductions appeared earlier in adults and were more prolonged in neonates. In vitro inhibition studies indicated that ChE in neonatal tissues was markedly more sensitive to inhibition by the active metabolite of chlorpyrifos (i.e., chlorpyrifos oxon, CPO) than enzyme in adult tissues (IC(50) values: neonates, 17 nM; adults, 200 nM). Chelation of free calcium with EDTA had relatively little effect on in vitro cholinesterase inhibition, suggesting that differential A-esterase activity was not responsible for the age-related difference in cholinesterase sensitivity between age groups. Pre-incubation of neonatal and adult tissues with selective inhibitors of AChE and butyrylcholinesterase (BChE) indicated that a majority (82-90%) of ChE activity in the heart of both neonates and adults was BChE. The rapid onset (by 4h after dosing) of changes in muscarinic receptor binding in adult heart may be a reflection of the more potent direct binding to muscarinic receptors by chlorpyrifos oxon previously reported in adult tissues. The results suggest that ChE activity (primarily BChE) in neonatal heart may be inherently more sensitive to inhibition by some anticholinesterases and that toxicologically significant binding to muscarinic receptors may be possible with acute chlorpyrifos intoxication, potentially contributing to age-related differences in sensitivity.
ESTHER : Howard_2007_Toxicology_238_157
PubMedSearch : Howard_2007_Toxicology_238_157
PubMedID: 17644233

Title : Comparative carboxylesterase activities in infant and adult liver and their in vitro sensitivity to chlorpyrifos oxon - Pope_2005_Regul.Toxicol.Pharmacol_42_64
Author(s) : Pope CN , Karanth S , Liu J , Yan B
Ref : Regul Toxicol Pharmacol , 42 :64 , 2005
Abstract : Maturational expression of carboxylesterase activity in laboratory animals has been correlated with age-related differences in sensitivity to many organophosphorus insecticides including chlorpyrifos. Little information is available, however, on the maturational expression of liver carboxylesterases in humans. Human liver carboxylesterase activity was compared in tissues from infants (2-24 months) and adults (20-36 years). There was no significant difference between mean infant and adult carboxylesterase activities. The carboxylesterase activity rank order was: 2 months<3 months<20 years<24 months<4 months<36 years<21 years<8 months<34 years<35 years. Proteins (3 microg) were separated and blotted using antibodies against rat hydrolase S (HS), human carboxylesterase (HCE) types 1 and 2, and CYP3A4. Again, there were no significant differences in staining density between infant and adult tissues with any isozyme. Aliquots of each sample were pre-incubated (30 min, 37 degrees C) with chlorpyrifos oxon to evaluate in vitro sensitivity. Based on 95% confidence intervals, no significant differences in IC50 values were obtained in 3-month to 36-year samples (range: 1.42-2.12 nM), while the IC50 was significantly lower in the 2-month sample (0.45 nM). Carboxylesterase activity across samples was correlated with cytochrome b5 content and HS immunosignal but not with other microsomal activities (total cyt P450 content, testosterone hydroxylation, coumarin hydroxylation, and EROD). The results suggest that, in contrast to rodents, human liver carboxylesterase expression changes relatively little during postnatal maturation.
ESTHER : Pope_2005_Regul.Toxicol.Pharmacol_42_64
PubMedSearch : Pope_2005_Regul.Toxicol.Pharmacol_42_64
PubMedID: 15896444

Title : Effects of daily stress or repeated paraoxon exposures on subacute pyridostigmine toxicity in rats - Shaikh_2003_Arch.Toxicol_77_576
Author(s) : Shaikh J , Karanth S , Chakraborty D , Pruett S , Pope CN
Ref : Archives of Toxicology , 77 :576 , 2003
Abstract : Pyridostigmine (PYR) is a carbamate cholinesterase (ChE) inhibitor used during the Persian Gulf War as a pretreatment against possible chemical nerve agent attack. Because of its quaternary structure, PYR entry into the central nervous system is limited by the blood-brain barrier (BBB). Following reports of unexplained illnesses among Gulf War veterans, however, central nervous system effects of PYR have been postulated through either stress-induced alteration of BBB permeability or via interactions with other neurotoxic agents. We evaluated the effects of daily physical (treadmill running) stress or daily exposure to a subclinical dosage of the organophosphate ChE inhibitor paraoxon (PO) on ChE inhibition in blood, diaphragm and selected brain regions in young adult male Sprague-Dawley rats following subacute PYR exposures. In physical stress studies, rats were placed on a treadmill for 90 min each day for 14 days just prior to PYR (0, 3, or 10 mg/kg per day) administration. In PO-PYR interaction studies, rats were treated with PO (0, 0.05, or 0.1 mg/kg per day) 1 h prior to daily PYR (0 or 3 mg/kg per day) administration for 14 consecutive days. Rats were evaluated daily for signs of cholinergic toxicity and were killed 1 h after the final PYR treatment. Forced running increased plasma corticosterone levels throughout the experiment (on days 1, 3, 7 and 14) when measured immediately after termination of stress. PYR-treated rats in the high dosage (10 mg/kg per day) group exhibited slight signs of toxicity (involuntary movements) for the first 6 days, after which tolerance developed. Interestingly, signs of cholinergic toxicity following PYR were slightly but significantly increased in rats forced to run on the treadmill prior to dosing. ChE activities in whole blood and diaphragm were significantly reduced 1 h after the final PYR challenge, and ChE inhibition in diaphragm was significantly greater in stressed rats than in non-stressed controls following high dose PYR (10 mg/kg per day). No significant effects of treadmill running on PYR-induced ChE inhibition in brain regions were noted, however. Repeated subclinical PO exposure had no apparent effect on functional signs of PYR toxicity. As with repeated treadmill running, whole blood and diaphragm ChE activities were significantly reduced 1 h after the final PYR administration, and ChE inhibition was significantly greater with combined PO and PYR exposures. Brain regional ChE activity was significantly inhibited after daily PO exposure, but no increased inhibition was noted following combined PO and PYR dosing. We conclude that, while some stressors may under some conditions affect functional signs of toxicity following repeated pyridostigmine exposures, these changes are likely to occur via alteration of peripheral cholinergic mechanisms and not through enhanced entry of pyridostigmine into the brain.
ESTHER : Shaikh_2003_Arch.Toxicol_77_576
PubMedSearch : Shaikh_2003_Arch.Toxicol_77_576
PubMedID: 14574445

Title : Combined forced running stress and subclinical paraoxon exposure have little effect on pyridostigmine-induced acute toxicity in rats - Shaikh_2003_Toxicology_190_221
Author(s) : Shaikh J , Pope CN
Ref : Toxicology , 190 :221 , 2003
Abstract : Pyridostigmine is a short-acting inhibitor of cholinesterase (ChE) used as a pretreatment against potential nerve agent exposure during the Persian Gulf War. As pyridostigmine contains a quaternary ammonium group, it is generally believed to elicit changes in the peripheral nervous system function only. It has been hypothesized, however, that the neurotoxicity of pyridostigmine may be altered by either stress or combined exposures to other toxicants. We evaluated the effects of forced running stress, exposure to the organophosphate anticholinesterase paraoxon, or a combination of both on the acute neurotoxicity of pyridostigmine. ChE (blood, diaphragm, and selected brain regions) and carboxylesterase (CE; liver, plasma) inhibition was also evaluated. Young adult male Sprague-Dawley rats were either given vehicle or paraoxon (0.1 mg/kg, i.m.) and subsets placed in their home cage or forced to run on a treadmill for 60 min. Pyridostigmine (0, 10 or 30 mg/kg, p.o.) was given 60 min after paraoxon dosing and rats were evaluated for cholinergic toxicity just prior to sacrifice 60 min later. No signs of toxicity were noted following paraoxon exposure while both dosages of pyridostigmine (10 and 30 mg/kg, p.o.) elicited signs of functional toxicity. Toxicity was not different with combined paraoxon-pyridostigmine exposures and forced running did not influence toxicity under any conditions. Paraoxon (0.1 mg/kg, i.m.) caused moderate (23-46%) ChE inhibition in blood, diaphragm and brain 2 h after exposure. Pyridostigmine (10 or 30 mg/kg, p.o.) caused extensive inhibition of blood (88-94%) and diaphragm (75-85%) ChE activity but no significant effect on brain regional ChE activity. Forced running stress did not influence the degree of tissue ChE inhibition following either paraoxon, pyridostigmine or paraoxon-pyridostigmine combined exposures. CE activities were inhibited (26-43%) in plasma and liver by paraoxon but inhibition was not influenced by either stress or combined paraoxon-pyridostigmine exposures. These results suggest that subclinical paraoxon exposure and forced running stress, by themselves or in combination, have little effect on acute pyridostigmine toxicity in rats.
ESTHER : Shaikh_2003_Toxicology_190_221
PubMedSearch : Shaikh_2003_Toxicology_190_221
PubMedID: 12927376

