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D E Ray

Publications and source records attributed to D E Ray.

At least 37 records · Page 2Linked to original sources
PubMed1998

Chronic effects of low level exposure to anticholinesterases--a mechanistic review.

High dose exposure to anticholinesterases which results in symptomatic poisoning can have lasting consequences due to the trauma of intoxication, excitotoxicity, secondary hypoxic damage, and (for some agents) a delayed onset polyneuropathy (OPIDN). The potential effects of low level exposure are less well defined. The most reliable data comes from controlled clinical trials with specific agents. A single dose of sarin or repeated doses of metrifonate or mevinphos, have produced only transient adverse effects at doses causing substantial acetylcholinesterase inhibition. Other data comes from epidemiological surveys. These have often used more sensitive indices than the clinical studies, but are less reliable due to the difficulty of defining exposure and matching control and exposed populations. Subtle, mainly cognitive, differences between exposed and non-exposed populations are sometimes seen. Low level exposure can cause a reversible down-regulation of cholinergic systems, and a range of non-cholinesterase effects that are structure-specific, and do not always parallel acute toxicity. Novel protein targets sensitive to low level exposure to some organophosphates are known to exist in the brain, but their functional significance is not yet understood.

Animals↗
PubMed1998

The effects of the tremorgenic mycotoxin penitrem A on the rat cerebellum.

Within 10 minutes of intraperitoneal injection of penitrem A (3 mg/kg), rats develop severe generalized tremors and ataxia that persist for up to 48 hours. These are accompanied by a three- to fourfold increase in cerebellar cortical blood flow. Mitochondrial swelling occurs in cerebellar stellate and basket cells within 30 minutes of dosing and persists for more than 12 hours without leading to cell death. From 2 hours, Purkinje cell dendrites show early cytoplasmic condensation accompanied by fine vacuolation of smooth endoplasmic reticulum and enlargement of perikaryal mitochondria. From 6 hours, many Purkinje cells develop intense cytoplasmic condensation with eosinophilia that resembles "ischemic cell change," and from 12 hours, many other Purkinje cells show marked watery swelling. Astrocytes begin to swell from 0.5 hours after injection and show hypertrophy of organelles from 6 hours. Also from 6 hours onward, discrete foci of necrosis appear in the granule cell layer, while permeability of overlying meningeal vessels to horseradish peroxidase becomes evident at 8 hours. All changes are more severe in vermis and paravermis. Despite widespread loss of Purkinje cells, the animals' behavior becomes almost normal within a week. While tremor occurs with doses of 1.5 and 0.5 mg/kg, cellular damage is minimal. The tremor mechanism differs from that of harmaline since destruction of inferior olivary nuclei abolishes neither the tremor response to penitrem A nor the cellular damage. No morphological changes are found in other brain regions. The affinities of penitrem A for high-conductance calcium-dependent potassium channels and for gamma-aminobutyric acid receptors with the probability of resultant excitotoxity are considered to be important underlying factors for these changes.

Animals↗
PubMed1998

Neurotoxic potential of gadodiamide after injection into the lateral cerebral ventricle of rats.

