Biomedical subjects

K F Dean

Publications and source records attributed to K F Dean.

12 recordsLinked to original sources

PubMed1991

The effects of 2,4-dithiobiuret on sensory and motor function.

2,4-Dithiobiuret (DTB) exposure causes a delayed onset muscle weakness in rats that has been attributed to depressed neuromuscular transmission. The present study compares the effects of DTB on both sensory and motor function in rats. Adult male Long-Evans hooded rats were exposed to saline, 0.25, 0.5, or 1.0 mg/kg/day DTB, ip, for 5 consecutive days (Days 1-5). Body weights were monitored throughout the experiment. Motor activity was measured for 1 hr in figure-eight mazes on Days 0, 6, 13, and 27. Forelimb and hindlimb grip strength were assessed on Days 6, 13, and 27. Auditory thresholds were determined for 5- and 40-kHz tones using reflex modification of the startle response on Days 0, 7, 14, and 28. Visual function was examined on Day 6 in animals exposed at 0.5 mg/kg/day using flash- and pattern-elicited visual evoked potentials (FEPs and PEPs, respectively). Thermal sensitivity was measured using the hot plate procedure. All motor endpoints were decreased in a dosage- and time-dependent manner; the higher the dosage the longer the effects lasted. There were no effects on any measure of sensory function with the exception of peak N2 of the FEP. Both the amplitude and latency of FEP N2 were altered by DTB exposure. Decreases in body weight were maximal on Day 9 at 1.0 mg/kg/day (20% from control), but recovered by Day 22. Motor activity was suppressed on Day 6 only, whereas grip strength measures were decreased on both Days 6 and 13. Auditory thresholds were not significantly altered; however, baseline startle amplitude was decreased at the highest dosage on Days 7 and 14, but recovered by Day 28. Hot plate latencies were not altered by DTB treatment. These data demonstrate that DTB produces a reversible impairment of motor function, without altering auditory, thermal, or pattern visual function. FEP N2, which is thought to arise from activity generated in the superficial layers of visual cortex, was diminished by DTB treatment, indicating that DTB can alter the function of the CNS, although effects on the motor system are more pronounced.

Animals↗

PubMed1990

Trimethyltin effects on auditory function and cochlear morphology.

Trimethyltin (TMT) is a neurotoxicant known to alter auditory function. The present study was designed to compare TMT-induced auditory dysfunction using behavioral, electrophysiological, and anatomical techniques. Adult male Long-Evans hooded rats (n = 9-12/group) were acutely exposed to saline, 3, 5, or 7 mg/kg TMT. Auditory thresholds were determined 11 weeks postdosing for 5- and 40-kHz tones using reflex modification of the auditory startle response (ASR). Brainstem auditory evoked response (BAER) thresholds were determined for 5-, 40-, and 80-kHz tonal stimuli 9 weeks postdosing. Cochlear histology was assessed at 13 weeks postdosing. Functional endpoints demonstrated a high-frequency hearing loss. ASR thresholds for 40-kHz tones were elevated 25-35 dB in all dosage groups. BAER thresholds for 40- and 80-kHz tones were elevated 30-50 dB in the 5 and 7 mg/kg groups. Organ of Corti surface preparations revealed a pattern of damage suggesting classical ototoxicity. That is, outer hair cells died preferentially in regions associated with high-frequency hearing, in a dosage-dependent manner from base to apex. These data demonstrate the utility of the ASR and BAER in detecting functional alterations in audition and indicate that TMT-induced high-frequency hearing loss is associated with cochlear damage.

Animals↗

PubMed1989

Prenatal or postnatal exposure to bis(tri-n-butyltin)oxide in the rat: postnatal evaluation of teratology and behavior.

