Barone S, Jr.

References (9)

Title : Neuronal Differentiation in PC12 Cells Is Inhibited by Chlorpyrifos and Its Metabolites: Is Acetylcholinesterase Inhibition the Site of Action? - Das_1999_Toxicol.Appl.Pharmacol_160_217
Author(s) : Das KP , Barone S, Jr.
Ref : Toxicol Appl Pharmacol , 160 :217 , 1999
Abstract : Developmental expression of AChE has been associated with neuronal differentiation (P. G. Layer and E. Willbold, Prog. Histochem. Cytochem. 29, 1-94, 1995). In this study we used pheochromocytoma (PC12) cells, a noncholinergic cell line, rich in acetylcholinesterase (AChE) activity, to examine the effects of cholinesterase-inhibiting pesticides on neural differentiation. The experimental paradigm was focused on whether alterations in cholinesterase (ChE) activity by a pesticide or its metabolites would affect neurite outgrowth, a morphological marker of neuronal differentiation. Results indicated that (1) in controls, both total ChE and AChE activities were significantly increased in NGF-primed PC12 cells compared to NGF-unprimed cells, while the basal expression of butyrylcholinesterase (BCHE) activity was much lower (1.3-7% of total ChE activity) in either the presence or the absence of NGF; (2) an increase in AChE activity was highly correlated (r(2) = 0.99) with the extension of neurite outgrowth, suggesting a link between the expression of AChE activity and the elaboration of neurite outgrowth; (3) NGF increased neurite outgrowth in a time- and concentration-dependent manner; and (4) either chlorpyrifos (CPF) or its metabolites (CPF oxon and TCP) inhibited NGF-induced neurite outgrowth (branches per cell, fragments per cell, total neurite outgrowth per cell) in PC12 cells. These data suggest that the expression of AChE activity is associated with the extension of neurite outgrowth. Both enzyme activity and neurite branching were disrupted by CPF oxon; however, CPF and its other metabolite TCP (1 microgram/ml) caused inhibition of neurite outgrowth in the absence of ChE inhibition, suggesting an alternative mechanism(s) may be involved in pesticide-induced inhibition of differentiation.
ESTHER : Das_1999_Toxicol.Appl.Pharmacol_160_217
PubMedSearch : Das_1999_Toxicol.Appl.Pharmacol_160_217
PubMedID: 10544056

Title : Gestational exposure to chlorpyrifos: dose response profiles for cholinesterase and carboxylesterase activity - Lassiter_1999_Toxicol.Sci_52_92
Author(s) : Lassiter TL , Barone S, Jr. , Moser VC , Padilla S
Ref : Toxicol Sci , 52 :92 , 1999
Abstract : This study investigates the in vivo dose response profiles of the target enzyme cholinesterase (ChE) and the detoxifying enzymes carboxylesterase (CaE) in the fetal and maternal compartments of pregnant rats dosed with chlorpyrifos [(O,O'-diethyl O-3,5,6-trichloro-2-pyridyl) phosphorothionate], a commonly used organophosphorus insecticide. Pregnant rats were dosed daily (po) with chlorpyrifos in corn oil (0, 3, 5, 7, or 10 mg/kg) on gestational days (GD) 14-18. Animals were sacrificed 5 h after the last chlorpyrifos dose (time of maximum brain cholinesterase inhibition) for analysis of ChE and CaE activity in maternal blood, liver, brain, placenta, and fetal liver and brain. The in vitro sensitivity (i.e., IC50, 30 min, 26 degrees C) of CaE also was determined by assaying the activity remaining after incubation with a range of chlorpyrifos-oxon concentrations. In vivo exposure to 10 mg/kg chlorpyrifos from GD14-18 caused overt maternal toxicity, with dose-related decreases in ChE activity more notable in maternal brain than fetal brain. Dose-related effects were also seen with chlorpyrifos-induced inhibition of fetal liver ChE and maternal brain CaE activities. Gestational exposure caused no inhibition of placental ChE or CaE, fetal brain CaE, or maternal blood CaE. ChE activities in the maternal blood and liver, as well as fetal and maternal liver CaE, however, were maximally inhibited by even the lowest dosage of chlorpyrifos. The in vitro sensitivity profiles of CaE to chlorpyrifos-oxon inhibition were valuable in predicting and verifying the in vivo CaE response profiles. Both the in vivo and in vitro findings indicated that fetal liver CaE inhibition was an extremely sensitive indicator of fetal chlorpyrifos exposure.
ESTHER : Lassiter_1999_Toxicol.Sci_52_92
PubMedSearch : Lassiter_1999_Toxicol.Sci_52_92
PubMedID: 10568702