PURPOSE: Results of a previous report showed that, if administered by intraventricular injection to access tissue normally protected by the blood-brain barrier, gadopentetate dimeglumine produced acute excitation, persistent ataxia, and widespread brain lesions in rats at 5-micromol/g brain but not at 3.8-micromol/g brain. The present study using gadodiamide was undertaken to see whether the effects were agent-specific. METHODS: Rats, surgically prepared with a lateral ventricular cannula, were administered a slow injection at 2 microL/min of gadodiamide into the lateral ventricle, and behavioral and neuropathologic changes were noted. RESULTS: Both gadodiamide and gadopentetate dimeglumine produced focal and generalized myoclonus over several hours. Gadodiamide did not produce the medium-term tremor or persistent ataxia seen after treatment with gadopentetate dimeglumine. Neuropathologic changes developed over 1 to 3 days and took three distinct forms: vacuolated thalamic lesions closely resembling those produced by gadopentetate dimeglumine; small but similar vacuolated symmetrical caudate lesions not produced by gadopentetate dimeglumine; and severe swelling and astrocytic hypertrophy and hyperplasia in the cerebellar vermis, again not produced by gadopentetate dimeglumine. Unlike gadopentetate dimeglumine, gadodiamide produced no spinal cord lesions. The cerebellar changes were seen at 1.25-micromol/g brain and above, behavioral changes at 2.5-micromol/g brain and above, and thalamic and caudate lesions at 10-micromol/g brain, the maximal dose used. Markedly reducing the rate of injecting the same volume over 28 hours prevented the acute excitation but did not reduce the severity of the morphologic effects. CONCLUSION: The acute excitatory effects of high intraventricular doses of gadopentetate dimeglumine and gadodiamide are similar and appear to be attributable to local action at the infusion site, but differences exist between the two agents in the character and topography of the distant morphologic changes. The cerebellum was the brain area most sensitive to gadodiamide in this experimental model. It is unlikely that gadodiamide would gain access to the brain at these tissue doses when used intravenously for conventional clinical imaging, but our experimental model suggested that it had some unexpectedly specific neuropathologic potential.

Animals↗
PubMed1997

Physiological factors predisposing to neurotoxicity.

Many factors determine individual susceptibility to toxic agents in addition to their primary interaction with the target site. Absorption, delivery to target tissues, bio-activation, bio-inactivation, elimination, and adaptive or protective responses all play important parts in determining the overall response of the individual. In addition changes in the physiological significance of the function which is disrupted may be crucially important. Pulmonary absorption can be limited by ventilation or perfusion, both of which increase with work rate. Tissue uptake can be limited by local blood flow, which is strongly influenced by local functional activity. In areas with a blood-tissue barrier, such as brain and testis, tissue uptake can be strongly influenced by developmental state, protein binding or vascular damage. Metabolic transformation can show marked inter-individual variations at both hepatic and extra-hepatic sites, due to genetic or nutritional influences. The capacity for adaptation to toxicological insult can also vary markedly, depending on functional reserve capacity as well as on inherent plasticity. Examples used to illustrate these factors include: the influence of motor activity on the toxicity of carbon monoxide; of noise on the ototoxicity of aminoglycoside antibiotics; of brain activity on the neurotoxicity of dinitrobenzene; of acid-base balance on the toxicity of nicotine; and of developmental stage on the neurotoxicity of haloperidol. In addition disease states can influence sensitivity. Thus anaemia sensitises to manganese; calcium deficiency to lead; nerve trauma to hexane; and Wilson's disease to copper overload.

Age Factors↗
PubMed1997

Increasing or decreasing nervous activity modulates the severity of the glio-vascular lesions of 1,3-dinitrobenzene in the rat: effects of the tremorgenic pyrethroid, Bifenthrin, and of anaesthesia.

To test the hypothesis that altered neuronal activity may influence the extent and severity of the glio-vascular lesions produced by 1,3-dinitrobenzene (DNB), rats were either given the tremorgenic pyrethroid, Bifenthrin, or anaesthetised during various dosing schedules of DNB. When compared with controls dosed only with DNB, Bifenthrin tremor made both the ataxia and other functional effects caused by DNB more pronounced. Lesions in the brain stem were made significantly more severe and widespread across three dose levels of DNB. Centres such as facial nuclei, motor nuclei of fifth nerve, subthalamic nuclei and mamillary bodies, not damaged by DNB alone, were also affected in some animals. In contrast, general anaesthesia by either isoflurane ur urethane decreased the severity of the lesions, this being more pronounced with urethane. The character of the tissue changes, however, was not altered by these additional procedures. These findings support the suggestion that neuronal activity is one important determinant of the selective vulnerability of sensitive brain stem nuclei to glio-vascular damage from DNB intoxication.

Anesthetics↗
PubMed1997

Function in neurotoxicity: index of effect and also determinant of vulnerability.