The results of a series of screening tests to determine the potential teratogenicity and neurotoxicity of developmental exposure to TBTO in rats are presented in this paper. For prenatal exposure, pregnant Long Evans rats were intubated with 0-16 mg/kg/day bis(tri-n-butyltin)oxide TBTO from Days 6 to 20 of gestation (GD 6-20). For postnatal exposure, rat pups were intubated with 0-60 mg/kg TBTO on Postnatal Day 5 (PND 5). Following prenatal exposure, dams were allowed to litter and pups were evaluated using a postnatal teratology screen. Postnatal evaluation for both exposures included motor activity (PND 13-64), the acoustic startle response (PND 22-78), growth, and brain weight. The maximally tolerated dose (MTD) in pregnant rats was 5 mg/kg/day, which is one-third the MTD in nonpregnant rats. There were decreased numbers of live births, and decreased growth and viability at dosages greater than or equal to 10 mg/kg/day. Cleft palate was found in 3% of the 12 mg/kg/day group. There was mortality following postnatal exposure to 60 mg/kg and all prenatal dosages greater than or equal to 10 mg/kg/day. Preweaning body weight was significantly decreased for all postnatal dosages, and all prenatal dosages greater than 2.5 mg/kg/day. Body weight reductions persisted to the postweaning period only in the high dose groups (10 mg/kg/day and 60 mg/kg). Behavioral evaluation demonstrated transient alterations in motor activity development (prenatal exposure only) and the acoustic startle response (postnatal exposure only). Persistent behavioral effects were observed only at dosages that produced overt maternal toxicity and/or postnatal mortality. The demonstration of the teratogenic and neurotoxic potential of TBTO in rats is confounded by associated maternal toxicity and/or pup mortality.

Abnormalities, Drug-Induced↗

PubMed1988

Ontogeny of the acoustic startle response and sensitization to background noise in the rat.

The purpose of this study was to characterize the ontogeny of the acoustic startle response (ASR) and response sensitization to background noise in preweanling rats. Animals were tested daily from 11 to 21 days of age using one of four sets of background white noise levels [45-80 dB(A)]. With constant low-level (45 dB, SPL) background noise, response latency decreased steadily with age, whereas both response incidence and amplitude increased nonmonotonically with age. Two approaches were used to examine the ontogeny of sensitization to background noise: The first compared the ASR of animals tested at 75 dB background noise with ones tested at 45 dB; the second compared the ASR of animals tested at three background levels (30 dB range) within the test session. Sensitization was not evident before 15-16 days of age. By comparing these results with the results from naive animals, it was found that daily test experience does not alter ASR amplitude, latency, incidence, or the development of sensitization.

Acoustic Stimulation↗

PubMed1985

Development of locomotor activity of rat pups exposed to heavy metals.

Cadmium (Cd), triethyltin (TET), and trimethyltin (TMT) are heavy metals which are neurotoxic to developing animals. In the present experiment, preweaning assessment of locomotor activity was used to detect and differentiate between the developmental toxicity of these metals. On postnatal day (PND) 5, rat pups received a single injection of either Cd, TET, or TMT. A within-litter design was used for dosing; 1 male and 1 female pup from each litter (N = 10 litters/compound) received either the vehicle, low, medium, or high dosage of the compound. Preweaning motor activity was assessed in 30-min sessions in figure-eight mazes from PND 13 to 21. Motor activity of control animals progressively increased in the initial days of testing, and then both within-session and between-session habituation developed. A single exposure to Cd, TET, and TMT produced hyperactivity by the end of the preweaning period but these metals differed in the day of peak activity, the onset of hyperactivity, and the development of habituation.

Animals↗

PubMed1985

Development of locomotor activity of rat pups in figure-eight mazes.

In a series of four experiments, social and experiential factors that influence the development of motor activity in rat pups were examined. Motor activity was monitored from postnatal Days 13 to 21 as photocell interruptions in figure-eight mazes and comparisons were made between pups maintained in a nest box containing a dam and siblings and allowed access to the maze for 23 hr/day, pups tested daily for 1 hr/day vs pups tested only on postnatal Days 15, 18, or 21, pups tested daily for either 5 min, 30 min, or 1 hr/day, and pups tested daily for 30 min/day either singly in a maze, paired with a littermate, or paired with an anesthetized pup of the same age. A monotonic increase in activity was seen for nest-box testing, minimal developmental change was seen for pups tested on only a single day or for pups tested with an anesthetized pup, whereas all other groups showed an inverted U-shaped profile of activity which was influenced by the duration of testing and/or the presence of a littermate. These data emphasize the relevance of environmental factors as determinants of preweaning behavior.

