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Mosier JA, Hybart RL, Lewis AM, Carr RL Ref: Int J Sci Res Environ Sci Toxicol, 5:1, 2022 : PubMed ESTHER: Mosier_2022_Int.J.Sc.Res.Environ.Sci.Toxicol_5_1 PubMedSearch: Mosier 2022 Int.J.Sc.Res.Environ.Sci.Toxicol 5 1 Inhibitor(s) related to this paper: Chlorpyrifos Abstract developmental exposure. While the canonical mechanism of toxicity of CPF involves the inhibition of brain acetylcholinesterase (AChE), we have reported that exposure of juvenile rats to levels of CPF that do not yield any inhibition of brain AChE results in neurobehavioral alterations at later ages. However, it is unclear what effect exposure to these low levels of CPF has on blood esterase activities which are frequently used not only as biomarkers of exposure but also to set exposure levels in risk assessment. To determine this, male and female rat pups were exposed orally from postnatal day 10 to 16 to either corn oil (vehicle) or 0.5, 0.75, or 1.0 mg/kg CPF. At 12 h after the final exposure, serum cholinesterase (ChE), butyrylcholinesterase (BChE), and carboxylesterase (CES), and red blood cell (RBC) and brain AChE activities were determined. There were no differences between sexes in either the controls or individual treatments for all enzymes. Only the highest dosage of 1.0 mg/kg CPF yielded significant brain AChE inhibition (22-24%) but all dosages significantly inhibited the blood esterases with inhibition being highest with serum CES (65-85%) followed by serum BChE (57-76%), RBC AChE (35-65%), and then serum ChE (16-32%). Our data verify that blood esterases are inhibited at dosages of CPF that alter neurobehavioral performance in the absence of effects on brain AChE activity. Title: Inhibition of Serum Esterases in Juvenile Rats Repeatedly Exposed to Low Levels of Chlorpyrifos Mosier JA, Hybart RL, Lewis AM, Alugubelly N, Mohammed AN, Carr RL Ref: Int J Sci Res Environ Sci Toxicol, 5:, 2022 : PubMed ESTHER: Mosier_2022_Int.J.Sci.Res.Environ.Sci.Toxicol_5_ PubMedSearch: Mosier 2022 Int.J.Sci.Res.Environ.Sci.Toxicol 5 PubMedID: 36118291 Abstract Chlorpyrifos (CPF) is an organophosphorus insecticide that has gained significant attention cue to the reported toxicity associated with developmental exposure. While the canonical mechanism of toxicity of CPF involves the inhibition of brain acetylcholinesterase (AChE), we have reported that exposure of juvenile rats to levels of CPF that do not yield any inhibition of brain AChE results in neurobehavioral alterations at later ages. However, it is unclear what effect exposure to these low levels of CPF has on blood esterase activities which are frequently used not only as biomarkers of exposure but also to set exposure levels in risk assessment. To determine this, male and female rat pups were exposed orally from postnatal day 10 to 16 to either corn oil (vehicle) or 0.5, 0.75, or 1.0 mg/kg CPF. At 12 h after the final exposure, serum cholinesterase (ChE), butyrylcholinesterase (BChE), and carboxylesterase (CES), and red blood cell (RBC) and brain AChE activities were determined. There were no differences between sexes in either the controls or individual treatments for all enzymes. Only the highest dosage of 1.0 mg/kg CPF yielded significant brain AChE inhibition (22-24%) but all dosages significantly inhibited the blood esterases with inhibition being highest with serum CES (65-85%) followed by serum BChE (57-76%), RBC AChE (35-65%), and then serum ChE (16-32%). Our data verify that blood esterases are inhibited at dosages of CPF that alter neurobehavioral performance in the absence of effects on brain AChE activity. Title: The Mechanistic Basis for the Toxicity Difference Between Juvenile Rats and Mice following Exposure to the Agricultural Insecticide Chlorpyrifos Sette KN, Alugabelly N, Glenn LB, Guo-Ross SX, Parkes MK, Wilson JR, Seay CN, Carr RL Ref: Toxicology, :153317, 2022 : PubMed ESTHER: Sette_2022_Toxicology__153317 PubMedSearch: Sette 2022 Toxicology 153317 PubMedID: 36096317 Abstract At high exposure levels, organophosphorus insecticides (OPs) exert their toxicity in mammals through the inhibition of brain acetylcholinesterase (AChE) leading to the accumulation of acetylcholine in cholinergic synapses and hyperactivity of the nervous system. Currently, there is a concern that low-level exposure to OPs induces negative impacts in developing children and the chemical most linked to these issues is chlorpyrifos (CPF). Our laboratory has observed that a difference in the susceptibility to repeated exposure to CPF exists between juvenile mice and rats with respect to the inhibition of brain AChE. The basis for this difference is unknown but differences in the levels of the detoxification mechanisms could play a role. To investigate this, 10-day old rat and mice pups were exposed daily for 7 days to either corn oil or a range of dosages of CPF via oral gavage. Four hours following the last administration of CPF on day 16, brain, blood, and liver were collected. The inhibition of brain AChE activity was higher in juvenile rats as compared to juvenile mice. The levels of activity of the detoxification enzymes and the impact of CPF exposure on their activity were determined in the two species at this age. In blood and liver, the enzyme paraoxonase-1 (PON1) hydrolyzes the active metabolite of CPF (CPF-oxon), and the enzymes carboxylesterase (CES) and cholinesterase (ChE) act as alternative binding sites for CPF-oxon removing it from circulation and providing protection. Both species had similar levels of PON1 activity in the liver and serum. Mice had higher ChE activity in liver and serum than rats but, following CPF exposure, the percentage inhibition was similar between species at an equivalent dosage. Even though rats had slightly higher liver CES activity than mice, the level of inhibition following exposure was higher in rats. In serum, juvenile mice had an 8-fold higher CES activity than rats, and exposure to a CPF dosage that almost eliminated CES activity in rats only resulted in 22% inhibition in mice suggesting that the high serum CES activity in mice as compared to rats is a key component in this species difference. In addition, there was a species difference in the sensitivity of CES to inhibition by CPF-oxon with rats having a lower IC50 in both liver and serum as compared to mice. This greater enzyme sensitivity suggests that saturation of CES would occur more rapidly in juvenile rats than in mice, resulting in more CPF reaching the brain to inhibit AChE in rats. Title: Persistent proteomic changes in glutamatergic and GABAergic signaling in the amygdala of adolescent rats exposed to chlorpyrifos as juveniles Alugubelly N, Mohammed AN, Carr RL Ref: Neurotoxicology, :, 2021 : PubMed ESTHER: Alugubelly_2021_Neurotoxicol__ PubMedSearch: Alugubelly 2021 Neurotoxicol PubMedID: 34058248 Abstract Chlorpyrifos (CPF) remains one of the most widely used organophosphorus insecticides (OPs) despite the concerns about its developmental neurotoxicity. Developmental exposure to CPF has long-lasting negative impacts, including abnormal