Title : Comparison of Fetal and Maternal Brain Cholinesterase Activity Following Repeated Versus Single Late Gestational Exposure to Chlorpyrifos -
Author(s) : Lassiter TL , Padilla S , Chanda SM , Das K , Haykal-Coates N , Hunter D , Marshall R , Barone S, Jr.
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :554 , 1998

Title : Ontogenetic differences in the regional and cellular acetylcholinesterase and butyrylcholinesterase activity in the rat brain - Lassiter_1998_Brain.Res.Dev.Brain.Res_105_109
Author(s) : Lassiter TL , Barone S, Jr. , Padilla S
Ref : Brain Research Developmental Brain Research , 105 :109 , 1998
Abstract : Considering the novel functions for both acetylcholinesterase (AChE) and butyrylcholinesterase (BCHE) in the developing nervous system (reviewed in Layer and Willbold, Prog. Histochem. Cytochem., 1995) a quantitative survey of the spatiotemporal developmental profiles of both AChE and BCHE activity in the neonatal rat brain would be extremely useful. To that end, we collected six brain regions at seven developmental time points, (postnatal day 1, 4, 7, 12, 17, 21, adult; n > or = 3) and measured AChE and BCHE activity using both biochemical and histological methods. These results indicated that the developmental pattern of AChE and BCHE activity varied with respect to brain region and age: (1) the ontogeny of either AChE or BCHE specific activity in one region was not necessarily indicative of the developmental pattern of the same cholinesterase in other regions; (2) the AChE developmental profile in a given region did not necessarily predict the BCHE developmental pattern for that same region. The data were also analyzed from a different perspective, i.e., the ratio of BCHE-AChE activity, in order to determine if BCHE activity preceded AChE activity during development as has been proposed for the chick nervous system (Layer, Proc. Natl. Acad. Sci. USA, 1983). Our analysis showed that, in general, the BCHE-AChE ratio decreased as the region matured, data which parallel the pattern of development of these esterases in the chick nervous system.
ESTHER : Lassiter_1998_Brain.Res.Dev.Brain.Res_105_109
PubMedSearch : Lassiter_1998_Brain.Res.Dev.Brain.Res_105_109
PubMedID: 9497085

Title : Time course of changes in cholinergic and neurotrophin-related markers after infusion of colchicine into the basal forebrain - Shaughnessy_1998_Brain.Res_781_61
Author(s) : Shaughnessy LW , Mundy WR , Tilson HA , Barone S, Jr.
Ref : Brain Research , 781 :61 , 1998
Abstract : After bilateral infusions of colchicine or vehicle in the rat nucleus basalis magnocellularis, the time course of changes in several cholinergic and neurotrophin-related markers were assessed. Animals were sacrificed at 3, 7, 14, 28, 35 and 84 days post-lesion, and both the NBM and cortical areas were assessed. Sections were stained immunohistochemically for choline acetyltransferase (ChAT) or p140trk (trk) or histochemically for acetylcholinesterase (AChE). ChAT activity and neurotrophin protein levels were assessed regionally. The number of ChAT immunoreactive NBM neuronal profiles decreased beginning 3 days post-lesion and reach maximal loss by 28 days post-lesion, with no recovery. Examination of trk-IR around the NBM revealed a time-dependent decrease in trk-IR of magnocellular neuron and an increase in trk-IR of astrocytes at 14 and 28 days post-lesion. The density of AChE-stained cortical fibers was maximally decreased 3 days post-lesion followed by an increase in fiber staining across the remaining time points. Cortical ChAT activity showed the largest decrease at 7 days followed by recovery 84 days after colchicine infusion. There was an increase in NGF in the parietal cortex after colchicine infusion but no change in BDNF level. These patterns of changes in the cholinergic and neurotrophin-related markers suggest an association between NGF and lesion-induced compensatory responses in the basal forebrain cholinergic system.
ESTHER : Shaughnessy_1998_Brain.Res_781_61
PubMedSearch : Shaughnessy_1998_Brain.Res_781_61
PubMedID: 9507066