1. In neurotoxicity, functional indices may be the only available measures of effect, as many potent neurotoxic agents produce no morphological change. Examples of these are strychnine, dieldrin and pyrethroids, which produce excitation but no pathology, and barbiturates, xylene and lithium, which produce depression but no pathology. 2. In other cases where both functional and morphological effects are seen, functional measures often produce the most convenient, if not always the most specific, indices of toxicity. Appropriate functional measures can be highly sensitive, both in humans and in experimental animals, and can also give vital mechanistic information. However, it is essential that functional measures are reproducible and interpretable (some behavioural measures are not) and also provide a reasonably exacting test of function (passive observation of resting behaviour can miss many effects). 3. In addition to their use as an index of toxicity, changes in function, even within the normal range, can themselves influence susceptibility to toxins. Tissue perfusion can determine delivered dose and is influenced by function, while metabolic transformation is modified by nutritional state. Nutritional state can also influence absorption, with anaemia enhancing manganese toxicity and calcium deficiency enhancing lead toxicity. Functional activity can influence target susceptibility directly: thus, noise exposure enhances the ototoxicity of carbon monoxide, toluene or aminoglycoside antibiotics; noise, motor activity or anaesthesia all influence the central neurotoxicity of dinitrobenzene or metronidazole; motor activity enhances the peripheral nerve toxicity of lead or thallium; and nerve regeneration enhances the toxicity of hexane. These functional factors can be very important in determining individual susceptibility.

Animals↗
PubMed1997

Capacity of rat brain to metabolize m-dinitrobenzene: an in vitro study.

m-dinitrobenzene (m-DNB) is a neurotoxin producing selective brain lesions, but the in situ metabolic fate of m-DNB in brain is unknown. In this study, nitroreductive capacity of brain towards m-dinitrobenzene (m-DNB) has been investigated. Tissue slices from F344 rat brain stem, forebrain, and liver were separately incubated with 0.2 mM m-DNB. m-DNB and its metabolites were detected by HPLC, and identified by either HPLC or Mass Spectrometry (MS). All three types of tissues showed metabolic activity towards m-DNB. Metabolic disposal of m-DNB was 1.05 +/- 0.11 mumol/g wet weight/h in liver, 0.49 +/- 0.05 in brain stem, and 0.44 +/- 0.05 in forebrain (mean +/- SD, n = 4). m-Nitroaniline was found to be the main metabolite produced by both brain and liver slices, representing 57-66% of the disposal of m-DNB. Liver slices also produced 2(or 4)-amino-4(or 2)-nitrophenol, which was not detected in brain slices. We detected nitrosonitrobenzene in the slices from both parts of brain, but not in liver slices. The glucose consumption of brain slices from both areas were significantly increased in the presence of m-DNB: by 26% in the brain stem (p < 0.001) and by 17.9% in cerebral cortex (p < 0.01). This may be considered a pre-cytotoxic effect. The results demonstrate that brain has considerable nitroreductive capacity towards m-DNB, and that in situ reduction of m-DNB may be responsible for its neurotoxicity.

Animals↗
PubMed1997

Actions of pyrethroid insecticides on voltage-gated chloride channels in neuroblastoma cells.

Pyrethroid insecticides have the potential to act at several sites in excitable tissues in addition to their primary effect on sodium channels. We have assessed one such site, the voltage gated chloride channel. Following our previous demonstration of actions of deltamethrin on the voltage-gated chloride channel in rats and in neuroblastoma cells, we examined the dose-response relationship for deltamethrin by patch clamp analysis of voltage-gated channels in partially differentiated NIE115 cells. Open channel probability (P0) was assessed in channels stepped from 0 to +20 mV for 10 seconds. Deltamethrin significantly decreased P0 by 0.237+/-0.070 at 10(-10) M and, although construction of a dose-response relationship was rendered difficult by the very low water solubility of the pyrethroids, a decrease of 0.968+/-0.140 was reached at the highest concentration tested, 10(-4) M. A second Type II pyrethroid cypermethrin also decreased P0, by 0.430+/-0.09 at 5 x 10(-6) M, but the Type I pyrethroid cismethrin produced a decrease of only 0.188+/-0.08 at 2 x 10(-5) M. These effects were seen in 340 pS conductance, calcium-independent channels. A sample of 9 calcium-dependent channels with a conductance of 225 pS failed to show any response to deltamethrin. We conclude that actions on calcium-independent voltage-gated chloride channels are likely to contribute significantly to type II pyrethroid toxicity.