Age Factors↗

PubMed1984

Trimethyltin disrupts acoustic startle responding in adult rats.

Trimethyltin (TMT) is a limbic-system toxicant which also produces sensory dysfunction in adult animals. In the present experiment, we examined the effects of TMT on the acoustic startle response. Adult male, Long-Evans rats (N = 12/dose) received a single i.p. injection of either 0, 4.0, 5.0 or 6.0 mg/kg TMT hydroxide as the base. The number of responses, latency and peak amplitude of the startle response to a 13 kHz, 120 dB tone were measured 2 h, 2 weeks, and 4 weeks after dosing. For each test session, 10 stimuli were presented at each of three background noise levels (50, 65 and 80 dB). By 2 h after dosing, the number of responses and response amplitude were decreased following 4.0-6.0 mg/kg TMT; these treatment effects persisted through 4 weeks after dosing. Increases in latency were also seen following all dosages of TMT. These data suggest that TMT produces disruption of function within the acoustic-startle pathway.

Acoustic Stimulation↗

PubMed1984

Neurobehavioral toxicity of triethyltin in rats as a function of age at postnatal exposure.

Triethyltin (TET) has been shown to be neurotoxic when injected on postnatal day (PND) 5. In the present experiment we examined the toxicity of a single exposure to TET at several postnatal ages. Rat pups were injected ip with 0 (saline), 1.5, 3.0, or 6.0 mg/kg TET bromide on PND 1, 5, 10 or 15. In agreement with our previous data, PND-5 exposure to 6 mg/kg TET produced behavioral toxicity and decreased adult brain weight. High dose pups were less successful in descending on a rope at 20 and 21 days of age, and were hyperactive in figure-eight mazes at 29-30 and 57-58 days of age. The spatial distribution of activity was also altered: photocell counts were increased primarily in the figure-eight area of the maze. The size of the milk bands was reduced in 6 mg/kg pups injected on either PND 1 or PND 5. Preweaning growth was decreased following all injection ages; this reduction was most pronounced for pups exposed to TET on PND 1 and PND 5. Mating behavior was disrupted in 6 mg/kg males irrespective of age at exposure. These data demonstrate a differential sensitivity to the toxicity of TET during postnatal life, with maximal susceptibility on PND 5.

Age Factors↗

PubMed1983

Acute behavioral toxicity of carbaryl and propoxur in adult rats.

Motor activity and neuromotor function were examined in adult CD rats exposed to either carbaryl or propoxur, and behavioral effects were compared with the time course of cholinesterase inhibition. Rats received an IP injection of either 0, 2, 4, 6 or 8 mg/kg propoxur or 0, 4, 8, 16 or 28 mg/kg carbaryl in corn oil 20 min before testing. All doses of propoxur reduced 2 hr activity in a figure-eight maze, and crossovers and rears in an open field. For carbaryl, dosages of 8, 16 and 28 mg/kg decreased maze activity whereas 16 and 28 mg/kg reduced open field activity. In order to determine the time course of effects, rats received a single IP injection of either corn oil, 2 mg/kg propoxur or 16 mg/kg carbaryl, and were tested for 5 min in a figure-eight maze either 15, 30, 60, 120 or 240 min post-injection. Immediately after testing, animals were sacrificed and total cholinesterase was measured. Maximum effects of propoxur and carbaryl on blood and brain cholinesterase and motor activity were seen within 15 min. Maze activity had returned to control levels within 30 and 60 min whereas cholinesterase levels remained depressed for 120 and 240 min for propoxur and carbaryl, respectively. These results indicate that both carbamates decrease motor activity, but behavioral recovery occurs prior to that of cholinesterase following acute exposure.