emotional behaviors. These negative impacts are observed at exposure levels do not cause inhibition of acetylcholinesterase, the canonical target of OPs. Exposure to CPF at these levels inhibits the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) but it is not clear what the persistent effects of this inhibition are. To investigate this, male rat pups were exposed orally to either corn oil, 0.75 mg/kg CPF, or 0.02 mg/kg PF-04457845 (PF; a specific inhibitor of FAAH) daily from postnatal day 10 (PND10) - PND16. This dosage of CPF does not inhibit brain cholinesterase activity but inhibits FAAH activity. On PND38 (adolescence), the protein expression in the amygdala was determined using a label-free shotgun proteomic approach. The analysis of control vs CPF and control vs PF led to the identification of 44 and 142 differentially regulated proteins, respectively. Gene ontology enrichment analysis revealed that most of the proteins with altered expression in both CPF and PF treatment groups were localized in the synapse-related regions, such as presynaptic membrane, postsynaptic density, and synaptic vesicle. The different biological processes affected by both treatment groups included persistent synaptic potentiation, glutamate receptor signaling, protein phosphorylation, and chemical synaptic transmission. These results also indicated disturbances in the balance between glutamatergic ( Glutamate AMPA receptor 2, Excitatory amino acid transporter 2, and vesicular glutamate transporter 2) and GABAergic signaling ( GABA transporter 3 and glutamate decarboxylase 2). This imbalance could play a role in the abnormal emotional behavior that we have previously reported. These results suggest that there is a similar pattern of expression between CPF and PF, and both these chemicals can persistently alter emotional behavior as a consequence of inhibition of FAAH. Title: In vitro age-related differences in rats to organophosphates Meek EC, Carr RL, Chambers JE Ref: Toxicol In Vitro, :105102, 2021 : PubMed ESTHER: Meek_2021_Toxicol.In.Vitro__105102 PubMedSearch: Meek 2021 Toxicol.In.Vitro 105102 PubMedID: 33497710 Abstract The mechanism of toxic action for organophosphates (OPs) is the persistent inhibition of acetylcholinesterase (AChE) resulting in accumulation of acetylcholine and subsequent hyperstimulation of the nervous system. Organophosphates display a wide range of acute toxicities. Differences in the OP's chemistries results in differences in the compound's metabolism and toxicity. Acute toxicities of OPs appear to be principally dependent on compound specific efficiencies of detoxication, and less dependent upon efficiencies of bioactivation and sensitivity of AChE. Serine esterases, such as carboxylesterase (CaE) and butyrylcholinesterase (BChE), play a prominent role in OP detoxication. Organophosphates can stoichiometrically inhibit these enzymes, removing OPs from circulation thus providing protection for the target enzyme, AChE. This in vitro study investigated age-related sensitivity of AChE, BChE and CaE to twelve structurally different OPs in rat tissues. Sensitivity of esterases to these OPs was assessed by inhibitory concentration 50s (IC(50)s). The OPs displayed a wide range of inhibitory potency toward AChE with IC(50)s in the low nM-microM range with no differences among ages; however, the CaE IC(50)s generally increased with age reflecting greater protection in adults. These results suggest age-related differences in acute toxicities of OPs in mammals are primarily a result of their detoxication capacities. Title: Effects of Chlorpyrifos on Serine Hydrolase Activities, Lipid Mediators, and Immune Responses in Lungs of Neonatal and Adult Mice Szafran BN, Borazjani A, Seay CN, Carr RL, Lehner R, Kaplan BLF, Ross MK Ref: Chemical Research in Toxicology, :, 2021 : PubMed ESTHER: Szafran_2021_Chem.Res.Toxicol__ PubMedSearch: Szafran 2021 Chem.Res.Toxicol PubMedID: 33900070 Abstract Chlorpyrifos (CPF) is an organophosphate (OP) pesticide that causes acute toxicity by inhibiting acetylcholinesterase (AChE) in the nervous system. However, endocannabinoid (eCB) metabolizing enzymes in brain of neonatal rats are more sensitive than AChE to inhibition by CPF, leading to increased levels of eCBs. Because eCBs are immunomodulatory molecules, we investigated the association between eCB metabolism, lipid mediators, and immune function in adult and neonatal mice exposed to CPF. We focused on lung effects because epidemiologic studies have linked pesticide exposures to respiratory diseases. CPF was hypothesized to disrupt lung eCB metabolism and alter lung immune responses to lipopolysaccharide (LPS), and these effects would be more pronounced in neonatal mice due to an immature immune system. We first assessed the biochemical effects of CPF in adult mice (<=8 weeks old) and neonatal mice after administering CPF (2.5 mg/kg, oral) or vehicle for 7 days. Tissues were harvested 4 h after the last CPF treatment and lung microsomes from both age groups demonstrated CPF-dependent inhibition of carboxylesterases (Ces), a family of xenobiotic and lipid metabolizing enzymes, whereas AChE activity was inhibited in adult lungs only. Activity-based protein profiling (ABPP)-mass spectrometry of lung microsomes identified 31 and 32 individual serine hydrolases in neonatal lung and adult lung, respectively. Of these, Ces1c/Ces1d/Ces1b isoforms were partially inactivated by CPF in neonatal lung, whereas Ces1c/Ces1b and Ces1c/BChE were partially inactivated in adult female and male lungs, respectively, suggesting age- and sex-related differences in their sensitivity to CPF. Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) activities in lung were unaffected by CPF. When LPS (1.25 mg/kg, i.p.) was administered following the 7-day CPF dosing period, little to no differences in lung immune responses (cytokines and immunophenotyping) were noted between the CPF and vehicle groups. However, a CPF-dependent increase in the amounts of dendritic cells and certain lipid mediators in female lung following LPS challenge was observed. Experiments in neonatal and adult Ces1d(-)(/-) mice yielded similar results as wild type mice (WT) following CPF treatment, except that CPF augmented LPS-induced Tnfa mRNA in adult Ces1d(-)(/-) mouse lungs. This effect was associated with decreased expression of Ces1c mRNA in Ces1d(-)(/-) mice versus WT mice in the setting of LPS exposure. We conclude that CPF exposure inactivates several Ces isoforms in mouse lung and, during an inflammatory response, increases certain lipid mediators in a female-dependent manner. However, it did not cause widespread altered lung immune effects in response to an LPS challenge. Title: Inhibition of Endocannabinoid-Metabolizing Enzymes in Peripheral Tissues Following Developmental Chlorpyrifos Exposure in Rats Buntyn RW, Alugubelly N, Hybart RL, Mohammed AN, Nail CA, Parker GC, Ross MK, Carr RL Ref: Int J Toxicol, :1091581817725272, 2017 : PubMed ESTHER: Buntyn_2017_Int.J.Toxicol__1091581817725272 PubMedSearch: Buntyn 2017 Int.J.Toxicol 1091581817725272 PubMedID: 28820005 