Biomedical subjects

H A Tilson

Publications and source records attributed to H A Tilson.

At least 127 records · Page 7Linked to original sources

PubMed1987

Chlordecone-induced effects on thermoregulatory processes in the rat.

To investigate the mechanism(s) involved in chlordecone (CLD)-induced hypothermia, we examined colonic (Tcol) and tail skin (Tsk) temperatures, preferred ambient temperature (Ta), evaporative water loss, and metabolic rate following CLD exposure in the rat. Single ip dosages (0, 50, and 75 mg/kg) in corn oil were administered to Fischer-344 rats. At a Ta of 22.5 degrees C, Tcol was reduced by 50 and 75 mg/kg as early as 0.5 hr, and this effect persisted for 4 hr after dosing. Tcol was increased 24 hr after both CLD dosages. Tsk was elevated 2, 3, 4, and 6 hr after 75 mg/kg and 2 hr after 50 mg/kg. At Ta of 30.5 degrees C, Tcol was decreased at early exposure times after both dosages and was increased 3, 4, and 6 hr after 75 mg/kg. At 10.0 degrees C, an enhanced hypothermia was observed 1-6 hr following 50 and 75 mg/kg CLD. The preferred Ta was significantly decreased by approximately equal to 2.8 degrees C following CLD exposure while activity within the temperature gradient was unchanged. At 25.0 degrees C, evaporative water loss was decreased while metabolic rate was not affected by CLD administration. To study the enhanced hypothermia at 10.0 degrees C, metabolic rate was measured continuously for 2 hr following 75 mg/kg CLD and found to be significantly different from controls. The intensified hypothermia in the cold may be due to the inability of the CLD-treated rat to stimulate metabolic thermogenesis in response to cold in addition to the loss of body heat following cutaneous vasodilation. These data suggest that CLD-induced hypothermia at a neutral Ta is associated with cutaneous vasodilation and not with a decreased metabolic rate or increased evaporative water loss.

Animals↗

PubMed1987

Neurotoxic effects of combined treatment of 2,5-hexanedione and triethyllead chloride.

Triethyllead chloride and 2,5-hexanedione are known neurotoxicants that apparently work through separate mechanisms. The effect of combined treatment of triethyllead chloride and 2,5-hexanedione for 6 weeks on Fischer 344 rats was investigated. Ten rats were given 0.7 mg/kg triethyllead chloride in a volume of 2 ml/kg by gavage while another group was given 0.5% 2,5-hexanedione in drinking water and vehicle by gavage (2 ml/kg). A third group was given a combination of the two treatments. A fourth group served as controls and was given vehicle by gavage. 2,5-Hexanedione produced a reversible loss of body weight, decreased grip strength, and decreased horizontal motor activity. Triethyllead chloride alone increased hot-plate latencies. Triethyllead chloride and 2,5-hexanedione treated animals recovered 4 weeks after cessation of treatment. Neither treatment alone produced fatalities. In combination (2,5-hexanedione + triethyllead chloride) decreases in body weight appeared additive and there was a 40% mortality by 6 weeks of dosing. Rats given the combined treatment had significant loss of both grip strength and increased hot-plate latencies. Neurobehavioral deficits and neuropathological changes were greater in the combined treatment with 2,5-HD and TEL than when either chemical was used alone; there was little indication of a synergistic interaction between these two types of neurotoxicants.

Administration, Oral↗

PubMed1987

Direct administration of chlordecone into Japanese quail eggs has persistent effects on conditioned behavior of adults.