Title : Gestational exposure to chlorpyrifos: apparent protection of the fetus? - Lassiter_1998_Toxicol.Appl.Pharmacol_152_56
Author(s) : Lassiter TL , Padilla S , Mortensen SR , Chanda SM , Moser VC , Barone S, Jr.
Ref : Toxicol Appl Pharmacol , 152 :56 , 1998
Abstract : Previous studies have shown that, in general, young, postnatal animals are more sensitive than adults to the toxic effects of anticholinesterase (antiChE) pesticides. Paradoxically, often fetal brain cholinesterase (ChE) is less inhibited than maternal brain after gestational exposure to an antiChE, presumably due to placental and fetal detoxification of the antiChE. The present investigation was designed to study selected toxicokinetic and toxicodynamic factors surrounding the toxicity of chlorpyrifos (CPF; [O,O'-diethyl O-3,5,6-trichloro-2-pyridyl] phosphorothionate) in pregnant rats dosed repeatedly or singly during late gestation. Dams were dosed daily (po) with CPF in corn oil (0 or 7 mg/kg) on gestational days (GD) 14 to 18. Animals were euthanized at 2 to 120 h after the last dose and tissues were collected for enzyme analysis. Using this dosing regimen, we found that (1) the time of maximal ChE inhibition was the same (i.e., 5-10 h after dosing) for both maternal and fetal brain, (2) the degree of fetal brain ChE inhibition was 4.7 times less than maternal brain inhibition, and (3) the detoxification potential (i.e., carboxylesterase and chlorpyrifos-oxonase) of the fetal tissues was very low compared to the maternal tissues. A separate group of experiments showed that if pregnant dams received only one oral dose of 7 or 10 mg/kg CPF on GD18, the degree of ChE inhibition in the fetal brain was comparable to the maternal brain ChE inhibition. Taking into consideration the net increase (more than fourfold) in fetal brain ChE activity from GD14 to 18 in control animals, and the fact that maternal brain ChE was inhibited more than fetal brain ChE only in a repeated-dosing regimen, we conclude that the fetus is not genuinely protected from the toxic effects of a given dose of CPF. We propose that fetal brain ChE is simply able to recover more fully between each dose as compared to maternal brain ChE, giving the illusion that the fetal compartment is less affected than the maternal compartment.
ESTHER : Lassiter_1998_Toxicol.Appl.Pharmacol_152_56
PubMedSearch : Lassiter_1998_Toxicol.Appl.Pharmacol_152_56
PubMedID: 9772200

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

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 : Effects of organophosphates on the visual system of rats. - Boyes_1994_J.Appl.Toxicol_14_135
Author(s) : Boyes WK , Tandon P , Barone S, Jr. , Padilla S
Ref : Journal of Applied Toxicology , 14 :135 , 1994
Abstract : The possibility that exposure to organophosphate insecticides can lead to ocular damage is suggested by Japanese studies from the 1960s and 1970s indicating that exposed humans developed chronic ocular degeneration, in addition to showing more commonly accepted effects of cholinesterase-inhibiting compounds. Other papers reported ocular lesions in laboratory animals treated with organophosphates. More recently, retinal degeneration following chronic organophosphate treatment has been reported to the Environmental Protection Agency by pesticide manufacturers in studies conducted in compliance with good laboratory practice regulations. Several factors, however, have prompted scepticism regarding organophosphate-induced ocular toxicity, including the widespread use of organophosphate compounds for both agricultural and ophthalmological practices without numerous additional reports of comparable ocular toxicity. We are developing a research program to address these issues involving electrophysiological, biochemical and histological investigations of rats treated with organophosphate insecticides. The research program is young, but early results are available. Notably, retinas from rats treated with a single subcutaneous injection of 100 mg kg-1 fenthion showed decreases in carbachol-stimulated release of inositol phosphate, an indicator of cholinergically-mediated intracellular second messenger systems. These effects persisted at least 56 days after fenthion administration. This could indicate several different toxicological actions, which are currently under investigation. It is concluded that the possible association between exposure to organophosphates and ocular toxicity cannot be dismissed, and that several important research issues need to be resolved.
ESTHER : Boyes_1994_J.Appl.Toxicol_14_135
PubMedSearch : Boyes_1994_J.Appl.Toxicol_14_135
PubMedID: 8027509