Animals↗
PubMed1996

An in vitro study of m-dinitrobenzene toxicity on the cellular components of the blood-brain barrier, astrocytes and endothelial cells.

We have studied the effects of an industrial compound, m-dinitrobenzene (DNB), on cultured astrocytes and brain capillary endothelial cells in an in vitro blood-brain barrier (BBB) model. In single cultures, the threshold DNB concentration that induced cell death, as assessed by morphology and lactose dehydrogenase leakage into the culture medium, was 1 mM for both cell types after 1 day of incubation. In cocultures, astrocytes showed a dose-response curve similar to that obtained in single cultures, while endothelial cells showed an increased sensitivity to DNB cytotoxicity. DNB induced a dose-dependent increase in glucose consumption and lactate production in both cell types in single cultures, although astrocytes appeared to be more sensitive than endothelial cells. The role of oxidative stress was also studied using the reduction of nitroblue tetrazolium as an index of generation of active oxygen species. A dose-dependent increase was observed for both cell types in single cultures, although this could not be prevented by the addition of superoxide dismutase to the culture medium. Addition of 0.3 mM carmustine to the culture medium increased the cytotoxicity of 0.5 mM DNB in both astrocytes and endothelial cells, indicating a role of oxidative stress in DNB-induced damage. Desferrioxamine (20 mm) completely protected endothelial cells from damage by 1 mM DNB, suggesting that hydroxyl radicals mediated at least part of the DNB neurotoxicity. However, astrocytic damage by 2 mM DNB was only partially prevented by desferrioxamine. We conclude that our in vitro model is suitable for studying interactions between astrocytes and endothelial cells in toxicological situations.

Analysis of Variance↗
PubMed1996

Biochemical markers of neurotoxicity. A review of mechanistic studies and applications.

Neurotoxicology presents major challenges to the development of biological markers in accordance to conventional research strategies. Because of the inaccessibility of the nervous system, one of the proposed alternatives is the study of biochemical signals in peripheral tissues which can easily and ethically be obtained in humans, and which could represent surrogate indicators of equivalent parameters in the nervous tissue. Considerable scientific support to this approach is provided by the results of recent investigations in major areas of pharmacology and psychobiology. Studies examining parameters of neurotransmission and second messenger systems in peripheral blood cells, and variations in the peripheral body fluid content of endogenous substances reflecting nervous tissue dysfunction or damage are presented in this paper as examples of efforts toward rational development and validation of novel indicators of nervous system toxicity. Cholinergic muscarinic receptors and calcium signalling in peripheral blood lymphocytes, myelin basic protein in cerebrospinal fluid, and blood polyamines are discussed as potential surrogate indicators based on the results of in vitro or in vivo animal studies of neurotoxic metals (mercury, triethyltin), pesticides (disulfoton), drugs of abuse (d-fenfluramine) and model epileptogenic compounds (kainic acid). Data from investigations examining serum prolactin, type B monoamine oxidase (MAO-B) and dopamine beta-hydroxylase (DBH) in workers occupationally exposed to manganese, lead or styrene are also presented. Although research in this field is still at its very early stage, current evidence suggests that (i) certain neurochemical markers may be valuably used in animal studies as a complement to conventional laboratory tests to augment their sensitivity or predictivity; (ii) a mechanistic research approach is required to establish which markers offer the greatest promise for application in human biomonitoring.

Animals↗
PubMed1996

Neurotoxic effects of gadopentetate dimeglumine: behavioral disturbance and morphology after intracerebroventricular injection in rats.