Abstract Repeated developmental exposure to the organophosphate (OP) insecticide chlorpyrifos (CPF) inhibits brain fatty acid amide hydrolase (FAAH) activity at low levels, whereas at higher levels, it inhibits brain monoacylglycerol lipase (MAGL) activity. FAAH and MAGL hydrolyze the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG), respectively. Peripherally, AEA and 2-AG have physiological roles in the regulation of lipid metabolism and immune function, and altering the normal levels of these lipid mediators can negatively affect these processes. Exposure to CPF alters brain endocannabinoid hydrolysis activity, but it is unclear whether low-level exposure alters this activity in peripheral tissues important in metabolic and immune function. Therefore, rat pups were exposed orally from day 10 to 16 to 0.5, 0.75, or 1.0 mg/kg CPF or 0.02 mg/kg PF-04457845 (a specific FAAH inhibitor). At 12 hours postexposure, FAAH, MAGL, and cholinesterase (ChE) activities were determined. All treatments inhibited FAAH activity in brain, spleen, and liver. CPF inhibited ChE activity in spleen and liver (all dosages) and in brain (highest dosage only). CPF inhibited total 2-AG hydrolysis and MAGL-specific activity in brain and spleen (high dosage only). In liver, total 2-AG hydrolysis was inhibited by all treatments and could be attributed to inhibition of non-MAGL-mediated 2-AG hydrolysis, indicating involvement of other enzymes. MAGL-specific activity in liver was inhibited only by the high CPF dosage, whereas PF-04457845 slightly increased this activity. Overall, exposure to low levels of CPF and to PF-04457845 can alter endocannabinoid metabolism in peripheral tissues, thus potentially affecting physiological processes. Title: Decreased anxiety in juvenile rats following exposure to low levels of chlorpyrifos during development Carr RL, Armstrong NH, Buchanan AT, Eells JB, Mohammed AN, Ross MK, Nail CA Ref: Neurotoxicology, 59:183, 2017 : PubMed ESTHER: Carr_2017_Neurotoxicol_59_183 PubMedSearch: Carr 2017 Neurotoxicol 59 183 PubMedID: 26642910 Inhibitor(s) related to this paper: Chlorpyrifos Abstract Exposure to chlorpyrifos (CPF) during the late preweanling period in rats inhibits the endocannabinoid metabolizing enzymes fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL), resulting in accumulation of their respective substrates anandamide (AEA) and 2-arachidonylglycerol (2-AG). This occurs at 1.0mg/kg, but at a lower dosage (0.5mg/kg) only FAAH and AEA are affected with no measurable inhibition of either cholinesterase (ChE) or MAGL. The endocannabinoid system plays a vital role in nervous system development and may be an important developmental target for CPF. The endocannabinoid system plays an important role in the regulation of anxiety and, at higher dosages, developmental exposure to CPF alters anxiety-like behavior. However, it is not clear whether exposure to low dosages of CPF that do not inhibit ChE will cause any persistent effects on anxiety-like behavior. To determine if this occurs, 10-day old rat pups were exposed daily for 7 days to either corn oil or 0.5, 0.75, or 1.0mg/kg CPF by oral gavage. At 12h following the last CPF administration, 1.0mg/kg resulted in significant inhibition of FAAH, MAGL, and ChE, whereas 0.5 and 0.75mg/kg resulted in significant inhibition of only FAAH. AEA levels were significantly elevated in all three treatment groups as were palmitoylethanolamide and oleoylethanolamide, which are also substrates for FAAH. 2-AG levels were significantly elevated by 0.75 and 1.0mg/kg but not 0.5mg/kg. On day 25, the latency to emerge from a dark container into a highly illuminated novel open field was measured as an indicator of anxiety. All three CPF treatment groups spent significantly less time in the dark container prior to emerging as compared to the control group, suggesting a decreased level of anxiety. This demonstrates that repeated preweanling exposure to dosages of CPF that do not inhibit brain ChE can induce a decline in the level of anxiety that is detectable during the early postweanling period. Title: Effects of Chlorpyrifos or Methyl Parathion on Regional Cholinesterase Activity and Muscarinic Receptor Subtype Binding in Juvenile Rat Brain Guo-Ross SX, Meek EC, Chambers JE, Carr RL Ref: J Toxicol Pharmacol, 1:, 2017 : PubMed ESTHER: Guo-Ross_2017_J.Toxicol.Pharmacol_1_ PubMedSearch: Guo-Ross 2017 J.Toxicol.Pharmacol 1 PubMedID: 30035273 Abstract The effects of developmental exposure to two organophosphorus (OP) insecticides, chlorpyrifos (CPF) and methyl parathion (MPS), on cholinesterase (ChE) activity and muscarinic acetylcholine receptor (mAChR) binding were investigated in preweanling rat brain. Animals were orally gavaged daily with low, medium, and high dosages of the insecticides using an incremental dosing regimen from postnatal day 1 (PND1) to PND20. On PND12, PND17 and PND20, the cerebral cortex, corpus striatum, hippocampus, and medulla-pons were collected for determination of ChE activity, total mAChR density, and the density of the individual mAChR subtypes. ChE activity was inhibited by the medium and high dosages of CPF and MPS at equal levels in all four brain regions at all three ages examined. Exposure to both compounds decreased the levels of the M1, M2/M4, and M3 subtypes and the total mAChR level in all brain regions, but the effects varied by dosage group and brain region. On PND12, only the high dosages induced receptor changes while on PND17 and PND20, greater effects became evident. In general, the effects on the M1 subtype and total receptor levels appeared to be greater in the cerebral cortex and hippocampus than in the corpus striatum and medulla-pons. This did not appear to be the case for the M2/M4 and M3 subtypes effects. The differences between CPF and MPS were minimal even though in some cases, CPF exerted statistically greater effects than MPS did. In general, repeated exposure to organophosphorus insecticides can alter the levels of the various mAChR subtypes in various brain regions which could induce perturbation in cholinergic neurochemistry during the maturation of the brain regions. Title: Comparison of inhibition kinetics of several organophosphates, including some nerve agent surrogates, using human erythrocyte and rat and mouse brain acetylcholinesterase Coban A, Carr RL, Chambers HW, Willeford KO, Chambers JE Ref: Toxicol Lett, 248:39, 2016 : PubMed ESTHER: Coban_2016_Toxicol.Lett_248_39 PubMedSearch: Coban 2016 Toxicol.Lett 248 39 PubMedID: 26965078 Inhibitor(s) related to this paper: NCMP, IMP-pNP, PIMP, NEMP, TEMP, Methylparaoxon Abstract Because testing of nerve agents is limited to only authorized facilities, our laboratory developed several surrogates that resemble nerve agents because they phosphylate the acetylcholinesterase (AChE) with the same moiety as the actual nerve agents. The inhibition kinetic parameters were determined for AChE by surrogates of cyclosarin (NCMP), sarin (NIMP, PIMP and TIMP) and VX (NEMP and TEMP) and other organophosphorus compounds derived from insecticides. All compounds were tested with rat