Title : Neither forced running nor forced swimming affect acute pyridostigmine toxicity or brain-regional cholinesterase inhibition in rats - Tian_2002_Toxicology_176_39
Author(s) : Tian H , Song X , Bressler J , Pruett S , Pope CN
Ref : Toxicology , 176 :39 , 2002
Abstract : Stress-induced change in the distribution of the drug pyridostigmine (PYR) has been proposed as a contributing factor to unexplained illnesses in Persian Gulf War veterans. We evaluated the effects of two stress models, forced running and forced swimming, on acute PYR (30 mg/kg, p.o.) toxicity and cholinesterase (ChE) inhibition in the blood and selected brain regions of young adult male Sprague-Dawley rats (6 weeks of age). Plasma corticosterone levels were measured at 0, 1 and 3 h after termination of forced swimming or forced running to confirm the induction of stress. PYR was given either immediately before stress (15 min swimming; 20 min running) or immediately after stress (15 min swimming; 90 min running) and cholinergic toxicity and ChE inhibition were evaluated at 1, 2 or 4 h after PYR exposure. Additionally, rats were subjected to either swimming (15 min) or running (90 min) stress, anesthetized, injected with horseradish peroxidase (HRP, 100 mg/kg, transcardial) and brain-regional HRP activity measured as an indicator of altered blood-brain barrier integrity. Both forced swimming and forced running resulted in significant elevations of plasma corticosterone levels. PYR caused cholinergic toxicity at all time-points evaluated. Swimming and running stress had little influence on expression of PYR-induced toxicity, however. Blood ChE activity was generally inhibited 77-91% at 1-4 h after PYR, but rats pretreated with PYR prior to forced swimming showed lesser inhibition (64%) 1 h after dosing, possibly because of swimming-induced hypothermia and delayed absorption of the drug. Minimal changes in ChE activity were noted in frontal cortex, cerebellum and hippocampus following PYR exposure (maximal inhibition 28%), and neither swimming nor running stress affected the degree of inhibition. Neither stress model increased HRP accumulation in any brain region. The results suggest that stress associated with forced running or forced swimming has little effect on acute PYR toxicity, entry of PYR into the brain or PYR-induced brain-regional ChE inhibition.
ESTHER : Tian_2002_Toxicology_176_39
PubMedSearch : Tian_2002_Toxicology_176_39
PubMedID: 12062928

Title : Age-related effects of chlorpyrifos on muscarinic receptor-mediated signaling in rat cortex - Zhang_2002_Arch.Toxicol_75_676
Author(s) : Zhang H , Liu J , Pope CN
Ref : Archives of Toxicology , 75 :676 , 2002
Abstract : Chlorpyrifos (CPF) is a widely used organophosphorus pesticide. Earlier work from our laboratory and others has demonstrated that the sensitivity to CPF exposure changes markedly during maturation. A number of studies suggest that in addition to inhibiting acetylcholinesterase (AChE), CPF oxon may also interact directly with m2 and/or m4 subtypes of muscarinic acetylcholine receptors (mAChRs). In the present study, we investigated the in vivo effects of CPF exposure on phosphoinositide (PI) hydrolysis and cAMP formation, second-messenger systems coupled to m1, m3 and m5 (PI hydrolysis) or m2 and m4 (cAMP formation) mAChRs. Neonatal (7-day), juvenile (21-day) and adult (90-day) rats were treated with either peanut oil s.c. or CPF s.c. at 0.3x or 1x the maximum tolerated dosage (MTD: 45, 127 and 279 mg/kg for 7-day, 21-day and 90-day rats, respectively). Neurochemical end-points including AChE activity, muscarinic receptor ([3H]quinuclidinyl benzilate, and [3H]oxotremorine) binding, PI hydrolysis, and cAMP formation in cortex were evaluated at 4 h, 24 h, or 96 h after treatment. Under these conditions, relatively similar maximal degrees of cholinesterase (ChE) inhibition were noted, but times to peak inhibition varied among these age groups (24 h in neonates and juveniles, 96 h in adults). Total muscarinic receptor (QNB) binding was reduced in all three age groups with 1x MTD exposure, at both 24 h and 96 h in neonates and juveniles, but only at 96 h in adults. Oxotremorine binding was also reduced at 96 h after MTD exposure in all three age groups. Neither basal nor carbachol-stimulated IP accumulation was affected in any age group or at any time point following CPF exposure. In contrast, basal cAMP formation was significantly increased by MTD exposure in all three age groups 4 h after exposure, and at 4 h, 24 h, and 96 h after exposure in juveniles. Forskolin/Mn2+-stimulated cAMP formation was increased in neonates and juveniles at 96 h, and in juveniles also at 24 h, but was significantly decreased in adults at 96 h after MTD exposure. Oxotremorine-mediated inhibition of cAMP formation was significantly greater at 96 h after MTD exposure in all three age groups. These results provide further evidence that the cortical cAMP signaling pathway may be particularly sensitive to CPF exposure in neonatal, juvenile, and adult rats, possibly due to a direct interaction between CPF (or its oxon) and mAChRs or other components of the adenylyl cyclase cascade.
ESTHER : Zhang_2002_Arch.Toxicol_75_676
PubMedSearch : Zhang_2002_Arch.Toxicol_75_676
PubMedID: 11876500

Title : In vitro effects of chlorpyrifos, parathion, methyl parathion and their oxons on cardiac muscarinic receptor binding in neonatal and adult rats - Howard_2002_Toxicology_170_1
Author(s) : Howard MD , Pope CN
Ref : Toxicology , 170 :1 , 2002
Abstract : Organophosphorus insecticides elicit toxicity by inhibiting acetylcholinesterase. Young animals are generally more sensitive than adults to these toxicants. A number of studies reported that some organophosphorus agents also bind directly to muscarinic receptors, in particular the m(2) subtype, in tissues from adult rats. As both the density and agonist affinity states of cardiac muscarinic receptors (primarily m(2)) have been reported to change in an age-related manner, we evaluated the relative in vitro sensitivity of cardiac muscarinic receptors in tissues from neonatal (7-11 days of age) and adult (90 days of age) rats to selected organophosphorus compounds (chlorpyrifos, parathion, methyl parathion and their oxygen analogs or oxons). The effects of the cholinergic agonist carbachol (100 pM-5 microM) or an organophosphorus toxicant (50 pM-10 microM) on muscarinic receptor binding were determined using the nonselective muscarinic ligand [3H]quinuclidinyl benzilate or the m(2)-preferential ligand [3H]oxotremorine-M acetate. Carbachol displaced [3H]oxotremorine labeling in adult and neonatal membranes in a relatively similar manner (IC(50)=7-20 nM). The oxons all displaced [3H]oxotremorine binding in a concentration-dependent manner, with chlorpyrifos oxon being the most potent (IC(50): neonates, 15 nM; adults, 7 nM) and efficacious (maximum displacement: neonates, 42%; adults, 56%). Interestingly, methyl parathion was an extremely potent displacer of [3H]oxotremorine binding in adult tissues (IC(50)=0.5 nM, maximum displacement=37%) but had no effect in neonatal tissues. The displacement of [3H]oxotremorine binding by chlorpyrifos oxon (10 microM) was still apparent after washing the tissues, suggesting the oxon irreversibly blocked agonist binding to the receptor while interaction with MePS appeared reversible. As effective concentrations of the oxons were relatively similar to their anticholinesterase potencies, these findings suggest that direct interaction with cardiac muscarinic receptors by some organophosphorus agents may occur at relevant exposure levels and contribute to cardiac toxicity.
ESTHER : Howard_2002_Toxicology_170_1
PubMedSearch : Howard_2002_Toxicology_170_1
PubMedID: 11750078