PURPOSE: To determine the neurotoxic potential of gadopentetate dimeglumine in an animal model that allowed the agent to avoid the blood-brain barrier. Gadopentetate dimeglumine is known to produce functional changes when injected into the cerebrospinal fluid, and we hypothesized that such changes might be associated with morphologic damage. METHODS: Conscious rats, surgically prepared with a lateral ventricular cannula, were given a slow injection of gadopentetate dimeglumine into the lateral ventricle, and behavioral and neuropathologic changes were noted. RESULTS: Gadopentetate dimeglumine produced signs of acute neurotoxicity over several hours (stereotyped movements and myoclonus), medium-term signs over several days (ataxia and tremor), and neuropathologic changes over 24 hours, with reactive changes persisting for 42 days. All of the above were dose-dependent over the range of 2.5 to 15 mumol/g brain. The lowest dose producing morphologic or behavioral changes was 5 mu mol/g brain. Iso-osmotic, isovolumetric injections of sucrose produced no such effects. Focal lesions occurred within the thalamus, brain stem, and spinal cord, with necrosis of glia, loss of myelin, and, usually, sparing of neurons and nerve fibers. Persisting ataxia was always associated with brain stem or spinal cord lesions. CONCLUSION: Intraventricular administration of contrast medium allows toxicity to be evaluated in areas such as the spinal cord that are not accessible by osmotic opening. While it is unlikely that these toxic effects would be seen at the doses used for clinical imaging by the intravenous route, gadopentetate dimeglumine clearly has some neurotoxic and neuropathologic potential. Although the acute excitation could be attributed to a transiently high local concentration of the agent at the injection site, the lesions were widely distributed through the brain and spinal cord and may reflect a region-specific neurotoxic action, possibly related to central pontine myelinolysis.

Animals↗
PubMed1995

Early metabolic changes during m-Dinitrobenzene neurotoxicity and the possible role of oxidative stress.

m-Dinitrobenzene (m-DNB) is an industrial chemical causing gliovascular lesions in the brain stem similar to those produced by nitroimidazoles and by thiamine deficiency. To identify early preneuropathic indices of toxicity we examined the action of m-DNB on glycolysis and on measures of oxidative stress in the brain both in vivo and in vitro. Significant increases in local cerebral glucose utilization were seen in 14 of 30 brain regions prior to development of lesions. Rat brain astrocyte cultures also showed increases in both glucose consumption and lactic acid formation in the first 24 h following exposure to 0.5 mM m-DNB and prior to the development of cytotoxicity. The concentration of reduced glutathione in these cultures was decreased to about half of control values over a 2-h incubation period, indicating an early disturbance of redox balance. The rate of reduction of nitroblue tetrazolium increased eightfold during a 1-h incubation period, suggesting a free radical-mediated process. Superoxide dismutase partially prevented this increase, although other protective agents failed to do so possibly due to lack of cellular penetration. These observations show that m-DNB neurotoxicity involves early metabolic stimulation and redox disruption that may be causally associated with the production of free radicals.

Animals↗
PubMed1993

Inhibition of a neuronal voltage-dependent chloride channel by the type II pyrethroid, deltamethrin.

Following the previous finding that the Type II pyrethroid, deltamethrin, increased membrane resistance in peripheral nerve and muscle in a chloride-dependent manner, the action of deltamethrin on neuronal voltage-dependent chloride channels was assessed using inside-out patches from NIE-115 neuroblastoma cells. These were bathed in symmetrical solutions, containing 149 mM chloride and the membrane potential stepped from 0 mV to voltages ranging from +/- 10 to 80 mV for 2 or 5 sec. Active patches contained large conductance channels (343 +/- 11 pS, n = 8), which inactivated relatively slowly during the voltage step and could be resolved into a number of substates. The channels were confirmed as being chloride specific on the basis of substitution experiments with isethionate and pharmacological blockade by 9-anthracene carboxylic acid (9-ACA). Within 20 min of adding deltamethrin (2 microM) to the bath solution, open channel probability (Po) fell from 0.50 +/- 0.06 to 0.24 +/- 0.04 (n = 11) a highly significant result. Glycerinformal solvent alone (0.1% v/v) caused a non-significant rise to 0.65 +/- 0.09 (n = 4). The decreased open channel probability after deltamethrin was due to an increased incidence of both the closed channel state and low conductance substates. In addition, deltamethrin frequently caused flickering between substrates similar to that seen after 9-ACA. Deltamethrin did not change single channel conductance, current-voltage relationship or time-dependent channel inactivation, but decreased open channel probability over the complete range of membrane voltage tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Influence of season and microclimate on fertility of dairy cows in a hot-arid environment.