brain and a subset was tested with mouse brain and purified human erythrocyte AChE. Within the compounds tested on all AChE sources, chlorpyrifos-oxon had the highest molecular rate constant followed by NCMP and NEMP. This was followed by NIMP then paraoxon and DFP with rat and mouse brain AChE but DFP was a more potent inhibitor than NIMP and paraoxon with human AChE. With the additional compounds tested only in rat brain, TEMP was slightly less potent than NEMP but more potent than PIMP which was more potent than NIMP. Methyl paraoxon was slightly less potent than paraoxon but more potent than TIMP which was more potent than DFP. Overall, this study validates that the pattern of inhibitory potencies of our surrogates is comparable to the pattern of inhibitory potencies of actual nerve agents (i.e., cyclosarin>VX>sarin), and that these are more potent than insecticidal organophosphates. Title: Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition Carr RL, Graves CA, Mangum LC, Nail CA, Ross MK Ref: Neurotoxicology, 43:82, 2014 : PubMed ESTHER: Carr_2014_Neurotoxicol_43_82 PubMedSearch: Carr 2014 Neurotoxicol 43 82 PubMedID: 24373905 Abstract The prevailing dogma is that chlorpyrifos (CPF) mediates its toxicity through inhibition of cholinesterase (ChE). However, in recent years, the toxicological effects of developmental CPF exposure have been attributed to an unknown non-cholinergic mechanism of action. We hypothesize that the endocannabinoid system may be an important target because of its vital role in nervous system development. We have previously reported that repeated exposure to CPF results in greater inhibition of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide (AEA), than inhibition of either forebrain ChE or monoacylglycerol lipase (MAGL), the enzyme that metabolizes the endocannabinoid 2-arachidonylglycerol (2-AG). This exposure resulted in the accumulation of 2-AG and AEA in the forebrain of juvenile rats; however, even at the lowest dosage level used (1.0mg/kg), forebrain ChE inhibition was still present. Thus, it is not clear if FAAH activity would be inhibited at dosage levels that do not inhibit ChE. To determine this, 10 day old rat pups were exposed daily for 7 days to either corn oil or 0.5mg/kg CPF by oral gavage. At 4 and 12h post-exposure on the last day of administration, the activities of serum ChE and carboxylesterase (CES) and forebrain ChE, MAGL, and FAAH were determined as well as the forebrain AEA and 2-AG levels. Significant inhibition of serum ChE and CES was present at both 4 and 12h. There was no significant inhibition of the activities of forebrain ChE or MAGL and no significant change in the amount of 2-AG at either time point. On the other hand, while no statistically significant effects were observed at 4h, FAAH activity was significantly inhibited at 12h resulting in a significant accumulation of AEA. Although it is not clear if this level of accumulation impacts brain maturation, this study demonstrates that developmental CPF exposure at a level that does not inhibit brain ChE can alter components of endocannabinoid signaling. Title: Induction of endocannabinoid levels in juvenile rat brain following developmental chlorpyrifos exposure Carr RL, Adams AL, Kepler DR, Ward AB, Ross MK Ref: Toxicol Sci, 135:193, 2013 : PubMed ESTHER: Carr_2013_Toxicol.Sci_135_193 PubMedSearch: Carr 2013 Toxicol.Sci 135 193 PubMedID: 23761300 Inhibitor(s) related to this paper: Chlorpyrifos Abstract The endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) play vital roles during nervous system development. The degradation of 2-AG and AEA is mediated by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively. These enzymes are inhibited following developmental chlorpyrifos (CPF) exposure. To investigate whether this inhibition is persistent or whether accumulation of endocannabinoids in the brain occurs, 10-day-old rat pups were orally exposed daily for 7 days to either corn oil or increasing dosages of CPF (1, 2.5, or 5mg/kg), and forebrains were collected at 4, 12, 24, and 48h following the last administration. All dosages inhibited cholinesterase (ChE), FAAH, and MAGL, and elevated AEA and 2-AG levels with the greatest effect occurring at 12h with ChE, FAAH, AEA, and 2-AG and at 4h with MAGL. With the high dosage, return to control levels occurred with 2-AG (48h) only. With the medium dosage, return to control levels occurred with MAGL, 2-AG, and AEA (48h) but not with ChE or FAAH. With the low dosage, return to control levels occurred with MAGL (12h), ChE and 2-AG (24h), and AEA (48h) but not with FAAH. With the lowest dosage, peak inhibition of FAAH (52%) is greater than that of ChE (24%) and that level of FAAH inhibition is sufficient to induce a persistent pattern of elevated AEA. It is possible that this pattern of elevation could alter the appropriate development of neuronal brain circuits. Title: Effect of developmental chlorpyrifos exposure, on endocannabinoid metabolizing enzymes, in the brain of juvenile rats Carr RL, Borazjani A, Ross MK Ref: Toxicol Sci, 122:112, 2011 : PubMed ESTHER: Carr_2011_Toxicol.Sci_122_112 PubMedSearch: Carr 2011 Toxicol.Sci 122 112 PubMedID: 21507991 Abstract The endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA or anandamide) play vital roles during nervous system development including regulating axonal guidance and synaptogenesis. The enzymatic degradation of 2-AG and AEA is highly susceptible to inhibition by organophosphate compounds in vitro. Furthermore, acute in vivo exposure of adult animals to the agricultural insecticide chlorpyrifos (CPS) caused moderate inhibition of both 2-AG and AEA hydrolysis. However, the effects of repeated exposure to lower levels of CPS, especially during development, on endocannabinoid metabolism in the brain is not known. To examine this, rat pups were orally exposed daily from postnatal days 10-16 to either 1.0, 2.5, or 5.0 mg/kg CPS. Body weight gain was reduced by 5.0 mg/kg on all days of treatment whereas 2.5 mg/kg reduced the weight gain only on the last two days of treatment. At 4-h postexposure on day 16, forebrain cholinesterase (ChE) activity and hydrolysis of 2-AG and AEA were inhibited in a dose-related manner, and the extent of inhibition from highest to lowest level was AEA hydrolysis > ChE activity > 2-AG hydrolysis. The extent of inhibition of AEA hydrolysis was approximately twice than that of ChE activity with AEA hydrolysis being virtually eliminated by 2.5 and 5.0 mg/kg and 1.0 mg/kg causing 40% inhibition. The sensitivity of AEA hydrolysis, compared with canonical targets such as ChE activity, suggests a potential alternative developmental target for CPS. Inhibition of AEA hydrolysis could result in accumulation of endocannabinoids, which could alter normal endocannabinoid transmission during brain maturation. Title: Developmental chlorpyrifos and methyl parathion exposure alters radial-arm maze performance in juvenile and adult rats Johnson FO, Chambers JE, Nail CA, Givaruangsawat S, Carr RL Ref: Toxicol Sci, 109:132, 2009 : PubMed ESTHER: Johnson_2009_Toxicol.Sci_109_132 