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T R Ward

Publications and source records attributed to T R Ward.

30 records · Page 2Linked to original sources
PubMed1995

Increased [3H]phorbol ester binding in rat cerebellar granule cells by polychlorinated biphenyl mixtures and congeners: structure-activity relationships.

Our previous reports indicate that polychlorinated biphenyl (PCB) congeners in vitro perturbed cellular Ca2+ homeostasis and protein kinase C (PKC) translocation. We have now studied the structure-activity relationship (SAR) of 3 PCB mixtures, 24 PCB congeners, and 1 dibenzofuran for their effects on PKC translocation by measuring [3H]phorbol ester ([3H]PDBu) binding in cerebellar granule cells (7 days in culture). All the PCB mixtures studied increased [3H]PDBu binding significantly and in a concentration-dependent manner. However, Aroclor 1016 and Aroclor 1254 were more potent than Aroclor 1260. Of the 24 congeners studied, di-ortho congeners such as 2,2',5,5'-tetrachlorobiphenyl (-TeCB), 2,2',4,6,6'-pentachlorobiphenyl (-PeCB), 2,2',4,6-TeCB, and 2,2'-dichlorobiphenyl (-DCB) were the most potent (E50 = 28-43 microM) while non-ortho congeners such as 3,3',4,4'-TeCB and 3,3',4,4'5-PeCB were not effective. The potential contaminant of PCB mixtures, 1,2,3,7,8-pentachlorodibenzofuran had no significant effect on [3H]PDBu binding. The SAR among these congeners revealed: (i) congeners with ortho-chlorine substitution such as 2,2'-DCB (EC50 = 43 +/- 3 microM) or ortho-lateral (meta, para) chlorine substitution such as 2,2',5,5'-TeCB (EC50 = 28 +/- 3 microM) and 2,2'4,6-TeCB (E50 = 41 +/- 6 microM) were most potent; (ii) congeners with only para-substitution such as 4,4'-DCB or high lateral content in the absence of ortho-substitution such as 3,3',4,4',5,5'-HCB were not effective; and (iii) increased chlorination was not clearly related to the effectiveness of these congeners, although hexa- and heptachlorination was less effective than di- and tetrachlorination. Low lateral substitution, especially without para-substitution, or lateral content in the presence of ortho-substitution, may be the most important structural requirement for the in vitro activity of these PCB congeners in neuronal preparations.

Analysis of Variance↗
PubMed1994

Differential effects of polychlorinated biphenyl congeners on phosphoinositide hydrolysis and protein kinase C translocation in rat cerebellar granule cells.

Previous reports from our laboratory have suggested that the neuroactivity of some polychlorinated biphenyl (PCB) congeners is associated with perturbations in cellular Ca(2+)-homeostasis. We have characterized further the neurochemical effects of PCBs on signal transduction in primary cultures of cerebellar granule cells. The present experiments found that neither 2,2'-dichlorobiphenyl (DCBP), an ortho-substituted congener, nor 3,3',4,4',5-pentachlorobiphenyl (PCBP), a non-ortho-substituted congener, affected basal phosphoinositide (PI) hydrolysis in cerebellar granule cells. However, at concentrations up to 50 microM, DCBP potentiated carbachol-stimulated PI hydrolysis, while decreasing it at 100 microM. PCBP, on the other hand, had no effect on carbachol-stimulated PI hydrolysis in concentrations up to 100 microM. [3H]Phorbol ester ([3H]PDBu) binding was used to determine protein kinase C (PKC) translocation. DCBP increased [3H]PDBu binding in a concentration-dependent manner and a twofold increase was observed at 100 microM in cerebellar granule cells. PCBP had no effect on [3H]PDBu binding at concentrations up to 100 microM. The effect of DCBP on [3H]PDBu binding was time-dependent and was also dependent on the presence of external Ca2+ in the medium. To test the hypothesis that DCBP increases [3H]PDBu binding by acting on receptor-activated calcium channels, the effects of DCBP were compared to those of L-glutamate. The effects of DCBP (50 microM) and glutamate (20 microM) were additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Repeated inhibition of cholinesterase by chlorpyrifos in rats: behavioral, neurochemical and pharmacological indices of tolerance.