Title : Influence of temperature and dissolved oxygen on the acute toxicity of profenofos to fathead minnows (Pimephales promelas) - Baer_2002_Drug.Chem.Toxicol_25_231
Author(s) : Baer KN , Olivier K , Pope CN
Ref : Drug & Chemical Toxicology , 25 :231 , 2002
Abstract : The purpose of this study was to investigate the influence of temperature and dissolved oxygen levels on the acute toxicity of profenofos to fathead minnows (Pimephales promelas). Exposure conditions were as follows: normal temperature and normal dissolved oxygen (NTNO; 20 +/- 2 degrees C and 6.0-9.0 mg/L, respectively); normal temperature and low dissolved oxygen (NTLO; 20 +/- 2 degrees C and 1.7-2.6 mg/L, respectively); high temperature and normal dissolved oxygen (HTNO; 30 +/- 2 degrees C and 6.6-6.9 mg/L, respectively); high temperature and low dissolved oxygen (HTLO; 30 +/- 2 degrees C and 1.5-3.0 mg/L, respectively). Initial 96-h acute toxicity studies with profenofos were conducted at NTNO and HTLO exposure conditions. The 96-h LC50 at NTNO was 333 micrograms/L with 95% confidence limits ranging from 244 to 558 micrograms/L. However, the 96-h LC50 at HTLO was significantly lower at 21.5 micrograms/L with 95% confidence limits ranging from 17.4 to 28.8 micrograms/L. Acetylcholinesterase (AChE) activity was measured in the head and torso of surviving fish at 96-h. A weak dose-related decrease in AChE was observed at NTNO but no dose-response relationship was observed at HTLO exposure condition. Additional experiments were conducted using 50 micrograms/L profenofos at NTNO, NTLO, HTNO, and HTLO exposure conditions. Mortality, sublethal effects (erratic and hyperactive swimming), and AChE activity in the head and torso were measured at 2, 4, and 12-h following exposure to profenofos. No mortality or significant sublethal effects were observed in controls or profenofos-treated groups in NTNO and NTLO exposure conditions. However, significant mortality and sublethal effects were observed in profenofos-treated fish in HTNO at 12 h and at all time points in HTLO. Both high temperature and low dissolved oxygen, as well as combinations of high temperature and low dissolved oxygen significantly decreased AChE activity in control fish. Exposure to 50 micrograms/L profenofos in all exposure conditions further decreased AChE activity, but no apparent correlations between mortality and AChE activity were observed. These results suggest that the acute toxicity of profenofos to fathead minnows may be exacerbated during summer conditions in southern U.S. aquatic ecosystems.
ESTHER : Baer_2002_Drug.Chem.Toxicol_25_231
PubMedSearch : Baer_2002_Drug.Chem.Toxicol_25_231
PubMedID: 12173245

Title : Glucose feeding exacerbates parathion-induced neurotoxicity - Olivier_2001_J.Toxicol.Environ.Health.A_63_253
Author(s) : Olivier K , Liu J , Karanth S , Zhang H , Roane DS , Pope CN
Ref : J Toxicol Environ Health A , 63 :253 , 2001
Abstract : Excessive dietary intake of sugars could alter various biotransformation processes and the pharmacological and toxicological properties of numerous xenobiotics. In the present study, the effects of glucose supplementation were examined on the neurotoxicity of the organophosphorus (OP) pesticide parathion (PS) and its active metabolite, paraoxon (PO), a potent inhibitor of acetylcholinesterase (AChE). Rats (n = 6-12/treatment group) were given free access to tap water or 15% glucose (w/v) in tap water beginning 7 d prior to OP toxicant exposure. Food, caloric intake, and body weight were measured daily. Animals were challenged with either PS (4.5, 9, or 18 mg/kg, sc) or PO (0.3 0.5, or 0.7 mg/kg, sc) and clinical signs of neurotoxicity (i.e., autonomic dysfunction, involuntary movements) were recorded daily for the following 13 d. Glucose feeding was associated with a dramatic drop (approximately 50%) in feed intake and an increase (approximately 20% in total caloric consumption over the 7 d prior to OP exposure. Functional toxicity associated with PS exposure was increased in glucose-fed (GF) rats, but the glucose diet had no apparent effect on clinical signs of toxicity following PO treatment. Glucose feeding increased the magnitude of AChE inhibition in the frontal cortex and plasma at lower dosages (i.e., 4.5 and 9 mg/kg) 3 d following PS treatment. Time-course studies (3, 7, and 11 d after PS exposure, 18 mg/kg, sc) indicated significantly greater brain and plasma AChE inhibition in glucose-fed animals at later time points. In contrast, glucose feeding had no effect on the degree of AChE inhibition following PO exposure. Neither liver microsomal oxidative desulfuration of PS, nor liver or plasma paraoxonase, nor liver or plasma carboxylesterase activities were measurably affected by glucose feeding. Downregulation of muscarinic receptors 7 d after PS exposure (18 mg/kg, sc) was more extensive in GF rats. It is postulated that excessiveglucose consumption decreases the intake of other dietary components, in particular amino acids, limiting the de novo synthesis of AChE and consequent recovery of synaptic transmission. Due to the shorter duration of inhibition following PO exposure, sponta neous reactivation of AChE may be more important than de novo protein synthesis in recovery of function, and thus with the effects of glucose feeding on its toxicity. Individuals that derive a large proportion of their calories from sugars may be at higher risk of acute toxicity from organophosphorus pesticides such as PS.
ESTHER : Olivier_2001_J.Toxicol.Environ.Health.A_63_253
PubMedSearch : Olivier_2001_J.Toxicol.Environ.Health.A_63_253
PubMedID: 11437059

Title : Age-related effects of chlorpyrifos on acetylcholine release in rat brain - Won_2001_Neurotoxicol_22_39
Author(s) : Won YK , Liu J , Olivier K , Zheng Q , Pope CN , Olivier K, Jr.
Ref : Neurotoxicology , 22 :39 , 2001
Abstract : Chlorpyrifos (CPF) is an organophosphorus insecticide that elicits toxicity through inhibition of acetylcholinesterase (AChE). Young animals are markedly more sensitive than adults to the acute toxicity of CPF. We evaluated acetylcholine (ACh) release and its muscarinic receptor-mediated regulation (i.e. muscarinic autoreceptor function, MAF) during maturation as a possible contributing factor to age-related differences in sensitivity. Cortical and striatal slices were prelabeled with [3H]choline chloride, superfused in the presence or absence of the anticholinesterase physostigmine (PHY, 20 microM) and stimulated twice (S1 and S2) with a high concentration of potassium chloride (20 mM). Depolarization-stimulated ACh release (DSAR) was lowest in neonatal, intermediate in juvenile and markedly higher in adult tissues. MAF was not detectable in tissues from neonatal rats but was present in juvenile and adult tissues. ACh release and MAF were studied at 4, 24 and 96 h following oral exposure to CPF (0, 0.5 or 1 x LD10). In general, 40-60% and 80-90% maximal AChE inhibition followed exposure to the respective 0.5 and 1 x LD10 dosages. DSAR was decreased in neonatal cortex 1 day after LD10 exposure but increased in juvenile striatum 1 day after LD10 treatment. In adults, DSAR was reduced at 4 and 24 h after exposure, but increased 96 h after CPF exposure. In juveniles, MAF was reduced in both brain regions at 24 h after 0.5LD10 exposure and at 24 and 96 h after LD10 exposure in cortex. A later reduction in MAF was noted in adult tissues (i.e. only at 96 h after LD10 treatment). Together, the results suggest that ACh release dynamics in brain vary markedly during postnatal maturation and that acute CPF exposure can alter ACh release in an age-related manner. The functional status of presynaptic processes regulating neurotransmitter release may contribute to age-related neurotoxicity elicited by high-dose exposures to chlorpyrifos.
ESTHER : Won_2001_Neurotoxicol_22_39
PubMedSearch : Won_2001_Neurotoxicol_22_39
PubMedID: 11307850