PubMedSearch: Johnson 2009 Toxicol.Sci 109 132 PubMedID: 19293373 Abstract Although the use of organophosphate (OP) insecticides has been restricted, sufficient exposure can occur to induce detrimental neurobehavioral effects. In this study, we measured physical and reflex development and spatial learning and memory in rats repeatedly exposed to incremental doses of chlorpyrifos (CPS) and methyl parathion (MPS) from postnatal day (PND) 1 to PND21. Other than decreased body weight in the higher dosage groups, no effects on physical or reflex development were observed. Significant hippocampal cholinesterase inhibition was induced in all treatment groups for up to 19 days following exposure. Beginning on PND36, working and reference memory was tested using a 12-arm radial maze, with subject animals trained and tested 4 days a week for 4 weeks. In males, working memory was decreased with the medium and high dosage of MPS but only the high dosage of CPS; while in females, no deficits were observed. For reference memory, errors were significantly increased in males exposed to the high dosage of CPS and all dosages of MPS. In females, enhanced performance was observed within the medium and high dosages of CPS but not with MPS. These data show that repeated developmental exposure to OP insecticides can induce sex-selective alterations and long-lasting changes in spatial learning and memory formation when measured using a radial arm maze and that MPS and CPS induce different neurobehavioral outcomes. Title: Effect of different administration paradigms on cholinesterase inhibition following repeated chlorpyrifos exposure in late preweanling rats Carr RL, Nail CA Ref: Toxicol Sci, 106:186, 2008 : PubMed ESTHER: Carr_2008_Toxicol.Sci_106_186 PubMedSearch: Carr 2008 Toxicol.Sci 106 186 PubMedID: 18703558 Abstract Chlorpyrifos (CPS) is widely used in agricultural settings and residue analysis has suggested that children in agricultural communities are at risk of exposure. This has resulted in a large amount of literature investigating the potential for CPS-induced developmental neurotoxic effects. Two developmental routes of administration of CPS are orally in corn oil at a rate of 0.5 ml/kg and subcutaneously in dimethyl sulfoxide (DMSO) at a rate of 1.0 ml/kg. For comparison between these methods, rat pups were exposed daily from days 10 to 16 to CPS (5 mg/kg) either orally dissolved in corn oil or subcutaneously dissolved in DMSO, both at rates of either 0.5 or 1.0 ml/kg. A representative vehicle/route group was present for each treatment. Both the low and high volume CPS in DMSO subcutaneous groups were lower than that of the low and high volume CPS in oil oral groups. At 4 h following the final administration, serum carboxylesterase was inhibited > 90% with all treatments. For cholinesterase activity in the cerebellum, medulla-pons, forebrain, and hindbrain, and serum, inhibition in the CPS-oil groups was similar and inhibition in the CPS-DMSO groups was similar. However, significantly greater inhibition was present in the high volume CPS-DMSO group as compared to the CPS-oil groups. Inhibition in the low volume CPS-DMSO group was generally between that in the CPS-oil groups and the high volume CPS-DMSO group. These data suggest that using DMSO as a vehicle for CPS may alter the level of brain ChE inhibition. Title: Alteration of neurotrophins in the hippocampus and cerebral cortex of young rats exposed to chlorpyrifos and methyl parathion Betancourt AM, Filipov NM, Carr RL Ref: Toxicol Sci, 100:445, 2007 : PubMed ESTHER: Betancourt_2007_Toxicol.Sci_100_445 PubMedSearch: Betancourt 2007 Toxicol.Sci 100 445 PubMedID: 17893397 Abstract Exposure to either chlorpyrifos (CPS) or methyl parathion (MPS) results in the inhibition of acetylcholinesterase and leads to altered neuronal activity which normally regulates critical genes such as the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). The effects of postnatal exposure to CPS and MPS on the expression of messenger RNA (mRNA) and protein levels for NGF and BDNF were investigated in the frontal cerebral cortex (cortex) and hippocampus of rats. Oral administration of CPS (4.0 or 6.0 mg/kg), MPS (0.6 or 0.9 mg/kg), or the safflower oil vehicle was performed daily from postnatal day 10 (PND10) through PND20. Exposure induced significant effects on growth and cholinesterase activity. Increased NGF protein levels were observed in the hippocampus but not the cortex on PND20 with some reduction occurring on PND28 in both regions. These changes did not correlate with the changes in NGF mRNA. BDNF mRNA was increased in both regions on PND20 and PND28, whereas BDNF protein levels were increased on PND20. On PND12, c-fos mRNA, a marker of neuronal activation, was increased in both regions. Total BDNF protein was increased in the hippocampus but decreased in the cortex. No changes in NGF protein were observed. These results indicate that repeated developmental OP exposure during the postnatal period alters NGF and BDNF in the cortex and the hippocampus and the patterns of these alterations differ between regions. Title: Altered muscarinic acetylcholine receptor subtype binding in neonatal rat brain following exposure to chlorpyrifos or methyl parathion Guo-Ross SX, Chambers JE, Meek EC, Carr RL Ref: Toxicol Sci, 100:118, 2007 : PubMed ESTHER: Guo-Ross_2007_Toxicol.Sci_100_118 PubMedSearch: Guo-Ross 2007 Toxicol.Sci 100 118 PubMedID: 17666426 Abstract The neurodevelopmental effects of two organophosphorus (OP) insecticides, chlorpyrifos (CPS) and methyl parathion (MPS), on cholinesterase (ChE) activity and muscarinic acetylcholine receptor (mAChR) binding were investigated in neonatal rat brain. Animals were orally gavaged using an incremental dosing regimen from postnatal day 1 (PND1) until PND8 with a low, medium, and high dosage for both CPS and MPS. On PND4 and PND8, ChE activity was measured in whole brain while the total and subtype densities of mAChRs were measured in three brain sections: area anterior to optic chiasma (anterior forebrain), area from the optic chiasma to the medulla/pons (posterior forebrain); and the medulla/pons excluding the cerebellum. The ligands 3H-pirenzepine, 3H-AF-DX 384, 3H-4-DAMP, and 3H-QNB were used to measure the maximal binding of the M1, M2/M4, and M3 subtypes and total mAChR receptors, respectively. In the anterior and the posterior forebrain, the levels of all mAChRs nearly doubled from PND4 to PND8, while in the medulla/pons, M1- and M3-subtype mAChR densities were low and did not increase and M2/M4 subtype and total mAChR slightly increased from PND4 to PND8. Reduction of ChE activity and mAChR binding by CPS or MPS was more evident in rats at PND8 than at PND4. With respect to mAChR binding, the greatest effects were observed in the medulla/pons and the least effects were observed in the posterior region of the forebrain. These results demonstrate that OPs exert adverse effects on rat central nervous system development through the cholinergic system in an age- and region-dependent manner. Title: Effect of developmental exposure to