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Biomedical subjects

L D Fechter

Publications and source records attributed to L D Fechter.

At least 37 records · Page 2Linked to original sources
PubMed1994

Trimethyltin disrupts N1 sensitivity, but has limited effects on the summating potential and cochlear microphonic.

Trimethyltin (TMT), a model neurotoxicant, has previously been demonstrated to disrupt auditory thresholds in laboratory subjects. In this experiment we characterized the potency of this ototoxicant by means of a dose response study and then evaluated the functional effects of TMT administration when tone-bursts were presented at supra-threshold levels. Guinea pigs were anaesthetized and prepared for electrophysiological measurement of the compound action potential (CAP) and cochlear microphonic (CM). Subsequently averaged wave forms generated by tone-bursts of 0-80 dB SPL were evaluated in order to calculate both a N1 and a summating potential (SP) input-output function. We show that TMT at doses as low as 0.2 mg/kg produce elevations in N1, but not in the CM isopotential curve. Using exposures to 0.5 mg/kg TMT we show a profound reduction in the slope of the N1 input-output curve, but no shift in the SP. The results are consistent with the hypothesis that TMT disrupts function at the synapse between the inner hair cell and the Type 1 spiral ganglion cell.

Acoustic Stimulation↗
PubMed1993

In vitro organotin administration alters guinea pig cochlear outer hair cell shape and viability.

Trimethyltin (TMT) and triethyltin (TET) disrupt auditory function at doses far below those shown to be neurotoxic. In vivo studies suggest that the initial effect of TMT on hearing occurs at the inner hair cell/spiral ganglion cell synapse, while later, the outer hair cell (OHC) undergoes structural and functional damage. TET produces acute effects upon afferent neurotransmission similar to those observed following TMT, but TET's effects on OHC structure and function have not been examined. OHCs are motile elements within the cochlea, believed to modulate the sensitivity and tuning within the inner ear. Changes in OHC length may alter hearing function, and length changes have been reported following exposure to various ototoxic agents in vitro. In the present study, 77 OHCs from 45 pigmented male guinea pigs were isolated in primary culture and exposed for 90 min to concentrations between 30 microM and 1.0 mM of TMT or TET and then to bathing medium for 30 min to remove the toxicant. Significant shortening of the OHC cell body occurred at all doses to both organotins, with a mean reduction in length of 15.1 and 20.2% for 1.0 mM TMT and TET, respectively, at the end of testing; control cells were only 3.4% shorter at the end of 90 min of perfusion with bathing medium. The effect of organotin exposure on OHC volume was not consistently related to either TMT or TET concentration or altered cell length. In addition, disruption of the plasma membrane characterized by bleb formation, the forceful ejection of cytoplasm, or bursting was seen in 80% of cells exposed to 1.0 mM TET, although not TMT; lower concentrations of both organotins disrupted the cell membrane in 10-30% of cells. Membrane rupture was not reliably associated with either increased cell volume or decreased length, implicating a weakening of the plasma membrane or cortical lattice as the basis for this effect. Consistent with the irreversible structural weakening of the lateral wall, resorption of organotin-induced cytoplasmic blebs was never evidenced. Qualitatively, subcellular elements in the central core of many organotin-treated OHCs appeared pathological. These changes are similar to histopathological changes observed following in vivo organotin administration and may represent one target of acute alkyltin ototoxicity.

Animals↗
PubMed1992

Rapid disruption of cochlear function and structure by trimethyltin in the guinea pig.

Trimethyltin (TMT) is a potent ototoxicant which acutely disrupts generation of the action potential evoked by a broad range of tone frequencies and subsequently produces selective high frequency impairment and outer hair cell (OHC) damage in the extreme basal turn of the cochlea. We investigated the development of TMT ototoxicity in the guinea pig 6-48 h following treatment using the compound action potential (CAP), cochlear microphonic (CM), endocochlear potential (EP) and light and electron microscopic examinations. At all time intervals studied, TMT reduced CAP sensitivity and CM amplitude. The effect was relatively broad across test frequencies at 6 h and subsequently became restricted to higher frequencies. No disruption of the EP was observed between 6 and 24 h following TMT. OHC pathology in the basal turn of the cochlea 12 h following TMT consisted of vacuolization in the supranuclear region and disruption of the cuticular plate; some mitochondria exhibited dark inclusions. Type 1 spiral ganglion cells appeared swollen at 24 h with separation of myelin from the cell bodies. No pathological changes were observed in the inner hair cells (IHC). The present data identify the OHC as targets responsible for the loss of CM sensitivity after TMT as the EP was unaffected. These data suggest that CAP and CM recovery at low and middle frequencies following acute TMT administration is accompanied by recovery of neurotransmission at the IHC or Type 1 SGC level and OHC recovery at apical regions of the cochlea.

Action Potentials↗
PubMed1991

Acute ototoxicity of trialkyltins in the guinea pig.