Chlordecone (0.1 to 10 mg) or corn oil vehicle was injected into Japanese quail eggs on day 1 of incubation. Higher doses (0.5-10 mg per egg) produced tremor and ataxia at hatching and dose-related decreases in hatchability and survivability. Doses lower than 0.25 mg per egg had no effects. Gonad weights were not affected at 12 weeks of age. A second study examined the effect of injecting 0.5 mg of chlordecone into the egg on day 1, 3, 7 or 14 of incubation. Chlordecone-induced tremor was present at hatching regardless of the day of injection. Significant decreases in hatchability and increases in embryonic mortality were seen when chlordecone was injected on day 1 of incubation. Survivability to 5 weeks of age was decreased in birds receiving chlordecone on day 1 or 3 of incubation. At 75 to 84 days of age, egg production was decreased only in birds injected on day 1 of incubation. The offspring from these studies were mated and the hatchability and reproductive capability of these birds was studied at 75 to 84 days of age and found to be not significantly affected. In a third study, birds exposed to 0.5 mg of chlordecone or vehicle on day 1 of incubation were trained as adults in a food reinforced operant task. Exposure to chlordecone affected performance during the first 3 of 15 days of a match-to-sample task. The baseline response rate of these animals on a food reinforced random interval 60 sec schedule was then determined. During the last two weeks of asymptotic performance, chlordecone-exposed birds had a significantly lower rate of responding than controls. These data indicate that in ovo exposure to chlordecone can have significant long-term effects on conditioned behavior and egg production, particularly if exposure occurs on day 1 of incubation.

Animals↗

PubMed1987

Practical considerations in establishing valid and sensitive neurobehavioral test methods.

Validity and Sensitivity are discussed as key concepts for the Evaluation of neurobehavioral tests; validity refers to the meaning of an observed behavioral change, and sensitivity to the capability of a test to detect behavioral changes relative to dose and/or to other tests. Examples are given to explain these concepts. It is proposed to validate tests by means of compounds with known neurotoxic properties, and to cover sensitivity by described dose-response characteristics.

Animals↗

PubMed1986

Colchicine-induced granule cell loss in rat hippocampus: selective behavioral and histological alterations.

Bilateral injection of 3.5 micrograms of colchicine into two levels of the dentate gyrus produced a selective loss of dentate granule cells and persistent behavioral effects in male Fischer rats. Histological analysis confirmed that this dosage of colchicine resulted in the selective loss of most granule cells in both superior and inferior blades of the dentate gyrus near the injection sites, while sparing pyramidal cells in CA1, CA2, CA3, and CA4, and GABAergic interneurons throughout the hippocampus. Rats injected with colchicine were significantly more active than cerebrospinal fluid-injected controls 2, 7, 14, 21 and 28 days after treatment. Behavioral reactivity, assessed by the magnitude of the acoustic startle response and the latency to respond in a hot-plate test, was not affected at any of these time points. Retention of a step-through passive avoidance task was impaired in the colchicine group one month after surgery. Their step-through latencies were significantly shorter than control latencies, and they exhibited more partial entries during the retention test. Acquisition and performance in a radial-arm maze, measured up to 3 months after surgery, were also impaired by colchicine. Animals injected with colchicine required more trials to acquire the task and were less accurate in the task even after their performance had stabilized. These data suggest that the hippocampus modulates motor behavior and cognitive function. The results of these experiments also support the use of colchicine as a means of defining the functional and anatomical consequences following selective destruction of the granule cell population of the dentate gyrus.

Animals↗

PubMed1986

Inhibition of ornithine decarboxylase alters neurological responsiveness to a tremorigen.

Difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC; 200-800 mg/kg, s.c.), to rats has no detectable behavioral effects using a battery of tests to assess sensorimotor function. In contrast, the induction of tremor by chlordecone, a neurotoxic agent that affects neuronal ionic processes, is significantly attenuated by pretreatment with DFMO. The effects of DFMO on chlordecone-induced tremor were reversed by pretreatment with putrescine. DFMO had no effects on p,p'-DDT, a tremorigen having a mechanism of action different from chlordecone. These findings imply that polyamines may play a role in select neuronal processes.

Animals↗

PubMed1986

Acute exposure to triethyl lead enhances the behavioral effects of dopaminergic agonists: involvement of brain dopamine in organolead neurotoxicity.