Title : Comparative cholinergic neurotoxicity of oral chlorpyrifos exposures in preweanling and adult rats - Zheng_2000_Toxicol.Sci_55_124
Author(s) : Zheng Q , Olivier K , Won YK , Pope CN
Ref : Toxicol Sci , 55 :124 , 2000
Abstract : Chlorpyrifos (CPF) is a common organophosphorus (OP) pesticide. Previous studies have demonstrated that neonatal rats are more sensitive than adults to the acute toxicity of high dosages of CPF. The present study examined lethality and age-related differences in neurochemical indicators and functional signs of neurotoxicity following a broad range of acute and repeated oral CPF exposures. There was about a 9-fold difference in sensitivity to the acute-dose lethality of chlorpyrifos among neonatal (7 days-of-age) and adult (90 days-of-age) rats (LD(10): neonates = 15 mg/kg; adults = 136 mg/kg), while juvenile rats (21 days-of-age) exhibited intermediate sensitivity (LD(10) = 47 mg/kg). Neonatal and adult rats (n = 5-7/treatment/age group/time point) were given CPF (0, 0.15, 0.45, 0. 75, 1.5, 4.5, 7.5, or 15 mg/kg/day) for 14 days and sacrificed 4 h after either the first or 14th dose for neurochemical measurements (cholinesterase activity in frontal cortex, plasma and RBC, and muscarinic ([(3)H]QNB) and nicotinic ([(3)H]epibatidine) receptor binding in frontal cortex. No overt signs of functional toxicity (involuntary movements, SLUD signs) were noted in either age group by 4 h after the first dose. With repeated CPF exposures, however, signs of cholinergic toxicity were noted in both age groups at the higher dose levels [no observed effect levels (NOELs): neonate = 4.5 mg/kg/day; adult = 7.5 mg/kg/day]. Similar degrees of ChE inhibition were noted in neonatal brain and blood fractions following acute exposure, but substantial ChE inhibition was only noted in adult plasma and RBC 4 h after the first treatment. Following repeated CPF exposures, similar degrees of ChE inhibition were again noted in tissues from immature animals, but a wide range of sensitivity to inhibition was noted in adult tissues. NOELs based on ChE inhibition for adults were about 1->/=10-fold higher than in neonates with acute exposure but only 0.2-2 times higher with repeated dosing. Moreover, dose-related inhibition of brain ChE was similar between age groups, and similar reductions in both QNB and epibatidine binding were noted between the age groups after repeated dosing, even though by the end of the dosing period young animals (juveniles) were still about 3 times more sensitive than adults, based on acute lethality. We conclude that while immature animals can be markedly more sensitive to lethal effects of high doses of CPF, lesser or no age-related differences are apparent, based on non-lethal endpoints, in particular with repeated exposures.
ESTHER : Zheng_2000_Toxicol.Sci_55_124
PubMedSearch : Zheng_2000_Toxicol.Sci_55_124
PubMedID: 10788567

Title : Organophosphorus pesticides: do they all have the same mechanism of toxicity? - Pope_1999_J.Toxicol.Environ.Health.B.Crit.Rev_2_161
Author(s) : Pope CN
Ref : J Toxicol Environ Health B Crit Rev , 2 :161 , 1999
Abstract : Organophosphorus (OP) pesticides are used extensively to control agricultural, household and structural pests. These pesticides constitute a diverse group of chemical structures exhibiting a wide range of physicochemical properties, with their primary toxicological action arising from inhibition of the enzyme acetylcholinesterase (AChE, EC 3.1.1.7). Historically, risk characterizations for these toxicants have been based on hazard and exposure data pertaining to individual chemicals. The Food Quality Protection Act of 1996 now requires, however, that combined risk assessments be performed with pesticides having a common mechanism of toxicity. It is therefore critical to consider whether OP pesticides all exert toxicity through a common mechanism. This brief review evaluates the comparative toxicity of the 38 OP AChE inhibitors currently registered for use as pesticides in the United States and examines the data which suggest that some OP pesticides have toxicologically relevant sites of action in addition to AChE. It is concluded that all OP anticholinesterases potentially have a mechanism of toxicity in common, that is, phosphorylation of AChE causing accumulation of acetylcholine, overstimulation of cholinergic receptors, and consequent clinical signs of cholinergic toxicity. Additional macromolecular targets for some OP pesticides, however, may alter the cascade of events following AChE phosphorylation and thereby modify that common mechanism. Furthermore, other macromolecular targets of some OP pesticides appear capable of altering noncholinergic neurochemical processes. These additional actions may contribute to qualitative and quantitative differences in toxicity sometimes noted in the presence of similar levels of AChE inhibition induced by different OP pesticides. Further investigation of these additional sites of action may allow subclassification and influence the decision to perform combined risk assessments on this class of pesticides based on common mechanism of toxicity.
ESTHER : Pope_1999_J.Toxicol.Environ.Health.B.Crit.Rev_2_161
PubMedSearch : Pope_1999_J.Toxicol.Environ.Health.B.Crit.Rev_2_161
PubMedID: 10230392

Title : Comparative neurochemical effects of repeated methyl parathion or chlorpyrifos exposures in neonatal and adult rats - Liu_1999_Toxicol.Appl.Pharmacol_158_186
Author(s) : Liu J , Olivier K , Pope CN
Ref : Toxicol Appl Pharmacol , 158 :186 , 1999
Abstract : Several studies have reported higher sensitivity based on lethality in young animals compared to adults following acute exposure to organophosphorus insecticides (OPs). We propose that age-related differences in sensitivity to OPs may differ qualitatively and quantitatively with different OPs and varying exposure conditions (e. g., high vs. low dose, acute vs. repeated). To test this hypothesis, we treated neonatal (7 days of age) and adult (90 days of age) rats with either methyl parathion (MPS) or chlorpyrifos (CPF) daily for 14 days and measured neurochemical endpoints {cholinesterase (ChE) inhibition, total muscarinic receptor ([(3)H]quinuclidinyl benzilate, QNB) and muscarinic M2 subtype-preferential ([(3)H]AF-DX 384) binding} in frontal cortex and striatum at timepoints both during (1 day after the 7(th) and 14(th) dose) and after (8 days after the 14(th) dose) exposures. Repeated CPF exposures were associated with relatively similar degrees of ChE inhibition between the age groups during dosing but more extensive inhibition was noted in adults after termination of exposures. Relatively similar changes in muscarinic receptor binding were also noted between age groups following CPF exposures. Moreover, the degree of muscarinic receptor binding reduction relative to ChE inhibition appeared similar in both age groups following CPF exposures. In contrast, ChE activity and muscarinic receptor binding were generally more reduced in neonatal relative to adult brain regions following repeated MPS exposures. Furthermore, the relationship between the degree of ChE inhibition and the reduction in cortical muscarinic receptor binding appeared different between the age groups, i.e., more extensive reduction was noted in neonates compared to adults with a given level of ChE inhibition. We conclude that OP-selective differences in in vivo ChE sensitivity, differential rates of enzyme recovery following inhibition, and age-dependent differences in muscarinic receptor adaptations can all influence the nature of age-related susceptibility to OPs.
ESTHER : Liu_1999_Toxicol.Appl.Pharmacol_158_186
PubMedSearch : Liu_1999_Toxicol.Appl.Pharmacol_158_186
PubMedID: 10406933

Title : Comparative presynaptic neurochemical changes in rat striatum following exposure to chlorpyrifos or parathion - Liu_1998_J.Toxicol.Environ.Health_53_531
Author(s) : Liu J , Pope CN
Ref : J Toxicol Environ Health , 53 :531 , 1998
Abstract : Organophosphorus pesticides (OPs) exert acute toxicity through inhibition of acetylcholinesterase (AChE) in target tissues. Previous studies in our laboratory have demonstrated, however, that dosages of the OPs chlorpyrifos (CPF) or parathion (PS), which cause similar degrees of brain AChE inhibition in adult male rats, can produce marked differences in toxicity. While compensatory changes in postsynaptic receptors can modulate the clinical expression of AChE inhibition and lead to tolerance to these toxicants, we propose that OP-selective changes in presynaptic cholinergic processes can also regulate the ultimate consequences of AChE inhibition. The relative effects of either vehicle (peanut oil, 2 ml/kg, sc), CPF (280 mg/kg), or PS (6.6 mg/kg) on clinical signs of toxicity and AChE activity, high-affinity choline uptake (HACU), and potassium-evoked acetylcholine (ACh) release in striatum were examined for a 7-d period after exposure in adult female Sprague-Dawley rats. In vitro effects of CPF-oxon or paraoxon, the active oxidative metabolites of CPF and PS, on HACU were also examined in comparison with the prototype inhibitor hemicholinium-3 (HC-3). Similar to our previous findings in male rats, female rats treated with dosages of CPF or PS causing similar maximal degrees of AChE inhibition (82-96%) exhibited marked differences in response; that is, PS produced more extensive signs of acute toxicity (salivation, lacrimation, urination and/or defecation, i.e., SLUD signs and involuntary movements). CPF reduced striatal synaptosomal HACU at 1, 2, and 7 d after exposure, whereas PS only decreased HACU at 2 d posttreatment. While CPF-oxon was a weak inhibitor of HACU (IC50 > 200 microM), paraoxon had no effect on this process in vitro. Potassium-evoked ACh release in the presence of physostigmine (20 microM) was not affected by either OP at 1 d but was increased 2 d after either CPF or PS treatment and remained elevated at 7 d after exposure in CPF-treated rats only. ACh release in the presence of both physostigmine and the muscarinic antagonist atropine (1 microM) was decreased by both OPs as early as 1 d after exposure and remained lower at 2 d posttreatment. By 7 d, however, ACh release in response to atropine was decreased in CPF-treated animals only, suggesting that both CPF and PS affected muscarinic autoreceptor function but with somewhat different time courses. These results suggest that different OPs may selectively modify presynaptic cholinergic processes and that early, OP-selective changes in HACU/ACh synthesis may contribute to the differential toxicity noted following extensive AChE inhibition by either CPF or PS.
ESTHER : Liu_1998_J.Toxicol.Environ.Health_53_531
PubMedSearch : Liu_1998_J.Toxicol.Environ.Health_53_531
PubMedID: 9561967