chlorpyrifos on the expression of neurotrophin growth factors and cell-specific markers in neonatal rat brain Betancourt AM, Burgess SC, Carr RL Ref: Toxicol Sci, 92:500, 2006 : PubMed ESTHER: Betancourt_2006_Toxicol.Sci_92_500 PubMedSearch: Betancourt 2006 Toxicol.Sci 92 500 PubMedID: 16675515 Abstract Chlorpyrifos (CPS), a known neurotoxicant, is a widely used agricultural organophosphorus insecticide. The effects of postnatal exposure to CPS on the expression of mRNA for two factors critical to brain development, nerve growth factor (NGF) and reelin, were investigated in the forebrain of rats. In addition, the expression of mRNA for the muscarinic acetylcholine receptor (mAChR) M(1) subtype and cell-specific markers for developing neurons (beta-III tubulin), astrocytes (glial fibrillary acidic protein, GFAP), and oligodendrocytes (myelin-associated glycoprotein, MAG) was also investigated. Oral administration of CPS (1.5 or 3.0 mg/kg) or the corn oil vehicle was performed daily from postnatal days (PNDs) 1 through 6. No signs of overt toxicity or of cholinergic hyperstimulation were observed after CPS administration. Body weight was significantly different from controls on PND7 in both males and females exposed to 3.0 mg/kg CPS. Quantitative PCR was performed on the forebrain. The expression of NGF, reelin, and M(1) mAChR mRNA was significantly reduced with both dosages of CPS in both sexes. beta-III Tubulin mRNA expression remained unchanged after exposure, whereas MAG mRNA expression was significantly decreased with both dosages of CPS in both sexes, suggesting effects on the developing oligodendrocytes. In contrast, GFAP mRNA levels were significantly increased with both dosages of CPS in both sexes, suggesting increased astrocyte reactivity. Our findings indicate that dosages of CPS which cause significant cholinesterase inhibition but do not exert overt toxicity can adversely affect the expression levels of critical genes involved in brain development during the early postnatal period in the rat. Title: The effect of chlorpyrifos and chlorpyrifos-oxon on brain cholinesterase, muscarinic receptor binding, and neurotrophin levels in rats following early postnatal exposure Betancourt AM, Carr RL Ref: Toxicol Sci, 77:63, 2004 : PubMed ESTHER: Betancourt_2004_Toxicol.Sci_77_63 PubMedSearch: Betancourt 2004 Toxicol.Sci 77 63 PubMedID: 14600285 Abstract Chlorpyrifos (CPS) is a widely used diethyl organophosphorus insecticide in agricultural settings. Household and urinary residue analysis has suggested that children in agricultural communities are at risk of exposure to diethyl organophosphorus insecticides. The effects of repeated postnatal exposure to CPS and its metabolite chlorpyrifos-oxon (CPO) on total muscarinic acetylcholine receptor (mAChR) binding, nerve growth factor (NGF) levels, and brain derived neurotrophic factor (BDNF) levels in the forebrain of neonatal rats were investigated. Peak inhibition of brain cholinesterase (ChE) for CPS and CPO was determined after acute exposure to dosages of each compound (a low and a high for each), which produced similar degrees of initial ChE inhibition. Pups were administered CPS (1.5 or 3.0 mg/kg), CPO (0.25 or 0.35 mg/kg), or the corn oil vehicle by daily gavage from postnatal day 1 (PND 1) through PND 6. This exposure paradigm resulted in persistent ChE inhibition by CPS but only transient inhibition by CPO, suggesting that, even though the initial ChE inhibition is similar between compounds, the effects of repeated exposure differ significantly. Forebrain mAChR density, as measured by the binding of 3H-QNB, and NGF levels were significantly reduced on PND 4 and 7 after CPS but not on PND 12. No effects on mAChR density or NGF levels were observed with CPO. No effects on BDNF levels were observed with either compound. The data suggest that the persistent ChE inhibition and decreased mAChR binding may play a role in the decreased NGF levels following CPS exposure. Title: The effects of repeated oral exposures to methyl parathion on rat brain cholinesterase and muscarinic receptors during postnatal development Tang J, Carr RL, Chambers JE Ref: Toxicol Sci, 76:400, 2003 : PubMed ESTHER: Tang_2003_Toxicol.Sci_76_400 PubMedSearch: Tang 2003 Toxicol.Sci 76 400 PubMedID: 14514956 Abstract Dimethyl phosphorylated cholinesterase (ChE) is known to be more rapidly reactivated, spontaneously, and have a higher aging rate than diethyl phosphorylated ChE. This may result in differences in toxic signs and tolerance development after treatment of juvenile rats with methyl parathion (MPS), a dimethyl phosphorothionate, than after treatment with chlorpyrifos (CPS), a diethyl phosphorothionate. The effects of repeated MPS exposures on brain ChE activity and surface and total muscarinic acetylcholine receptor (mAChR) density were studied in postnatal rats gavaged daily from postnatal day 1 (PND1) through PND 21. Results of this study were compared to our recent report with CPS (Tang et al., 1999, Toxicol. Sci. 51, 265-272). Rats received MPS daily starting at 0.3 mg/kg and increasing gradually to 0.6 mg/kg (for the medium-dosage groups) and then to 0.9 mg/kg (for the high-dosage group). ChE activity was assayed in brain homogenates. Synaptosomal mAChR densities, surface, and total were assayed using 3H-N-methylscopolamine (NMS) and 3H-quinuclidinyl benzilate (QNB), respectively, as ligands. Developmental increases in brain ChE activities and mAChR densities were observed from PND 6 through PND 22. On PND 22, inhibition of ChE activity was observed in the low (26%)-, medium (42%)-, and high (55%)-dosage groups. Significant inhibition was still present on PND 30 (16-24%) and PND 40 (12-14%), which were 9 and 19 days after the last treatment, respectively. Densities of 3H-NMS and 3H-QNB binding sites in treated groups were significantly reduced by PND 22, 1 day following cessation of treatment, and were significantly increased during the recovery period. After MPS exposure, the initial recovery of phosphorylated ChE was more rapid and the density of 3H-NMS binding sites was less readily reduced than following CPS exposure. The lesser effects on surface mAChR may explain why more severe signs appeared after each treatment with the high dosage of MPS than were observed previously with CPS, indicating little or no tolerance had developed to MPS. Title: Effects of PCB exposure on the toxic impact of organophosphorus insecticides Carr RL, Richardson JR, Guarisco JA, Kachroo A, Chambers JE, Couch TA, Durunna GC, Meek EC Ref: Toxicol Sci, 67:311, 2002 : PubMed ESTHER: Carr_2002_Toxicol.Sci_67_311 PubMedSearch: Carr 2002 Toxicol.Sci 67 311 PubMedID: 12011491 Abstract Exposure to polychlorinated biphenyls (PCBs) can alter the metabolism of organophosphorus (OP) insecticides. Female rats were fed vanilla wafers containing either 4 mg/kg/day of Aroclor 1254 (PCB-treated) or safflower oil (oil-treated) for 50 days. Rats were then injected, ip, with corn oil, parathion (P=S), methyl parathion (MP=S), chlorpyrifos (C=S), paraoxon (P=O), methyl paraoxon (MP=O), or chlorpyrifos-oxon (C=O). In the