Acute exposure to triethyl lead chloride (7.88 mg/kg) enhanced the behavioral effects of both direct- and indirect-acting dopaminergic agonists. Rats treated with lead 1 week before testing exhibited an increased response to the motor stimulant effects of D-amphetamine and apomorphine. The dose-response curves for D-amphetamine (1.25, 2.0, 3.15 and 5.0 mg/kg)- and apomorphine (0.2, 0.5, 1.25 and 2.0 mg/kg)-induced hyperactivity were shifted to the left in the triethyl lead group. Finally, apomorphine (1 mg/kg) produced more stereotypy in rats pretreated with triethyl lead. This enhanced sensitivity to dopaminergic agonists was not due to altered pharmacokinetics of the challenge drugs, since the onset and duration of their behavioral effects were not affected by triethyl lead. Furthermore, the regional distribution and accumulation of D-[3H]amphetamine was not altered by triethyl lead. These data suggest that acute exposure to triethyl lead enhances the responsiveness of dopaminergic processes which contribute to locomotor activity. The involvement of brain dopamine in other aspects of organolead neurotoxicity is discussed.

Animals↗

PubMed1986

Influence of pre- and postnatal exposure of rats to 2.45-GHz microwave radiation on neurobehavioral function.

Rats exposed to microwaves prenatally (2,450 MHz, 10 mW/cm2, 3 h/day, days 5-20 of gestation) or perinatally (same as above plus days 2-20 postnatally) were examined by a neurobehavioral test battery on postnatal days 30 and 100. Body mass, locomotor activity, startle to acoustic and air-puff stimuli, fore- and hindlimb grip strength, negative geotaxis, reaction to thermal stimulation, and swimming endurance were assessed. The prenatally and the perinatally exposed rats (male and female) weighted more than sham-exposed rats at 30, but not at 100, days of age. In addition, the perinatally exposed animals had less swimming endurance at 30, but not at 100, days of age relative to sham-exposed rats. For the other measures, only the air-puff startle response was altered and was limited to the prenatally exposed female pups; ie, at postnatal day 30, the startle response was increased in magnitude, and at postnatal day 100, the response was decreased. No other reliable effects were observed. In a second experiment, rats treated as described above were examined for alterations in body mass, locomotor activity, reaction to air-puff stimuli, reaction to thermal stimulation, and swimming endurance at postnatal days 30-36. Again, perinatally exposed rats were larger in body mass and had less swimming endurance compared with sham-exposed rats. The latency to the air-puff startle response was longer in female pups exposed prenatally. These data indicate that altered endurance and gross motor activity result from perinatal exposure to microwave irradiation.

Animals↗

PubMed1986

Neurochemical effects of DDT in rat brain in vivo.

p,p'-DDT and related agents act to hold the sodium channel open once opened and this effect is believed to be responsible for neurological effects of tremor and hyperexcitability in vivo. There is a good correlation between DDT-induced tremor and an increase in the levels of the metabolites of norepinephrine (NE), serotonin (5HT) and, to a lesser extent, dopamine (DA) in the brain stem (BS), hypothalamus (HYP), striatum (STR), or hippocampus (HPC). DDT also increases levels of excitatory amino acids glutamate (GLU) and aspartate (ASP), but the effect occurs only in the brain stem. These effects are dose- and time-related. Pharmacological studies found that blockade of alpha 1-adrenergic receptors attenuate DDT-induced tremor, while blockade of serotonergic, cholinergic muscarinic, and dopaminergic receptors augment the toxicity of DDT. Tremor was almost completely blocked in rats pretreated with hydantoin, an anticonvulsant believed to block repetitive firing of nerves by interfering with the inactivation gate of the sodium channel. A similar antagonism was observed for permethrin, a Type I pyrethroid believed to have a mechanism of action very similar to that of DDT. However, hydantoin increased the tremorigenic effects of chlordecone, an organochlorine whose mechanism has not been linked to the sodium channel. These data are consistent with the hypothesis that the in vivo neurotoxicity of some organochlorine insecticides is related to their effects on the sodium channel.

Amino Acids↗

PubMed1986

Pharmacological modification of DDT-induced tremor and hyperthermia in rats: distributional factors.