Two trialkyltin compounds, trimethyltin chloride (TMT) and triethyltin bromide (TET) were evaluated for their acute effects on cochlear function in pigmented guinea pigs. Compound action potential (CAP) thresholds and 1 microV RMS cochlear microphonic (CM) isopotential curves were generated for 25 subjects following ip injection of TMT (2 mg/kg), TET (12 or 24 mg/kg) or inert vehicle (0.9% saline or 15% ethanol). The CAP is generated by the release of neurotransmitters from the inner hair cells and the subsequent depolarization of spiral ganglion cells. However, the sensitivity of the CAP is influenced by other cochlear structures including the outer hair cells which are thought to influence sensitivity of the inner hair cells. By contrast, CM reflects electromechanical function of the outer hair cells. CAP function was severely disrupted by organotin exposure while CM was unaffected by these agents. TMT administration impaired CAP thresholds at all frequencies within 30 min of administration. Thresholds deteriorated slightly more between 30 and 60 min. TET also reduced the sensitivity of the CAP to all frequencies. At the lower dose moderate impairments of function were observed at 30 min which became more noticeable at 60 min. Following 24 mg/kg TET injection, CAP sensitivity was markedly impaired even at 30 min. The CM isopotential values were not significantly altered 30 min or 60 min after either TMT or TET treatment at any of the 11 frequencies tested. These data document far more rapid toxic effects of TMT and TET than have been seen in most intact neuronal systems. They indicate that both organotins initially disrupt the functional integrity of either inner hair cells or spiral ganglion cells within the cochlea such that depolarization occurs only following a significant increase in stimulus intensity.

Action Potentials↗
PubMed1991

Unusual morphology of the stria vascularis in pigmented strain 2/NCR guinea pigs.

This paper reports an abnormality in the morphology of the apical stria vascularis of inbred 2/NCR guinea pigs as compared to outbred animals. Cochleas were embedded in plastic, sectioned, and examined in the light and electron microscopes. In the 2/NCR animals, the apical stria vascularis consisted of a cuboidal epithelium composed of a monolayer of poorly differentiated cells. Few or no capillaries were associated with this epithelium. No melanin pigment was present in the abnormal region of the stria in these animals, although pigmentation appeared normal in lower turns of the cochlea. Measurements of compound action potential thresholds between 2 and 40 kHz revealed no differences in auditory function between the two strains.

Action Potentials↗
PubMed1990

Auditory dysfunction and cochlear vascular injury following trimethyltin exposure in the guinea pig.

Trimethyltin chloride (TMT) produces an auditory impairment in the rat due, presumably, to cochlear injury. The loss is unusual in that it persists for several weeks, but ultimately resolves at least at low to middle frequencies. Recovery of high frequency auditory loss is less predictable. Given this pattern of injury and recovery plus the known ability of TMT to impair oxidative phosphorylation, it was hypothesized that TMT would damage the stria vascularis which is the most metabolically active area and a structure containing one of the primary vascular networks in the cochlea. Trimethyltin chloride ototoxicity was evaluated in guinea pigs treated with the toxicant and then subjected to weekly tests of the auditory brainstem response evoked by tonal stimuli. A high frequency impairment was found which tended to improve within the first 2 weeks after exposure. Subjects were euthanized 6 weeks after TMT for histopathological study of the cochlea. At that time point most subjects showed full functional recovery. Subjects showed significant changes both in the number of outer hair cells and in the condition of the stria vascularis. Outer hair cell loss was observed in a restricted portion of the most basal turn of the cochlea which is responsible for encoding high frequency sound despite recovery of function in some animals. A very marked increase in the diameter of the vessels of the stria vascularis was observed along with signs of atrophy in the stria vascularis. Enlarged vessel diameters were particularly apparent in the apical and middle turns of the cochlea, which did not show significant hair cell loss. The data confirm that TMT does produce both hair cell damage and vascular pathology in the cochlea.

Animals↗
PubMed1989

Disruption of auditory function by acute administration of a "room odorizer" containing butyl nitrite in rats.

Butyl nitrite is the predominant and presumed active ingredient in a variety of commercial preparations sold as "room odorizers." These compounds have significant abuse potential, giving the user the sensation of a "rush", which may be related to their intense cardiovascular effects. The pharmacological properties of butyl nitrites are similar to those of amyl nitrite which is also abused for its psychological effects, but whose availability is limited by prescription for treatment of angina. A significant body of literature suggests that the inner ear is vulnerable to acute hypoxic exposure. Since butyl nitrite induces high levels of methemoglobin and also reduces blood pressure due to peripheral vasodilation, we hypothesized that this compound might produce auditory dysfunction. We studied the effect of acute exposure to a butyl nitrite "room odorizer" on 10- and 40-kHz auditory function in rats. A loss in auditory sensitivity was found at both frequencies on the day following administration of the compound. Auditory dysfunction tended to subside over the next several days at 40 kHz, although a significant loss of sensitivity for tones of 10 kHz was observed over a 6-day period after administration of the agent. Methemoglobin levels measured in rats of the same age were elevated significantly 30 and 60 min after butyl nitrite to levels of 30-45%. Methemoglobin levels were found to be normal 18 hr after administration when the first audiometric tests were conducted. The data suggest that auditory function in the middle of the rats' auditory range, 10 kHz, was disrupted for a longer period than was high-frequency (40 kHz) auditory function.