livers of rats treated with PCBs but not OP compounds, there was induction of desulfuration (activation) of P=S, MP=S, and C=S, but dearylation (detoxication) was induced only with P=S and MP=S. Hepatic A-esterase hydrolysis of all three oxons was induced. Cholinesterase (ChE) activity was determined in the medulla-pons, hippocampus, corpus striatum, cerebral cortex, skeletal muscle, lung, and heart at 2 and 24 h post exposure. With C=S, P=S, and MP=S, differences in brain ChE inhibition were observed at 2 h (MP=S > P=S > C=S) but few differences were observed between oil- and PCB-treated rats. By 24 h, the level of brain ChE inhibition had increased with P=S and C=S but had decreased with MP=S. In rats exposed to P=S and C=S but not MP=S, ChE inhibition was lower in PCB-treated rats than in oil-treated rats. This suggests that pre-exposure to PCBs has a protective effect against the acute toxicity of P=S and C=S, but not MP=S. This protective effect does not appear to be related to the alteration of the metabolism of these compounds. The slower rate of ChE inhibition following P=S and C=S compared to MP=S suggests that the protection may be mediated by the PCB-induced increase in A-esterase activity. This protection appears to be related to the time between exposure and inhibition of ChE. With the oxons at 2 h, inhibition of ChE was substantial and no differences were present between the PCB- and oil-treated rats. Thus, the rapid rate of inhibition of ChE by the oxons does not afford time for the increase in A-esterase hydrolysis to effectively provide protection against inhibition of ChE. However, while no differences between oil- and PCB-treated rats were observed with MP=O by 24 h, PCB-treated rats exposed to P=O and C=O had lower ChE inhibition than did oil-treated rats with greater differences observed with P=O than C=O. Title: Effects of repeated oral postnatal exposure to chlorpyrifos on open-field behavior in juvenile rats Carr RL, Chambers HW, Guarisco JA, Richardson JR, Tang J, Chambers JE Ref: Toxicol Sci, 59:260, 2001 : PubMed ESTHER: Carr_2001_Toxicol.Sci_59_260 PubMedSearch: Carr 2001 Toxicol.Sci 59 260 PubMedID: 11158719 Abstract Organophosphorus (OP) insecticides have the potential to cause behavioral effects in children. This study was designed to determine if repeated oral exposure of preweanling rats to chlorpyrifos would produce behavioral changes at both pre- and postweanling ages. Treatment occurred every second day beginning on post-natal day (PND) 1, and continued through PND 21. The rats received one of the following regimens: a low-dosage (3 mg/kg) from PND 1-21; a medium dosage (mg/kg from PND 1-5, and then 6 mg/kg from PND 7-21; or a high-dosage schedule of 3 mg/kg on PND 1-5, then 6 mg/kg from PND 7-13, and 12 mg/kg from PND 15-21. There were no differences in body weights among the control-, low-, and medium-dosage groups but the high-dosage group had significantly lower body weights on PND 13-21. An open field was used to measure locomotor activity on PND 10, 12, 14, 16, 18, 20, 25, and 30. There were no differences in locomotor activity levels or treatment effects between males and females. On PND 10, 12, 14, 16, 18, and 20 there was no effect on locomotor activity with any dosage. On days 25 and 30, locomotor activity was significantly decreased with the medium- and high-dosage groups. Brain cholinesterase (ChE) inhibition was about 25-38% on PND 25 and 14-34% on PND 30. On PND 25 but not 30, lung and diaphragm ChE and serum butyrylcholinesterase (BChE), with the high-dosage animals, and heart ChE with the medium- and high-dosage groups were significantly inhibited. There was no significant inhibition of skeletal muscle ChE or serum acetylcholinesterase (AChE) on PND 25 and 30. These data suggest that early postnatal chlorpyrifos exposures will depress locomotor activity in juvenile rats, with the effects most pronounced after brain ChE activity has substantially recovered. Title: Changes in rat brain cholinesterase activity and muscarinic receptor density during and after repeated oral exposure to chlorpyrifos in early postnatal development Tang J, Carr RL, Chambers JE Ref: Toxicol Sci, 51:265, 1999 : PubMed ESTHER: Tang_1999_Toxicol.Sci_51_265 PubMedSearch: Tang 1999 Toxicol.Sci 51 265 PubMedID: 10543028 Abstract The effects of repeated oral exposures to the organophosphorus insecticide chlorpyrifos (CPS) on brain muscarinic receptor densities, together with cholinesterase (ChE) activity, were studied in early postnatal rats. Initially, the effects on esterases from lactational exposure to CPS were investigated in young rats by administering CPS (100, 150, or 200 mg/kg subcutaneously in corn oil) to dams 1 day postpartum, yielding a significant body burden of CPS in the dams for possible excretion in the milk. Brain ChE inhibition in pups was less severe than in dams, whereas liver carboxylesterase (CbxE) inhibition in pups was at the same level as in dams. Because of the limited brain ChE inhibition obtained following lactation, pups were exposed to CPS directly by gavage, using 3 dosing regimens to yield a dose response. The rats were gavaged with CPS in corn oil on alternate days from postnatal day (PND) 1 through PND 21. Rats in the low-dosage group received 11 treatments at 3 mg/kg, those in the medium-dosage group received 3 treatments at 3 mg/kg and 8 at 6 mg/kg, and those in the high dosage group received 3 treatments at 3 mg/kg, 4 at 6 mg/kg, and 4 at 12 mg/kg. ChE activity in brain homogenates were inhibited significantly by 29% and 63% in the low- and high-dosage groups, respectively, on PND 22 and by 17% in the high dosage group on PND 40. Muscarinic receptor densities in brain synaptosomes were reduced using 3H-N-methylscopolamine (NMS) and 3H-quinuclidinyl benzilate (QNB) as ligands, with the effects more prominent from 3H-NMS. Densities of both ligands recovered to the control level several days after terminating treatment. The results indicate that pups are apparently exposed to only limited amounts of chlorpyrifos and/or its oxon through the milk when dams are exposed to extremely high chlorpyrifos levels. In addition, repeated direct oral exposures of early postnatal rats to CPS will result in persistent brain ChE inhibition and will transiently reduce muscarinic receptor density. Title: Kinetic analysis of the in vitro inhibition, aging, and reactivation of brain acetylcholinesterase from rat and channel catfish by paraoxon and chlorpyrifos-oxon Carr RL, Chambers JE Ref: Toxicology & Applied Pharmacology, 139:365, 1996 : PubMed ESTHER: Carr_1996_Toxicol.Appl.Pharmacol_139_365 PubMedSearch: Carr 1996 Toxicol.Appl.Pharmacol 139 365 PubMedID: 8806854 Inhibitor(s) related to this paper: Chlorpyrifos, Chlorpyrifos-oxon, Paraoxon, Parathion Abstract In rats, the phosphorothionate insecticide parathion exhibits greater toxicity than chlorpyrifos, while in catfish the toxicities are reversed. The in vitro inhibition of brain acetylcholinesterase (AChE) by the active metabolites of the insecticides and the rates at which these inhibitor-enzyme complexes undergo