Pretreatment of rats with hydantoin (75 mg/kg, PO, an anticonvulsant), trihexyphenidyl (10 mg/kg, SC, a muscarinic cholinergic antagonist), or piperonyl butoxide (500 mg/kg, PO, a metabolic inhibitor) had no effect on the whole blood or brain tissue levels of orally administered DDT (75 mg/kg) or its metabolites DDD and DDE. Hydantoin and piperonyl butoxide decreased DDT-induced tremor and hyperthermia due to DDT when measured 12 h after DDT exposure, while trihexyphenidyl augmented some components of DDT-induced tremor. Additional experiments found that pretreatment with piperonyl butoxide increased tremor due to permethrin exposure (120 mg/kg, PO), while having no effect on tremor due to chlordecone administration (60 mg/kg, IP). Pretreatment with ellipticine (30 mg/kg, IP, a metabolic inhibitor) also decreased tremor 12 h after DDT exposure. The effects of piperonyl butoxide and ellipticine on DDT-induced tremor are postulated to occur through direct actions of these compounds on nerve or muscle tissue. Hydantoin-induced attenuation of DDT-induced neurotoxicity may be due to the ability of hydantoin to block repetitive firing of nerves by binding to the inactivation gates of sodium.

Animals↗

PubMed1986

A comparison of the effects of RO15,1788 and chlordiazepoxide on hot-plate latencies, acoustic startle, and locomotor activity.

RO15,1788, (a selective benzodiazepine antagonist) and chlordiazepoxide (an anxiolytic 1,4-benzodiazepine) produced time-dependent and dose-dependent effects on various indices of sensory-motor function. RO15,1788 increased hot-plate latencies at doses (10-60 mg/kg) that had no effect on locomotor activity. Furthermore, the increased hot-plate latencies were observed 15, but not 30, 60, or 120 min after injection of 10 mg/kg RO15,1788. In contrast, chlordiazepoxide (2.5, 5.0, 10.0, 20.0 mg/kg) produced a dose-dependent increase in response times on the hot-plate, which appeared to be related to the depressant effects of this compound on motor activity. CDZ significantly decreased overall motor activity in a dose-related manner, with the two lower doses decreasing activity approximately 75% relative to controls. RO15,1788 (10 mg/kg) also decreased the magnitude of the acoustic startle response measured over 20 stimulus presentations. The startle response was significantly depressed during each of four 5-trial blocks. The magnitude of both the first and the largest response recorded was also decreased by this compound. Chlordiazepoxide (2.5 mg/kg) significantly decreased the magnitude of the startle response only during the first block of five stimulus presentations. These results are discussed in terms of the involvement of benzodiazepine-mediated processes in the modulation of sensory function and behavioral reactivity to biologically-relevant information.

Acoustic Stimulation↗

PubMed1986

Noradrenergic influence on the prepulse inhibition of acoustic startle.

Oral administration of p,p'-1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), a chemical believed to increase neuronal membrane excitability increased the acoustic startle responsiveness of rats. Inhibition of the acoustic startle response with a brief, prepulse white-noise stimulus was evident at 12.5 to 25 mg/kg of p,p'-DDT, but not at 50 mg/kg. Pretreatment of rats with phenoxybenzamine, an adrenergic receptor antagonist, attenuated the effects of 12.5 mg/kg of p,p'-DDT on the acoustic startle reflex, and decreased the maximum magnitude reduction produced by the prepulse stimulus in DDT-exposed rats. These data extend previous work showing that p,p'-DDT augments startle reactivity in rats and is in accord with the existence of an excitatory norepinephrine(NE)-containing pathway modulating motor outflow in the acoustic startle reflex arc.

Analysis of Variance↗

PubMed1986

5,5-Diphenylhydantoin antagonizes neurochemical and behavioral effects of p,p'-DDT but not of chlordecone.