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 : Potentiation of organophosphorus-induced delayed neurotoxicity following phenyl saligenin phosphate exposures in 2-, 5-, and 8-week- old chickens - Harp_1997_Fundam.Appl.Toxicol_37_64
Author(s) : Harp P , Tanaka D, Jr. , Pope CN
Ref : Fundamental & Applied Toxicology , 37 :64 , 1997
Abstract : Phenylmethylsulfonyl fluoride (PMSF), a nonneuropathic inhibitor of neurotoxic esterase (NTE), is a known potentiator of organophosphorus-induced delayed neurotoxicity (OPIDN). The ability of PMSF posttreatment (90 mg/kg, sc, 4 hr after the last PSP injection) to modify development of delayed neurotoxicity was examined in 2-, 5-, and 8-week-old White Leghorn chickens treated either one, two, or three times (doses separated by 24 hr) with the neuropathic OP compound phenyl saligenin phosphate (PSP, 5 mg/kg, sc). NTE activity was measured in the cervical spinal cord 4 hr after the last PSP treatment. Development of delayed neurotoxicity was measured over a 16-day postexposure period. All PSP-treated groups exhibited > 97% NTE inhibition regardless of age or number of OP treatments. Two-week-old birds did not develop clinical signs of neurotoxicity in response to either single or repeated OP treatment regimens nor following subsequent treatment with PMSF. Five-week-old birds were resistant to the clinical effects of a single PSP exposure and were minimally affected by repeated doses. PMSF posttreatment, however, significantly amplified the clinical effects of one, two, or three doses of PSP. A single exposure to PSP induced slight to moderate signs of delayed neurotoxicity in 8-week-old birds with more extensive neurotoxicity being noted following repeated dosing. As with 5-week-old birds, PMSF exacerbated the clinical signs of neurotoxicity when given after one, two, or three doses of PSP in 8-week-old birds. Axonal degeneration studies supported the clinical findings: PMSF posttreatment did not influence the degree of degeneration in 2-week-old chickens but resulted in more severe degeneration (relative to PSP only exposure) in cervical cords from both 5- and 8-week-old birds. The results indicate that PMSF does not alter the progression of delayed neurotoxicity in very young (2 weeks of age) chickens but potentiates PSP-induced delayed neurotoxicity in the presence of 0-3% residual NTE activity in older animals. We conclude that posttreatment with neuropathic or nonneuropathic NTE inhibitors, following virtually complete NTE inhibition by either single or repeated doses of a neuropathic agent in sensitive age groups, can modify both the clinical and morphological indices of delayed neurotoxicity. This study further supports the hypothesis that potentiation of OPIDN occurs through a mechanism unrelated to NTE.
ESTHER : Harp_1997_Fundam.Appl.Toxicol_37_64
PubMedSearch : Harp_1997_Fundam.Appl.Toxicol_37_64
PubMedID: 9193923

Title : Neurochemical and neurobehavioral effects of repeated gestational exposure to chlorpyrifos in maternal and developing rats - Chanda_1996_Pharmacol.Biochem.Behav_53_771
Author(s) : Chanda SM , Pope CN
Ref : Pharmacology, Biochemistry & Behavior , 53 :771 , 1996
Abstract : Acute exposure to the organophosphate pesticide chlorpyrifos (CPF) on gestation day 12 (GD12, 200 mg/kg/ml, SC) causes extensive neurochemical changes in maternal brain but lesser changes in fetal brain. In the present study, we examined the relative neurotoxicity of repeated, lower-level CPF exposures during gestation in rats. Pregnant Sprague-Dawley rats were exposed to CPF (6.25, 12.5, or 25 mg/kg per day, SC) from GD12-19 and sampled at either GD16, GD20, or postnatal day 3 (PND3) for measurement of various maternal and developmental neurochemical markers. In contrast to the high acute dose exposure, no maternal toxicity was noted with repeated lower-level dosing. Extensive acetylcholinesterase (AChE) inhibition (83-90%) was noted in maternal brain at all three time points following repeated exposures (25 mg/kg). Higher AChE inhibition (58%) was noted in fetal brain at GD20 compared to 19-25% on PND3 in treated pups cross-fostered to control dams and in control pups cross-fostered to treated dams following repeated exposures (25 mg/kg per day). Whereas similar reductions in brain muscarinic receptor binding were noted at GD20 and PND3 in dams and developing brain between acute and repeated dosing regimens, greater changes in [3H]CD and [3H]cytisine binding were evident following repeated exposures. Righting reflex and cliff avoidance tests were markedly altered following repeated exposures. The results suggest that lower-level repeated exposures to CPF cause extensive neurochemical and neurobehavioral changes in developing rats in the absence of maternal toxicity.
ESTHER : Chanda_1996_Pharmacol.Biochem.Behav_53_771
PubMedSearch : Chanda_1996_Pharmacol.Biochem.Behav_53_771
PubMedID: 8801577

Title : Comparative developmental and maternal neurotoxicity following acute gestational exposure to chlorpyrifos in rats - Chanda_1995_J.Toxicol.Env.Health_44_189
Author(s) : Chanda SM , Harp P , Liu J , Pope CN
Ref : Journal of Toxicology & Environmental Health , 44 :189 , 1995
Abstract : Chlorpyrifos (CPF), an organophosphorus (OP) insecticide, exerts toxicity through inhibition of acetylcholinesterase (AChE). In the present study, pregnant Sprague-Dawley rats were given CPF (200 mg/kg, sc) as a single dose on gestation d 12 (GD12) and then sacrificed on either GD16, GD20, or postnatal d 3 (PND3) for measurement of maternal and developmental indicators of toxicity. While most CPF-treated rats exhibited no overt signs, a subset (4/28) showed moderate to severe signs of "cholinergic" toxicity at 2-3 d after treatment, and these rats were omitted from further studies. Extensive AChE inhibition (82-88%) was noted in maternal brain at all three time points following acute exposures. At GD16 and GD20, fetal brain AChE activity was inhibited 42-44%. While some degree of recovery in AChE activity was noted in pup brain by PND3, AChE activity was still inhibited (30%) in treated pups cross-fostered to control dams. In vitro inhibition of maternal and fetal (GD20) brain AChE activity by the active metabolite, chlorpyrifos oxon, suggested that the prenatal brain AChE activity was somewhat more sensitive (IC50 at 37.0 degrees C, 20 min: dam, 26.6 +/- 1.8 x 10(-9) M; fetus, 6.7 +/- 0.4 x 10(-9) M). Maternal brain muscarinic receptor binding was more extensively reduced (30-32%) at GD20 and PND3 as compared to the developing brain at GD20 (16%) and PND3 (11%). A simple postnatal reflex test (righting reflex) was transiently altered by CPF. The results suggest that CPF exposure to dams during gestation produces more extensive neurotoxicological effects in the dam relative to the developing fetus.
ESTHER : Chanda_1995_J.Toxicol.Env.Health_44_189
PubMedSearch : Chanda_1995_J.Toxicol.Env.Health_44_189
PubMedID: 7531776

Title : Organophosphate-Sensitive Cholinergic Receptors -
Author(s) : Pope CN , Chaudhuri J , Chakraborti TK
Ref : In Enzyme of the Cholinesterase Family - Proceedings of Fifth International Meeting on Cholinesterases , (Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P., Eds) Plenum Publishing Corp. :305 , 1995
PubMedID:

Title : Fenthion Treatment Produces Tissue-, Dose-, and Time-Dependent Decreases in Muscarinic Second Messenger Response in the Adult Rat CNS -
Author(s) : Tandon P , Pope CN , Barone S, Jr. , Boyes W , Tilson HA , Padilla S
Ref : In Enzyme of the Cholinesterase Family - Proceedings of Fifth International Meeting on Cholinesterases , (Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P., Eds) Plenum Publishing Corp. :396 , 1995
PubMedID:

Title : Fenthion produces a persistent decrease in muscarinic receptor function in the adult rat retina - Tandon_1994_Toxicol.Appl.Pharmacol_125_271
Author(s) : Tandon P , Padilla S , Barone S, Jr. , Pope CN , Tilson HA
Ref : Toxicol Appl Pharmacol , 125 :271 , 1994
Abstract : Several reports have suggested that exposure to organophosphate pesticides damages the visual system. The prolonged effects of an acute dose of fenthion (dimethyl 3-methyl-4-methylthiophenyl phosphorothionate) were studied on the cholinergic system of the rat retina. Fenthion was administered in a single dose of 0 or 100 mg/kg (sc, in corn oil) to adult, male, Long-Evans rats. The animals were killed 4, 14, or 56 days after treatment and cholinesterase (ChE) activity as well as muscarinic receptor (mChR) function measured in the retina and frontal cortex. Fenthion produced 89% inhibition of ChE activity in both tissues at 4 days, and, although there was recovery, slight (15%) inhibition of the enzyme activity was still observed at 56 days in both tissues. A long-lasting decrease in carbachol-stimulated inositolphosphate (IP) release was observed following fenthion treatment in the retina: IP release was depressed at 4 days and this depression persisted up to 56 days after dosing. The density of mChR in the retina as well as in the cortex was decreased by 14-20% at 4 days and returned to control levels by 56 days. Fenthion had no effect on the metabolism of phospholipids in the retina following intraocular injections of labeled precursors [3H]myo-inositol, [methyl-14C]choline, or [2-3H]glycerol 4 days after fenthion treatment. These prolonged effects of fenthion on mChR function (signal transduction) appear to be specific to the retina as the cortex showed no change in receptor-stimulated IP release even in the presence of significant mChR down-regulation and ChE inhibition. This dose of fenthion did not produce overt morphological changes in the retina or in the cortex, as observed with light microscopy, although an increase in glial fibrillary acidic protein immunoreactivity (GFAP IR) extending from the internal limiting membrane to the external limiting membrane of the retina was noted. This increase in GFAP IR was observed at 14 days and persisted as long as 56 days post-treatment in the retina, but was not noted in the cortex at any of the time points studied. Thus, this long-lasting perturbation in the retinal cholinergic second messenger system induced by fenthion may occur independently of depressed ChE activity and down-regulation of mChR.
ESTHER : Tandon_1994_Toxicol.Appl.Pharmacol_125_271
PubMedSearch : Tandon_1994_Toxicol.Appl.Pharmacol_125_271
PubMedID: 8171435

Title : Comparative Inhibition of Rodent and Human Erythrocyte Acetylcholinesterase by Carbofuran and Carbaryl - Rao_1994_Pestic.Biochem.Physiol_48_79
Author(s) : Rao PS , Roberts GH , Pope CN , Ferguson PW
Ref : Pesticide Biochemistry and Physiology , 48 :79 , 1994
Abstract : Acetylcholinesterase (AChE) inhibition is a common measure of carbamate toxicity. Since most studies predict AChE inhibition in humans using the rat as an animal model, this study evaluated the comparative inhibition of rodent and human erythrocyte AChE by two commonly used anticholinesterase carbamates. Comparative hematology, Km and Vmax, IC50, and Ki were established for erythrocyte AChE from male Sprague-Dawley rats (200-250 g) and healthy human volunteers (19-44 years old). Erythrocyte AChE activity was measured using a modified radiometric method. No significant species differences were present in hematology. Rodent AChE Km (0.69 +/- 0.15 mM) and Vmax (0.53 +/- 0.13 nmol/min/mg protein) were lower than human Km (1.87 +/- 0.26 mM) and Vmax (2.92 +/- 0.27 nmol/min/mg protein). Carbofuran IC50 values for rodent (0.04 +/- 0.01 uM) were similar to human IC50 (0.025 +/- 0.005 uM); however, the carbaryl IC50 for rodent AChE (4.84 +/- 0.42 uM) was higher than that for human AChE (1.23 +/- 0.108 uM). No significant species differences were evident in Ki for carbofuran (rodent Ki of 18.35 +/- 1.96 nM and human Ki of 16.81 +/- 1.75 nM) or carbaryl (rodent Ki of 2.63 +/- 0.36 uM and human Ki of 3.03 +/- 0.53 uM). These data suggest that, despite inherent differences in kinetics of substrate hydrolysis between rodent and human erythrocyte AChE, the kinetics of inhibition in vitro by carbofuran and carbaryl as estimated by the comparative bimolecular rate constants (Ki) are quite similar between species and may be useful in human risk assessment.
ESTHER : Rao_1994_Pestic.Biochem.Physiol_48_79
PubMedSearch : Rao_1994_Pestic.Biochem.Physiol_48_79
PubMedID:

Title : Comparative neurochemical and neurobehavioral effects of repeated chlorpyrifos exposures in young and adult rats - Chakraborti_1993_Pharmacol.Biochem.Behav_46_219
Author(s) : Chakraborti TK , Farrar JD , Pope CN
Ref : Pharmacology, Biochemistry & Behavior , 46 :219 , 1993
Abstract : Neonatal (7 days old) rats are markedly more sensitive than adults (3 months old) to the acute toxic effects of the insecticide, chlorpyrifos (CPF). In the present study, we have compared the effects of subacute CPF exposures in these same age groups. Repeated doses of CPF (40 mg/kg, SC, every 4 days, total of 4 doses) caused extensive inhibition of cortical, hippocampal, and striatal cholinesterase (ChE) activity in adult rats at 4 (90-92%) and 14 (71-78%) days after the last treatment. Rats treated similarly during postnatal maturation (beginning on day 7) showed a much lower degree of ChE inhibition (21-60%) at these time points. Muscarinic ([3H]quinuclidinyl benzilate, QNB) receptor binding in cortex, hippocampus, and striatum was reduced in adult brain at 4 (30-43%) and 14 (22-32%) days after the final treatment, whereas receptor densities were only marginally affected (5-11% reduction) in young rats. Basal motor activity levels were not affected in either young or adult rats as a function of CPF exposure. CPF-treated adult rats exhibited higher activity levels after challenge with scopolamine (1 mg/kg, IP) at 2, 4, 6, and 8 weeks after treatment, whereas CPF exposure did not affect the motoric response to scopolamine in rats treated during postnatal maturation. These data suggest that although neonatal rats are more sensitive to acute lethal effects from high doses of CPF, adult rats exhibit more persistent neurochemical and neurobehavioral alterations following repeated, lower-level exposures.
ESTHER : Chakraborti_1993_Pharmacol.Biochem.Behav_46_219
PubMedSearch : Chakraborti_1993_Pharmacol.Biochem.Behav_46_219
PubMedID: 7504821

Title : Behavioral and neurochemical effects of acute chlorpyrifos in rats: tolerance to prolonged inhibition of cholinesterase - Bushnell_1993_J.Pharmacol.Exp.Ther_266_1007
Author(s) : Bushnell PJ , Pope CN , Padilla S
Ref : Journal of Pharmacology & Experimental Therapeutics , 266 :1007 , 1993
Abstract : The preponderance of studies of tolerance to organophosphate (OP) cholinesterase (ChE) inhibitors indicates that functional recovery accompanies neurochemical compensations for the inhibited enzyme. Contrary to prediction, rats dosed with the OP diisopropylfluorophosphate (DFP) showed progressive and persistent impairment of cognitive and motor function over a 3-week period of daily exposure, despite neurochemical and pharmacological evidence of tolerance to its inhibition of ChE. To determine whether these functional effects of DFP resulted from inhibition of ChE and downregulation of muscarinic cholinergic receptors, rats were dosed with chlorpyrifos (CPF), an OP pesticide which inhibits blood and brain ChE of rats for weeks after a single injection. Long-Evans rats were trained to perform an appetitive test of memory and motor function and were then injected s.c. with 0, 60, 125 or 250 mg/kg of CPF in peanut oil and tested 5 days/week for 7 weeks. Unconditioned behavior was also rated for signs of cholinergic toxicity. CPF inhibited ChE activity in whole blood in a dose-related manner for more than 53 days. The degree and time course of ChE inhibition in blood and brain and the downregulation of muscarinic receptors in brain after 125 mg/kg of CPF closely paralleled the previously reported effects of 25 daily injections of 0.2 mg/kg of DFP. In addition, CPF-treated rats were subsensitive to oxotremorine-induced hypothermia for at least 32 days after CPF. However, functional deficits (in working memory and motor function) appeared within 2 days after injection of CPF and recovered within 3 weeks, long before ChE activity and receptor density returned to control levels. Thus, the effects of CPF were neither progressive nor as persistent as those seen during daily DFP injections. This difference suggests that the DFP-induced behavioral changes observed previously cannot be attributed entirely to its effects on ChE activity and changes in [3H]quinuclidinyl benzilate binding.
ESTHER : Bushnell_1993_J.Pharmacol.Exp.Ther_266_1007
PubMedSearch : Bushnell_1993_J.Pharmacol.Exp.Ther_266_1007
PubMedID: 7689099