Records were obtained over a 3 year period from six Holstein dairy farms of 300 to 500 cows each in the Phoenix, Ariz. area. Dairies were selected on the basis of similar management practices, herd size, milk production and facilities (with the exception of cooling systems). Microclimatic modifications (two dairies each) were shade only (approximately 3.7 m2/cow), evaporative-cooled shades and low-pressure water foggers under the shades. Data were categorized by season of calving (spring, Feb.-May; summer, June-Sept.; and fall, Oct.-Jan.). Traits evaluated were calving interval, days open and services/conception. Calving interval was shortest for cows calving in the spring (378 days), intermediate in fall (382 days) and longest in summer (396 days). Similar seasonal trends were observed for days open (103, 103 and 119 days, respectively) and services/conception (1.54, 1.81 and 1.93, respectively). All differences between spring and summer were significant (P less than 0.05). Calving interval and days open were less for evaporative-cooled groups (374 and 98 days, respectively), with no difference between shade only and foggers (391 and 392 days, 112 and 116 days, respectively). Services/conception were similar for all groups (1.72 to 1.79). A significant interaction between microclimate and season for services/conception could be interpreted as (i) smaller season differences for evaporative-cooled groups than for shade or foggers, or (ii) a change in the ranking of control and fogger groups during summer versus fall. Evaporative cooling was more effective than fogging for reducing the detrimental effects of seasonal high temperatures on fertility.

Animals↗
PubMed1992

A comparison of the acute toxicity, neuropathology, and electrophysiology of N,N-diethyl-m-toluamide and N,N-dimethyl-2,2-diphenylacetamide in rats.

The insect repellent DEET and the structurally related herbicide diphenamid both cause ataxia associated with a spongiform myelinopathy largely confined to the cerebellar roof nuclei. This local myelinopathy was accompanied by the formation of neuronal cytoplasmic clefts and was produced by a single dose of 1 to 3 g/kg N,N-diethyl-m-toluamide (DEET). These dose levels also produced a severe and often fatal prostration and clear electrophysiological signs of prolonged suppressed seizure activity. Diphenamid produced an identical myelinopathy after doses of 0.8 to 1.5 g/kg but without the severe prostration, suppressed seizures, or neuronal clefts. The effects of diphenamid were shown to be reversible over 3 to 7 days by neuropathological, motor, and auditory evoked response indices. Both compounds caused characteristic changes in auditory evoked response which may be useful in clinical diagnosis. Six other alkyl amides, two of which produce signs of CNS excitation, failed to produce myelinopathy at the maximum tolerated doses. Our findings show close parallels with a number of human cases of DEET poisoning and indicate that other amides, like diphenamid, also pose a potential hazard.

Aging↗
PubMed1992

Season and lactation number effects on milk production and reproduction of dairy cattle in Arizona.

Records representing 19,266 Holstein cows from Arizona DHIA data over a 5-yr period were analyzed to determine the effects of season and lactation number on milk production and reproduction. Seasons were winter (December, January, and February), spring (March, April, and May), summer (June, July, and August), and fall (September, October, and November). Traits analyzed by least squares ANOVA were 305-d FCM, complete lactation milk, calving interval, and services per conception. All sources of variation were significant except the interaction between lactation number and season of calving for complete lactation milk. Milk production was depressed for cows calving in summer and fall. First lactation cows had lowest milk production, and highest production occurred in either lactation 4 or 5. Cows calving in spring and summer had reduced reproductive performance, as measured by calving interval and services per conception. First lactation cows had lowest values for both reproductive traits. Previous days dry was negatively related to milk production for spring calvings but was positively related for all other seasons. Cows with higher milk production had reduced reproductive performance. Partial regression coefficients for calving interval and services per conception were 12 d and .25 services per conception per 1000 kg of 305-d FCM, respectively. Despite the negative effects of thermal stress, milk production and fertility in this study were not depressed as severely as in previous research reported from Arizona. Calving schedules may be adjusted to minimize the adverse effect of heat stress.

Animals↗