Rats were given 75 mg/kg of 5,5-diphenylhydantoin (phenytoin) or vehicle 30 min prior to 75 mg/kg of 1,1,1-trichloro-bis(p-chlorophenyl)ethane (p,p'-DDT) (p.o.) or chlordecone (i.p.) and tremor was measured 12 h later. Rats were then killed, and regional brain levels of biogenic amines and their acid metabolites and amino acids were determined. Pretreatment with phenytoin significantly attenuated the tremor produced by p,p'-DDT but enhanced that produced by chlordecone. p,p'-DDT had significant effects on the levels of aspartate, glutamate, 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), whereas chlordecone increased glycine, 5-HIAA, and MHPG levels. Pretreatment with phenytoin blocked p,p'-DDT-induced increases of aspartate in the brainstem and spinal cord, 5-HIAA in the hippocampus, and MHPG in the brainstem and hypothalamus. Phenytoin significantly enhanced chlordecone-induced increases of MHPG in the brainstem. These data indicate that organochlorine-induced increases in noradrenergic activity in the brainstem and spinal cord may be directly related to the tremorigenic effects of these chemicals.

Animals↗

PubMed1986

Trimethyltin-induced alterations in brain amino acids, amines and amine metabolites: relationship to hyperammonemia.

An investigation of several neurochemical consequences of exposure of the rat to 3/4 of the estimated single injection LD50 quantity of trimethyltin chloride (TMT) indicated that a significant elevation in the levels of glutamine (Gln) and 5-hydroxyindole acetic acid (5-HIAA) occurred at post-dosing day 7 in each examined region of the brain; elevated Gln persisted in the hippocampus through day 14 and returned to control levels at day 28. At post-dosing day 7, levels of glutamate were decreased in the hippocampus, while levels of GABA were decreased in hippocampus and frontal cortex, but not in corpus striatum; hippocampal glutamate and GABA returned to control levels by post-dosing day 14. Decreased levels of taurine (Tau) occurred on day 7 in both hippocampus and frontal cortex; hippocampal Tau remained below control levels through post-dosing day 28. Levels of other amino acids and of amines and amine metabolites were not altered by TMT in the 7 to 28 day post-dosing interval. At day 7, TMT treatment did not alter brain regional activities of glutamine synthetase; however, plasma ammonia was elevated 100% above the control value. Alterations in several serum enzymes (esp., alkaline phosphatase and aspartate aminotransferase) revealed several other peripheral consequences of TMT exposure which persist through post-dosing day 28. The more prominent and wide-spread neurochemical alterations resulting from TMT exposure appear to reflect consequences of hyperammonemia resulting from a peripheral effect of the organotin compound.

Amino Acids↗

PubMed1986

Neurobehavioral effects of permethrin are associated with alterations in regional levels of biogenic amine metabolites and amino acid neurotransmitters.

Oral administration of 120 or 240 mg/kg permethrin produced dose- and time-related tremor in rats with the peak effect occurring 5 hrs after dosing. Subsequent experiments done 5 hrs postdosing found that 45 to 180 mg/kg permethrin produced dose-related increases in rectal temperature and enhanced responsiveness to an acoustic stimulus. Tremor was detected at 90 and 180 mg/kg. Neurochemical analyses of regional biogenic amines and their metabolites and amino acids 5 hrs after 90 or 180 mg/kg indicated that 5-HIAA levels were increased in the hypothalamus (HYP), brain stem (BS), hippocampus (HPC), and striatum (STR); 5-HT was not affected. MHPG was increased in the HYP and BS, while NE was decreased at the high dose only. DOPAC and HVA were increased in the STR after 90 and 180 mg/kg, while DA was not affected. Aspartate levels were increased in the BS and STR; glutamate was increased in the BS. Taurine, glutamine, glycine, and GABA were not affected. A time-course analysis of neurochemical changes 2, 5, 12, and 24 hrs postdosing indicated that 5 hrs was the time of peak effect for permethrin. Permethrin-induced tremor and hyperthermia were significantly correlated with dose- and time-related changes in MHPG, 5-HIAA, and ASP.

Amino Acids↗

PubMed1986

Triethyl and trimethyl lead: effects on behavior, CNS morphology and concentrations of lead in blood and brain of rat.