Previous work from this laboratory showed that daily s.c. injections of the organophosphate diisopropylfluorophosphate caused prolonged inhibition of cholinesterase (ChE) activity in whole blood and brain and downregulation of muscarinic receptors in the central nervous system; these changes were accompanied by progressive, persistent deterioration of working memory and motor function. Further, a single s.c. injection of the organophosphate insecticide chlorpyrifos (O,O',-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothionate, CPF), caused neurochemical changes of the same magnitude and duration, but transient impairment of working memory and motor slowing. In the present study, weekly injections of CPF (0, 15, 30 or 60 mg/kg s.c.) inhibited ChE activity in whole blood of rats by 60% to 90% after 5 weeks; the highest dose also induced tremor, working memory impairment and motor slowing in daily delayed matching-to-position/visual discrimination tests. Reducing the CPF injection frequency to every other week relieved the inhibition of whole blood ChE activity (to 50%-75% of control) and ameliorated all the behavioral deficits. Reinstatement of weekly CPF injections (0, 15, 30, or 45 mg/kg) for 10 weeks inhibited whole blood ChE activity by 75% to 90%. Tremor was not observed during this period; however, motor slowing and working memory impairment persisted throughout the dosing period in all treated groups. Pharmacological evidence for tolerance to the muscarinic effects of CPF was observed on trial completion in the daily delayed matching-to-position/visual discrimination task: CPF-treated rats were supersensitive to scopolamine and subsensitive to pilocarpine. Nicotine reversed the reduction in trial completion associated with CPF. Changes in sensitivity to mecamylamine, d-amphetamine and haloperidol were not observed. Taken together, these studies indicate that inhibition of ChE activity by repeated injection of CPF produces a constellation of behavioral effects not evident after a single CPF treatment, even though both treatment regimens caused prolonged inhibition of ChE activity and downregulation of central muscarinic receptors.

Animals↗
PubMed1993

Correlation of the anticholinesterase activity of a series of organophosphates with their ability to compete with agonist binding to muscarinic receptors.

Some compounds that inhibit acetylcholinesterase (AChE) activity compete directly with quinuclidinyl benzilate (QNB) binding, a muscarinic antagonist which binds to all subtypes equally, and with cis-methyldioxolane (CD), an agonist that binds with high affinity to the M2 subtype of muscarinic receptors. The relationship between inhibition of AChE activity and the capability to affect muscarinic receptors directly has not been systematically explored. The interaction of eight organophosphates with muscarinic receptors was compared to their ability to inhibit AChE activity in vitro in tissue homogenates from rat hippocampus and frontal cortex, two cholinergically enriched areas of the brain. Of the compounds tested only echothiophate competed for [3H]QNB binding and only at concentrations greater than 100 microM. The anticholinesterase compounds were also tested for their ability to compete with a muscarinic receptor agonist, [3H]CD, which binds with high affinity (approximate KD = 3.5 nM) to 10 and 3% of the muscarinic receptors in the frontal cortex and hippocampus, respectively. The anticholinesterase compounds inhibited high-affinity [3H]CD binding up to 80% and the effects were similar in both tissues. Echothiophate and DFP were potent inhibitors of [3H]CD binding, as were the active "oxon" forms of parathion, malathion, and disulfoton. The parent "thio" forms of these insecticides, however, were much less effective in competing for [3H]CD binding. A similar pattern of potency was observed for the inhibition of brain AChE activity. A strong correlation was found between the ability of a compound to inhibit AChE activity and the ability to compete with [3H]CD binding. These data suggest that the biological effects of cholinesterase-inhibiting compounds may be due to more than their ability to inhibit AChE.

Acetylcholinesterase↗
PubMed1993

Effect of repeated organophosphate administration on carbachol-stimulated phosphoinositide hydrolysis in the rat brain.

The effects of repeated exposure to two organophosphates on the turnover of phosphoinositides, the second messenger system coupled to the M1 and M3 subtypes of muscarinic receptors, were examined in the rat hippocampus. Repeated diisopropylfluorophosphate (DFP) exposure (0.2-0.8 mg/kg, SC) decreased brain acetylcholinesterase activity and muscarinic receptor density. The incorporation of [3H]myoinositol into brain slices was also decreased. Phosphoinositide turnover was measured as the accumulation of [3H]inositol phosphates (IP) in the presence of lithium. DFP did not affect basal IP accumulation, but decreased carbachol-stimulated IP accumulation in the hippocampus after 0.4 and 0.8 mg/kg. The effects of repeated disulfoton administration (2.0 mg/kg, IP) were also examined in the hippocampus. Similar to DFP, repeated disulfoton exposure decreased acetylcholinesterase activity, receptor density, and carbachol-stimulated IP accumulation. The incorporation of myoinositol, however, was increased in disulfoton-treated rats. These data indicate that repeated organophosphate exposure results in a functional decrease in muscarinic receptor activity, as well as changes in myoinositol incorporation into phospholipids.

Animals↗
PubMed1990

Assessment of hepatic indicators of subchronic carbon tetrachloride injury and recovery in rats.