Animals↗

PubMed1983

Comparative developmental toxicity of triethyltin using split-litter and whole-litter dosing.

Previous work in our laboratory suggested that toxicity resulting from acute postnatal administration of triethyltin (TET) was influenced by the treatment condition of littermates. To test this possibility, two dosing models were compared. For the split-litter model (N = 20 litters/dose), 1 male and 1 female pup per litter received a single dose of O (saline), 3, 6, or 9 mg TET/kg on postnatal d 5; the remaining 6 littermates were not injected. In the whole-litter model, all 8 littermates received 0, 3, 6, or 9 mg TET/kg (N = 5 litters/dose). Differences between dosing models were found for preweaning body weight and adult figure-eight maze activity. Body weights were reduced in all TET-dosed pups; for 3-mg/kg animals, the reduction in preweaning growth was more persistent for pups in the split-litter group. Motor activity in a figure-eight maze was increased in both 6- and 9-mg/kg animals; for the high dose, the increase in activity was greater for animals in the split-litter group. There were no differences between dosing models in mortality, brain weight, or postweaning body weight. Approximately 50% of the 9-mg/kg animals died; there was no treatment related mortality at lower doses. Adult body weight also remained decreased only in the 9-mg/kg animals. Brain weight was reduced for all TET dose groups. These results indicate that developmental toxicity produced by TET is not primarily determined by the dosing regimen.

Animals↗

PubMed1981

Developmental and behavioral effects of early postnatal exposure to triethyltin in rats.

On Day 5 of postnatal life, rat pups received a single injection of triethyltin and were later tested for a variety of developmental and adult behaviors. A within-litter dosing design was used with one male and one female from each litter (N = 8 pups/litter) receiving either 0 (normal saline vehicle), 3, 6 or a high dose of either 9 or 12 mg/kg triethyltin bromide (TET). The high doses of TET produced 50% and 80% mortality, respectively. For the 3 and 6 mg/kg groups, TET-exposure resulted in a transient decrease in body weight, and a permanent decrease in brain weight. Preweaning TET-exposed pups were less successful in descending a rope, and were less active in both a homing orientation test and a figure-eight maze. When tested as adults, however, these animals were consistently more active than controls in the figure-eight maze. These results indicate that a single exposure to TET in ;the developing rat, unlike the adult, produces permanent alterations in both brain and behavior. Acute postnatal exposure to toxicants may have general applicability as a model for developmental neurotoxicity.

Aging↗

PubMedDate not supplied

Developmental and behavioral toxicity following acute postnatal exposure of rat pups to trimethyltin.

The purpose of this study was to extend our investigations on the developmental neurotoxicity of trialkyltin compounds. On postnatal day 5 (PND 5), rat pups received a single intraperitoneal injection of either 0 (saline), 4, 5 or 6 mg/kg trimethyltin hydroxide (TMT) calculated as the base. The size of the milk bands was decreased in 6 mg/kg TMT pups 48-96 hr after dosing, while in 5 mg/kg TMT pups, milk bands were reduced 96 hr after dosing only. Dosages of 5 and 6 mg/kg TMT reduced growth and impaired performance in rope descent during the preweaning period. As adults, motor activity in figure-eight mazes was increased for 6 mg/kg TMT animals. The startle response to an acoustic stimulus (a 13 kHz, 120 dB tone) was also affected by TMT when measured both during ontogeny and in adulthood. During development, on days 10-21, both 5 and 6 mg/kg TMT reduced the number of responses during 30-trial sessions for both males and females. Amplitudes were decreased for the 5 and 6 mg/kg dose on days 12-13, and for all dosages on days 18-19 and 20-21. Startle amplitude of adults was decreased at all dosages for males but not for females. These behavioral changes were accompanied by decreases in adult brain weight for both sexes. Whole brain weight and weight of the olfactory bulbs were decreased following all dosages of TMT, while hippocampal weight was decreased following both 5 and 6 mg/kg TMT. These results indicate that acute postnatal exposure to TMT produces long-term effects on the nervous system and behavior.

Animals↗