The dose-related behavioral effects produced by triethyl (TEL) (2.6 to 7.9 mg/kg) and trimethyl lead (TML) (8.8 to 26.2 mg/kg) were assessed 2, 7, 14, 21 and 28 days following injection. TEL, but not TML, produced dose- and time-related decreases in body weight. Both agents decreased vertical and horizontal components of motor activity 2 days postdosing; increased activity was seen consistently in TEL-exposed rats 7 to 21 days after dosing. TML increased fore- and hindlimb strength for up to 28 days postdosing. TEL had no consistent effect on this measure. Both TEL and TML decreased responsiveness to an acoustic stimulus during the first two weeks postdosing. Latency to respond to a thermal stimulus was increased 2 to 14 days after TEL with the peak change occurring from 2 to 7 days. The peak of effect following TML was two weeks postdosing. In general, there was a significant correlation between both TEL and TML-induced changes in blood and brain lead levels and decreased sensitivity to a thermal stimulus. The apparent delayed onset of TML-induced neurobehavioral effects may be related to a longer time to obtain peak blood or brain levels. Histopathological assessment of rats 7 or 28 days after TEL and TML indicated that TEL caused structural abnormalities in the hippocampus and dorsal root ganglion, while TML produced changes primarily in the spinal cord and brain stem.

Animals↗

PubMed1985

Injection of diethylstilbestrol on the first day of incubation affects morphology of sex glands and reproductive behavior of Japanese quail.

Japanese quail eggs were injected with DES (0.9-1,000 micrograms) dissolved in 50-microliter of corn oil on day 1 of incubation. Higher doses of DES (250-1,000 micrograms) reduced hatchability to 37-33% compared to 61% for corn oil-injected controls. Lower doses of DES (0.9-125 micrograms) had no effects on hatchability. In a second study, eggs were injected with 0.9 or 1.9 micrograms of DES and the survivors were assessed up to 12 weeks posthatch. DES did not affect hatchability, but did increase mortality during the first 4 weeks posthatch. Females were affected more than males. At 10 days of age, open-field activity of some birds was examined. The acquisition and reversal of a visual discrimination task was studied at 6 weeks of age. DES had no effect on these measurements. Ten females from each group were chosen randomly to determine egg production over a single 28-day period beginning at 6 weeks of age. Exposure to DES blocked egg production in these birds. The oviduct weights of 12-week-old females were decreased by 50%, but ovarian weights were not affected. Testicular weights were not affected. In a third study reproductive behaviors and social-dominance behaviors of males were markedly attenuated in birds exposed to 0.48 or 1.9 micrograms DES in ovo.

Animals↗

PubMed1985

Evaluation of long-term consequences in behavioral and/or neural function following neonatal chlordecone exposure.

The effects of neonatal exposure of rats to chlordecone, during the major postnatal period of neuroendocrine differentiation were assessed after the animals matured to 90 days of age. On day 4 postpartum, pups received a s.c. injection of either DMSO vehicle or chlordecone (1 mg/pup) dissolved in DMSO. The neonatal exposure produced a significant sex-dependent alteration in adult body weight; chlordecone-exposed males were lighter than vehicle-exposed controls and chlordecone-exposed females were heavier than vehicle-exposed controls. Behavioral tests sensitive to neonatal chlordecone exposure during preweaning development--i.e., spectral analysis of movement, activity, and auditory startle responsiveness--gave no statistically significant evidence for residual effects of the early organochlorine treatment. When challenged with harmine, a known tremorogen with putative effects on olivocerebellar pathways, chlordecone-exposed males were less responsive than vehicle-exposed littermates in a spectral analysis of movement. The movement spectrum of chlordecone-exposed females was not differentially sensitive to the harmine challenge. However, subsequent evaluation of the auditory startle reflex indicated that harmine interacted with the neonatal treatment and sex of the animal; chlordecone-exposed males were less responsive and chlordecone-exposed females more responsive than same sex vehicle-exposed littermates. The responsiveness to a d-amphetamine challenge, expressed as a ratio of baseline activity in a pre- and post-test design, suggested the chlordecone-exposed males gave an exaggerated response to the drug challenge. Collectively, these findings suggest that the neonatal chlordecone exposure had a significant organizational effect on the development of behavioral and/or neural function. These findings also suggest the predictive utility of early behavioral tests; that is, long-term alterations were noted in each component of the toxicological syndrome previously identified during preweaning development.

Animals↗