Title : The role of neurotoxic esterase (NTE) in the prevention and potentiation of organophosphorus-induced delayed neurotoxicity (OPIDN) - Pope_1993_Chem.Biol.Interact_87_395
Author(s) : Pope CN , Tanaka D, Jr. , Padilla S
Ref : Chemico-Biological Interactions , 87 :395 , 1993
Abstract : The first step in the initiation of organophosphorus-induced delayed neuropathy (OPIDN) is proposed to be the phosphorylation of an enzyme found in the nervous system called neurotoxic esterase (neuropathy target esterase, NTE). It has been known for over twenty years that non-neuropathic inhibitors of NTE exist and can actually prevent OPIDN when given before a neuropathic organophosphate (OP). Within the last three years it has become evident that another outcome is possible following in vivo interaction between neuropathic and nonneuropathic NTE inhibitors. When administered after OP exposure, nonneuropathic inhibitors can intensify or potentiate signs of OPIDN in adult chickens. Additionally, whereas developing chickens are typically resistant to the effects of neuropathic OPs, resistant age groups will develop OPIDN when exposure to a neuropathic OP is followed by the non-neuropathic NTE inhibitor phenylmethylsulfonyl fluoride. As in the case of prevention, studies of the potentiation of OPIDN may yield insight into mechanisms involved in the pathogenesis of delayed neurotoxicity. A brief review of current knowledge regarding the role of NTE in both the prevention and potentiation of OPIDN is presented.
ESTHER : Pope_1993_Chem.Biol.Interact_87_395
PubMedSearch : Pope_1993_Chem.Biol.Interact_87_395
PubMedID: 8343996

Title : Subacute ethanol consumption reverses p-xylene-induced decreases in axonal transport - Padilla_1992_Toxicology_75_159
Author(s) : Padilla S , Lyerly DL , Pope CN
Ref : Toxicology , 75 :159 , 1992
Abstract : Human exposure to organic solvents is often complicated by ethanol ingestion and the literature is replete with demonstrations of metabolic interactions between ethanol and organic solvents at a pharmacokinetic level. Because of the possible modulation of xylene toxicity by ethanol consumption, the present group of studies characterizes the effect of ethanol on the p-xylene-induced decrease in axonal transport in the rat optic system previously reported by our laboratory. Long-Evans, hooded, male rats were divided randomly into two groups: those receiving 10% ethanol in their drinking water and those receiving water only. These two groups were further subdivided into two groups which were either exposed by inhalation to 1600 ppm p-xylene for 6 h/day, 5 days/week for 8 exposure-days or were treated identically except that they were exposed to air while in the inhalation chambers. The ethanol-drinking rats were given ethanol 6 days prior to and on the days of the inhalation exposure. Immediately after removal from the inhalation chambers on the last exposure day, the animals were injected intraocularly with [35S]methionine and [3H]fucose to measure the synthesis and rapid axonal transport of proteins and glycoproteins, respectively, in the retinal ganglion cells. The animals were sacrificed 20 h later, and the amount of radioactivity in different areas of the retinal ganglion cells was determined by liquid scintillation counting. As in previous experiments, the xylene exposure group showed a significant reduction in axonal transport of proteins and glycoproteins, whereas the ethanol exposure alone produced no significant reductions in the transport of either proteins or glycoproteins. In the animals receiving both ethanol and xylene, however, the ethanol treatment prevented the decreased transport characteristic of the xylene only animals, i.e. in all areas of the optic projections the level of transport were similar to the level present in the control groups. These data suggest that the xylene-induced reduction in rapid axonal transport was reversed (or prevented) by subacute ethanol consumption.
ESTHER : Padilla_1992_Toxicology_75_159
PubMedSearch : Padilla_1992_Toxicology_75_159
PubMedID: 1281343

Title : Paraoxon toxicity is not potentiated by prior reduction in blood acetylcholinesterase - Padilla_1992_Toxicol.Appl.Pharmacol_117_110
Author(s) : Padilla S , Moser VC , Pope CN , Brimijoin S
Ref : Toxicol Appl Pharmacol , 117 :110 , 1992
Abstract : The role of blood acetylcholinesterase in moderating the effects of organophosphate challenge in rats was tested. Adult male rats (n = 42) were injected (iv) either with monoclonal antibodies (MAb) to rat acetylcholinesterase (EC 3.1.1.7; AChE) or normal mouse IgG (controls). Two days later, the rats were injected (sc) with either a mild (0.17 mg/kg) or moderate dosage (0.34 mg/kg) of paraoxon or with vehicle. Neurological integrity was assessed by a functional observational battery followed by motor activity, 3 to 4 hr after dosing. Blood, brain, and diaphragm tissues were then collected for determination of AChE activity. MAb treatment reduced whole blood and plasma AChE activity by 32 and 90%, respectively, but did not affect neurobehavioral parameters or the AChE activity of brain or diaphragm. The paraoxon challenge produced dose-related neurobehavioral changes and inhibition of brain and diaphragm AChE activity to the same extent in IgG- and MAb-treated rats. Thus, significant loss in blood AChE alone produced no detectable neurobehavioral deficits and did not alter the subsequent responses to paraoxon challenge.
ESTHER : Padilla_1992_Toxicol.Appl.Pharmacol_117_110
PubMedSearch : Padilla_1992_Toxicol.Appl.Pharmacol_117_110
PubMedID: 1440604

Title : Phenylmethylsulfonyl fluoride alters sensitivity to organophosphorus-induced delayed neurotoxicity in developing animals - Pope_1992_Neurotoxicol_13_355
Author(s) : Pope CN , Chapman ML , Tanaka D, Jr. , Padilla S
Ref : Neurotoxicology , 13 :355 , 1992
Abstract : The serine/cysteine hydrolase inhibitor phenylmethylsulfonyl fluoride (PMSF) markedly intensifies the clinical expression of organophosphorus-induced delayed neurotoxicity (OPIDN) in adult chickens when administered after organophosphate exposure. In this study, we have examined the ability of PMSF post-treatment to affect sensitivity to OPIDN in developing animals at ages normally showing resistance. Chickens (35, 49 or 70 days of age) were treated with diisopropylphosphorofluoridate (DFP, 2 mg/kg, sc) and then treated four hours later with PMSF (90 mg/kg, sc) or vehicle only and examined for clinical signs of ataxia and incoordination. Chickens treated with DFP alone showed a marked age-related increase in the severity of motor deficits. Birds treated with DFP followed by PMSF showed more extensive clinical deficits relative to those treated with DFP only, but relatively similar degrees of motor dysfunction among the age groups. Cervical spinal cord samples processed by the Fink-Heimer degeneration method indicated that PMSF post-treatment induced more extensive axonal degeneration in all age groups relative to treatment with DFP only. As the DFP treatment alone caused greater than or equal to 90% inhibition of neurotoxic esterase activity (NTE, the putative molecular target site for OPIDN), interaction with NTE by PMSF does not appear to be involved in potentiation. We hypothesize that PMSF potentiates OPIDN through impairment of a physiological process which normally imparts resistance to young animals and which regresses during development.
ESTHER : Pope_1992_Neurotoxicol_13_355
PubMedSearch : Pope_1992_Neurotoxicol_13_355
PubMedID: 1436755

Title : Retrograde axonal transport of locally synthesized phosphoinositides in the rat sciatic nerve - Padilla_1991_J.Neurochem_57_415
Author(s) : Padilla S , Pope CN
Ref : Journal of Neurochemistry , 57 :415 , 1991
Abstract : Although autoradiography has demonstrated local incorporation of [3H]inositol into axonal phospholipids after intraneural injection, retrograde axonal transport of phosphatidylinositol has only been demonstrated after injection of lipid precursor into the cell body regions (L4 and L5 dorsal root ganglia) of the sciatic nerve. We now report the retrograde axonal transport of inositol phospholipids synthesized locally in the axons. Following microinjection of myo-[3H]inositol into the rat sciatic nerve (50-55 mm distal to L4 and L5 dorsal root ganglia), a time-dependent accumulation of 3H label occurred in the dorsal root ganglia ipsilateral to the injection site. The ratio of dpm present in the ipsilateral dorsal root ganglia to that in the contralateral dorsal root ganglia was not significantly different from unity between 2 and 8 h following isotope injection but increased to 10-12-fold between 24 and 72 h following precursor injection. By 24 h following precursor injection, the ipsilateral/contralateral ratio of the water-soluble label in the dorsal root ganglia still remained approximately 1.0, whereas the corresponding ratio in the chloroform/methanol-soluble fraction was approximately 20. The time course of appearance of labeled lipids in the ipsilateral dorsal root ganglia after injection of precursor into the nerve at various distances from the dorsal root ganglia indicated a transport rate of at least 5 mm/h. Accumulation of label in the dorsal root ganglia could be prevented by intraneural injection of colchicine or ligation of the sciatic nerve between the dorsal root ganglia and the isotope injection site. These results demonstrate that inositol phospholipids synthesized locally in the sciatic nerve are retrogradely transported back to the nerve cell bodies located in the dorsal root ganglia.
ESTHER : Padilla_1991_J.Neurochem_57_415
PubMedSearch : Padilla_1991_J.Neurochem_57_415
PubMedID: 1712828