reactivation/ aging were investigated in both species. Rat AChE was more sensitive to inhibition than catfish AChE as demonstrated by greater bimolecular rate constants (ki) in rats than in catfish. In both species, chlorpyrifos-oxon yielded higher ki's than paraoxon. The higher association constant (KA) of chlorpyrifos-oxon than paraoxon in both species and the lack of significant differences in the phosphorylation constants (kp) suggest that association of the inhibitor with AChE is the principal factor in the different potencies between these two inhibitors. In catfish, the ki of chlorpyrifos-oxon was 22-fold greater than that of paraoxon, while in rats it was 9-fold greater, suggesting that target site sensitivity is an important factor in the higher toxicity of chlorpyrifos to catfish but not in the higher toxicity of parathion to rats. No spontaneous reactivation of phosphorylated catfish AChE occurred and there were no differences in the first oder aging constants (ka) between compounds. For phosphorylated rat AChE, there were no differences in the first order reactivation constants (kr) but the ka for chlorpyrifos-oxon was significantly greater than that for paraoxon. This difference suggests that the steric positioning of the diethyl phosphate in the esteratic site is not the same between the two compounds, leading to differences in aging. Title: Inhibition and aging of channel catfish brain acetylcholinesterase following exposure to two phosphorothionate insecticides and their active metabolites Carr RL, Straus DL, Chambers JE Ref: Journal of Toxicology & Environmental Health, 45:325, 1995 : PubMed ESTHER: Carr_1995_J.Toxicol.Env.Health_45_325 PubMedSearch: Carr 1995 J.Toxicol.Env.Health 45 325 PubMedID: 7541841 Inhibitor(s) related to this paper: Chlorpyrifos, Chlorpyrifos-oxon, Paraoxon, Parathion Abstract The inhibition and aging of acetylcholinesterase (AChE) in fingerling channel catfish (lctalurus punctatus) brain tissue was studied after single in vivo exposures to high levels of chlorpyrifos (0.25 mg/L), chlorpyrifos-oxon (7 micrograms/L), parathion (2.5 mg/L), or paraoxon (30 micrograms/L). Exposure to both parent compounds produced identical initial inhibition (95%), but in the later sampling times there was significantly more inhibited AChE in the chlorpyrifos-treated fish than in the parathion-treated fish (47% and 28%, respectively, on d 16). There were higher levels of aged AChE following chlorpyrifos exposure than following parathion exposure, but differences were not significant. Exposure to both oxons produced initial inhibition greater than 90%, and patterns of recovery and aging were statistically similar between both compounds; no significant inhibition was observed after d 11. The similar patterns of inhibition, recovery, and aging between the two oxon treatments, which have similar lipophilicities, suggest that the greater amount of AChE inhibition and aging observed in the chlorpyrifos-treated fish compared with the parathion-treated fish probably results from the higher lipophilicity of chlorpyrifos than of parathion. Overall, the prolonged brain AChE inhibition exhibited in catfish exposed to phosphorothionates is not the result of aging of the inhibited enzyme but is the result of either a slow rate or a lack of spontaneous reactivation. Title: Inhibition patterns of brain acetylcholinesterase and hepatic and plasma aliesterases following exposures to three phosphorothionate insecticides and their oxons in rats Chambers JE, Carr RL Ref: Fundamental & Applied Toxicology, 21:111, 1993 : PubMed ESTHER: Chambers_1993_Fundam.Appl.Toxicol_21_111 PubMedSearch: Chambers 1993 Fundam.Appl.Toxicol 21 111 PubMedID: 7689992 Inhibitor(s) related to this paper: Chlorpyrifos-oxon, Methylparathion, Paraoxon, Parathion Abstract Rats were administered high sublethal intraperitoneal dosages of the phosphorothionate insecticides parathion, methyl parathion, and chlorpyrifos, and their oxons. Acetylcholinesterase activities in cerebral cortex and medulla oblongata and aliesterase activities in liver and plasma were monitored at 2 hr and 1, 2, and 4 days after exposure. The maximal inhibition of brain acetylcholinesterase activity was not immediate with parathion and chlorpyrifos, reflecting the time required for bioactivation of the phosphorothionates as well as the effectiveness of the aliesterases to inactivate much of the hepatically generated oxons. In contrast, brain acetylcholinesterase activities were more quickly inhibited following administration of paraoxon and chlorpyrifos-oxon, which do not require bioactivation. Brain acetylcholinesterase was also rapidly inhibited following administration of methyl parathion and methyl paraoxon, reflecting the low sensitivity of the aliesterases to methyl paraoxon. Aliesterases were inhibited to a greater extent than acetylcholinesterase at each sampling time with parathion and chlorpyrifos and their oxons, whereas the reverse was true with methyl parathion and methyl paraoxon. All of the above patterns correlate with the in vitro sensitivities of acetylcholinesterase and aliesterases to the oxons. The very prolonged inhibition of esterase activities following chlorpyrifos treatment probably results from its substantially greater lipophilicity compared to the other compounds, which would allow it to be stored and released for gradual bioactivation. The data reported indicate that the disposition and effects of different phosphorothionate insecticides will be influenced by the sensitivities of target and nontarget esterases for their oxons and by their lipophilicity, and that predictions of in vivo responses can be made from in vitro data. Title: Acute effects of the organophosphate paraoxon on schedule-controlled behavior and esterase activity in rats: dose-response relationships Carr RL, Chambers JE Ref: Pharmacol Biochem Behav, 40:929, 1991 : PubMed ESTHER: Carr_1991_Pharmacol.Biochem.Behav_40_929 PubMedSearch: Carr 1991 Pharmacol.Biochem.Behav 40 929 PubMedID: 1816579 Abstract The effects of acute intraperitoneal administration of paraoxon on behavioral and biochemical parameters were studied in male rats. Rats were trained to press a lever under an FR10 schedule of reinforcement. Rats were injected with 3 sublethal doses of paraoxon (0.5, 0.75, and 1.0 mg/kg) and performance was monitored for four days after exposure. Response rates were depressed significantly for days 1 and 2 with 0.75 and 1.0 mg/kg, but not 0.5 mg/kg, even though there was inhibition of brain and plasma cholinesterases at all doses. Performance recovered prior to brain AChE recovery. There was no clear-cut threshold of brain AChE inhibition required to yield performance deficits, nor was there a direct correlation between significant inhibition in peripheral enzymes which could serve as markers (plasma aliesterases, butyrylcholinesterase, non-iso-OMPA-sensitive cholinesterase, and hepatic aliesterases) and performance deficits, suggesting that other noncholinergic targets may play a role in OP-induced behavioral deficits. | |||||||
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