To determine the course of hepatic recovery from subchronic oral administration of carbon tetrachloride (CCl4), male F-344 rats were gavaged with 0, 20, or 40 mg CCl4/kg, 5 days/week, for 12 weeks. Exposure to CCl4 caused dosage-dependent increases in relative liver weight and the serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, and cholesterol as well as a dosage-dependent decrease in hepatic cytochrome P450. Centrilobular hepatocellular vacuolar degeneration, necrosis, and cirrhosis occurred at both 20 and 40 mg/kg, with dosage-dependent severity. Reversibility of these reported effects varied with parameter. By Day 8 postexposure, necrosis had disappeared and all serum indicators and cytochrome P450 had returned to control levels. By Day 15 postexposure, the severity of the vacuolar degeneration had decreased. Reversibility of cirrhosis was dosage dependent; complete recovery occurred in the low- but not the high-dose group by Day 15. The disappearance of the increase in relative liver weight was also dependent on dosage; the low- but not the high-dose group had returned to the control level by Day 22. In an attempt to measure persistent hepatic damage, liver uptake relative to the spleen was determined for a sulfur colloid labeled with technetium-99m and for tritiated 2-deoxyglucose. Neither method consistently measured hepatic damage in cirrhotic livers due, in part, to the high degree of variability in the tracer uptake data.

Animals↗
PubMed1987

A finite-difference electromagnetic deposition/thermoregulatory model: comparison between theory and measurements.

The rate of the electromagnetic energy deposition and the resultant thermoregulatory response of a block model of a squirrel monkey exposed to plane-wave fields at 350 MHz were calculated using a finite-difference procedure. Noninvasive temperature measurements in live squirrel monkeys under similar exposure conditions were obtained using Vitek probes. Calculations exhibit reasonable correlation with the measured data, especially for the rise in colonic temperature.

Animals↗
PubMed1986

Brain temperature measurements in rats: a comparison of microwave and ambient temperature exposures.

In an effort to understand microwave heating better, regional brain and core temperatures of rats exposed to microwave radiation (2450 MHz) or elevated air temperatures were measured in two studies. In general, we have found no substantial evidence for temperature differentials, or "hot spots," in the brain of these animals. In the first study, after a 30-min exposure, no temperature differences between brain regions either after microwave or ambient air exposure were found. However, a highly significant correlation between brain and core temperatures was found and this correlation was the same for both microwave and ambient air heating. In the second study, time-temperature profiles were measured in rats exposed to either 30 mW/cm2 or 36.2 degrees C. In this study, the 30-min exposure period was divided into seven intervals and the change in temperature during each period was analyzed. Only the cortex showed significantly different heating rates between the air heating and microwave heating; however, this difference disappeared after the initial 5 min of exposure.

Air↗
PubMed1985

Blood-brain barrier permeation in the rat during exposure to low-power 1.7-GHz microwave radiation.

The permeability of the blood-brain barrier to high-and low-molecular-weight compounds has been measured as a function of continuous-wave (CW) and pulsed-microwave radiation. Adult rats, anesthetized with pentobarbital and injected intravenously with a mixture of [14C] sucrose and [3H] inulin, were exposed for 30 min at a specific absorption rate of 0.1 W/kg to 1.7-GHz CW and pulsed (0.5-microseconds pulse width, 1,000 pps) microwaves. After exposure, the brain was perfused and sectioned into nine regions, and the radioactivity in each region was counted. During identical exposure conditions, temperatures of rats were measured in eight of the brain regions by a thermistor probe that did not perturb the field. No change in uptake of either tracer was found in any of the eight regions as compared with those of sham-exposed animals.

Animals↗
PubMed1982

Measurement of blood-brain barrier permeation in rats during exposure to 2450-MHz microwaves.

Adult rats anesthesized with pentobarbital and injected intravenously with a mixture of [14C] sucrose and [3H] insulin were exposed for 30 min to an environment at an ambient temperature of 22, 30, or 40 degrees C, or were exposed at 22 degrees C to 2450-MHz CW microwave radiation at power densities of 0, 10, 20, or 30 mW/cm2. Following exposure, the brain was perfused and sectioned into eight regions, and the radioactivity in each region was counted. The data were analyzed by two methods. First, the data for each of the eight regions and for each of the two radioactive tracers were analyzed by regression analysis for a total of 16 analyses and Bonferroni's Inequality was applied to prevent false positive results from numerous analyses. By this conservative test, no statistically significant increase in permeation was found for either tracer in any brain region of rats exposed to microwaves. Second, a profile analysis was used for a general change in tracer uptake across all brain regions. Using this statistical method, a significant increase in permeation was found for sucrose but not for inulin. A correction factor was then derived from the warm-air experiments to correct for the increase in permeation of the brain associated with change in body temperature. This correction factor was applied to the data for the irradiated animals. After correcting the data for thermal effects of the microwave radiation, no significant increase in permeation was found.

Analysis of Variance↗
PubMed1975

Measure of enzymatic activity coincident with 2450 MHz microwave exposure.

Enzyme preparations were exposed to microwave radiation at 2450 MHz and enzymatic activity was simultaneously monitored spectrophotometrically with a crossed-beam exposure detection system. Enzymes studied were glucose 6-phosphate dehydrogenase from human red blood cells and yeast, adenylate kinase from rat liver mitochondria and rabbit muscle, and rat liver microsomal NADPH cytochrome c reductase. No difference was found between the specific activity at 25 degrees C of unirradiated controls and enzyme preparations irradiated at an absorbed dose rate of 42 W/kg.

Adenylate Kinase↗