Title : Promotion of organophosphate-induced delayed polyneuropathy by phenylmethanesulfonyl fluoride -
Author(s) : Pope CN , Padilla S
Ref : Toxicol Appl Pharmacol , 110 :179 , 1991
PubMedID: 1871770

Title : Behavioral and neurochemical changes in rats dosed repeatedly with diisopropylfluorophosphate - Bushnell_1991_J.Pharmacol.Exp.Ther_256_741
Author(s) : Bushnell PJ , Padilla SS , Ward T , Pope CN , Olszyk VB
Ref : Journal of Pharmacology & Experimental Therapeutics , 256 :741 , 1991
Abstract : Behavioral effects of organophosphates (OPs) typically decrease with repeated exposure, despite persistence of OP-induced inhibition of acetylcholinesterase (AChE) and downregulation of muscarinic acetylcholine (ACh) receptors. To characterize this tolerance phenomenon, rats were trained to perform an appetitive operant task which allowed daily quantification of working memory (accuracy of delayed matching-to-position), reference memory (accuracy of visual discrimination) and motor function (choice response latencies and inter-response times during delay). Daily s.c. injections of 0.2 mg/kg of diisopropylfluorophosphate (DFP) caused no visible cholinergic signs, did not affect body weight or visual discrimination, but progressively impaired matching accuracy and lengthened response latencies and interresponse times. These effects recovered in seven of eight treated rats after termination of DFP treatment. Resumption of daily DFP at 0.1 mg/kg caused smaller impairments of both matching accuracy and response latency. After 21 injections of 0.2 mg/kg/day of DFP, rats were subsensitive to the hypothermia induced by acute oxotremorine (0.2 mg/kg i.p.), as expected after OP-induced downregulation of muscarinic ACh receptors. Evidence for supersensitivity to scopolamine (0.03 and 0.056 mg/kg i.p.) in DFP-treated rats was mixed, with additive effects predominating on both the cognitive and motor aspects of the task. After 18 days of 0.1 mg/kg of DFP, AChE was inhibited 50 to 75% and muscarinic ACh receptor density was reduced 15 to 20% in hippocampus and frontal cortex. Progressive declines in AChE activity in hippocampus and frontal cortex across 15 daily doses with DFP at 0.1 and 0.2 mg/kg were observed in other rats; quinuclidinyl benzilate binding was significantly reduced in hippocampus after 15 doses at both levels of DFP. These results indicate that animals showing a definitive sign of tolerance to OP administration (subsensitivity to a cholinergic agonist) were also functionally impaired on both the mnemonic and motoric demands of a working memory task. The nature of this impairment suggests further that it results from compensatory changes in the central nervous system, e.g., muscarinic receptor downregulation, considered to produce "tolerance" to OPs in exposed animals.
ESTHER : Bushnell_1991_J.Pharmacol.Exp.Ther_256_741
PubMedSearch : Bushnell_1991_J.Pharmacol.Exp.Ther_256_741
PubMedID: 1994004

Title : Potentiation of organophosphorus-induced delayed neurotoxicity by phenylmethylsulfonyl fluoride - Pope_1990_J.Toxicol.Environ.Health_31_261
Author(s) : Pope CN , Padilla S
Ref : J Toxicol Environ Health , 31 :261 , 1990
Abstract : It is well known that pretreatment with the serine esterase inhibitor phenylmethylsulfonyl fluoride (PMSF) can protect experimental animals from organophosphorus-induced delayed neurotoxicity (OPIDN), presumably by blocking the active site of neurotoxic esterase (NTE) such that binding and "aging" of the neuropathic OP is thwarted. We report here that while PMSF (60 mg/kg, sc) given 4 h before the neuropathic organophosphate (OP) mipafox (50 mg/kg, im) completely prevented the clinical expression of OPIDN in hens, the identical PMSF treatment markedly amplified the delayed neurotoxicity (relative to hens treated with OP only) if administered 4 h after mipafox (5 or 50 mg/kg, im). Moreover, in a separate experiment using diisopropylphosphorofluoridate (DFP) as the neurotoxicant in place of mipafox, posttreatment with PMSF 4 h after DFP (0.5 mg/kg) also accentuated the severity of ataxia. These data indicate that PMSF only protects against OPIDN if given prior to exposure to the neurotoxicant; treatment with PMSF after OP exposure critically exacerbates the delayed neurotoxicity from exposure to organophosphorus compounds.
ESTHER : Pope_1990_J.Toxicol.Environ.Health_31_261
PubMedSearch : Pope_1990_J.Toxicol.Environ.Health_31_261
PubMedID: 2254952

Title : Modulation of neurotoxic esterase activity in vitro by phospholipids - Pope_1989_Toxicol.Appl.Pharmacol_97_272
Author(s) : Pope CN , Padilla S
Ref : Toxicol Appl Pharmacol , 97 :272 , 1989
Abstract : Neurotoxic esterase (NTE), the proposed molecular site for the initiation of organophosphorus-induced delayed neuropathy, is a membrane-associated enzyme. NTE activity was solubilized from chicken brain microsomal membranes with the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1- propanesulfonate and partially separated from other solubilized hen brain esterases by DEAE-Sephacel anion-exchange chromatography using stepwise increases in salt concentration; however, there was poor recovery of NTE activity and only a slight increase in NTE specific activity. NTE activity in the "high salt" fraction (i.e., the NTE-enriched fraction) was markedly activated by a heat-stable factor(s) present in other fractions eluted from the column. This activating factor was extracted with organic solvents, suggesting that it may be lipid. In a related study, purified phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine were also found to activate the partially separated NTE activity in a concentration-dependent manner while phosphatidyl-inositol was found to inhibit the same partially separated NTE fraction in a concentration-dependent manner. The results suggest that lipids may modulate NTE activity and that the loss of lipid cofactors during chromatographic separations may underlie some of the difficulties encountered in isolation of active NTE.
ESTHER : Pope_1989_Toxicol.Appl.Pharmacol_97_272
PubMedSearch : Pope_1989_Toxicol.Appl.Pharmacol_97_272
PubMedID: 2922759

Title : Chromatographic characterization of neurotoxic esterase - Pope_1989_Biochem.Pharmacol_38_181
Author(s) : Pope CN , Padilla SS
Ref : Biochemical Pharmacology , 38 :181 , 1989
Abstract : Neurotoxic esterase (neuropathy target enzyme, NTE) is an enzyme whose irreversible inhibition is the apparent first step in the induction of organophosphorus-induced delayed neuropathy. NTE is an integral membrane protein and thus must be solubilized before isolation can be attempted. This study describes solubilization of active chicken brain NTE with the nondenaturing detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) and characterization of the detergent-solubilized enzyme by gel exclusion chromatography. When detergent-solubilized membranes were chromatographed on Sepharose gel exclusion media, NTE activity eluted with an apparent molecular weight of 880-970 kD. When [3H]diisopropylphosphorofluoridate-radiolabeled membranes and unlabeled microsomal membranes were CHAPS-solubilized, combined and chromatographed on Sepharose 4B, NTE activity coeluted with two radiolabeled proteins (Mr = 148 kD and Mr = 112 kD using sodium dodecyl sulfate-polyacrylamide gel electrophoresis with reducing conditions). Another radiolabeled protein (Mr = 92 kD) coeluted exclusively with inhibitor-resistant esterase activity. This study provides strong evidence that the 148 and 112 kD proteins are subunits of a multicomponent NTE complex.
ESTHER : Pope_1989_Biochem.Pharmacol_38_181
PubMedSearch : Pope_1989_Biochem.Pharmacol_38_181
PubMedID: 2910299