Air Pollutants↗
PubMed1988

Potentiation of noise induced threshold shifts and hair cell loss by carbon monoxide.

Previous studies have determined that severe systemic hypoxia disrupts cochlear function acutely, but have suggested that augmentation of cochlear perfusion may successfully protect cochlear function under all but the most profound hypoxic treatments. In the current study we report on the chronic effects of simultaneous exposures to noise and carbon monoxide on pure tone thresholds and hair cell survival in rats. Following initial threshold determination, rats received acute exposure to carbon monoxide, noise, or both agents concurrently. Thresholds were evaluated 2-4 and 6-8 weeks later. The data show that carbon monoxide alone does not affect either auditory thresholds or compromise hair cells at the light microscopic level. The noise exposure alone produced variable, but quite limited permanent threshold shifts which were related to the power spectrum of the broad band noise that was employed. Hair cell loss was restricted to the basal turn of the cochlea. Simultaneous exposure to carbon monoxide and noise induced large threshold shifts at all frequencies studied, but the effect was greatest at the highest test frequency; an effect not consistent with the noise power spectrum. Widespread hair cell loss persisted over fully half of the basilar membrane in the most severely affected rat. Outer hair cells appear to be particularly vulnerable. Carbon monoxide plus noise did not appear to preferentially disrupt a particular row of outer hair cells. These data complement existing evidence that hyperoxia can mitigate against noise induced injury and reinforce the view that some types of noise induced damage may result from metabolic insufficiencies.

Acoustic Stimulation↗
PubMed1988

Sensory threshold estimation from a continuously graded response produced by reflex modification audiometry.

This article describes the use of reflex modification to determine sensory detection thresholds. The method is based upon the finding that low-intensity sensory stimuli presented shortly before a reflex eliciting stimulus are able to modify the amplitude of the reflex. The extent of such modification is related to the intensity of the initial low-intensity stimulus. In contrast to earlier reported procedures for threshold estimation, the method described in this article consists of fitting a smooth function to the relationship between startle response amplitude and the intensity of the inhibiting stimulus. The method entails fitting a cubic spline function to the medians of the square-root reflex amplitude at each prestimulus intensity. The resulting audiometric curves closely approximate audiometric data obtained from traditional operant methods both in sensitivity and shape. Parametric data are also presented that allow for optimizing stimulus presentation so as to obtain reliable thresholds using a minimal number of test trials. The procedures developed in this article may prove useful in other situations involving the estimation of a threshold effect from a continuously graded response.

Animals↗
PubMed1987

Effects of carbon monoxide on cochlear electrophysiology and blood flow.

The belief that the cochlea is particularly vulnerable to a reduction in oxygen availability comes predominantly from studies reporting the disruption of electrophysiological measures, such as the compound action potential, endocochlear potential, inner hair cell intracellular potentials or afferent nerve fiber responses by asphyxiation. Because hypoxia has frequently been suggested as an underlying mechanism by which many ototoxic agents produce injury, and because such agents are not likely to completely disrupt oxygen delivery, we investigated the effects of graded hypoxia (using doses of carbon monoxide) on cochlear blood flow, the compound action potential (CAP) and the cochlear microphonic (CM). High doses of carbon monoxide injected intra-peritoneally yielded reversible loss of the CAP sensitivity for high frequency tone bursts, the extent of which was dose dependent. The loss was observed first at the highest frequency tested (50 kHz) and as carboxyhemoglobin levels increased, contiguous lower frequencies were influenced. Recovery progressed from low to high frequencies as carboxyhemoglobin levels declined. Carbon monoxide administration also produced a dose dependent elevation in the cochlear blood flow measured by a laser Doppler flow monitor. The data suggest that carbon monoxide administration disrupts cochlear function only under extremely severe exposure conditions. An elevation in cochlear blood flow may well serve as a protective mechanism which maintains cochlear function in the face of declining blood oxygen carrying capacity and delivery. While the site of action of carbon monoxide in the cochlea is uncertain, the data clearly indicate that elements involved in the generation of the CAP for high frequency tones are particularly vulnerable.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Carbon monoxide exposure potentiates high-frequency auditory threshold shifts induced by noise.

Hypoxia has long been hypothesized to play a role in noise-induced hearing loss, and the disruption of auditory function by asphyxiation has been repeatedly demonstrated. Recent data, however, suggest that the cochlea is resistant to less extreme hypoxic events. The current report describes the combined effects of noise and hypoxia on a measure of auditory function, in an effort to clarify the role of hypoxia in hearing loss. Exposure to 1200 parts per million of carbon monoxide in air for 90 min preceding and 120 min concurrent with exposure to a broad-band noise at 110 dBA produced high-frequency threshold shifts of greater magnitude than those produced by exposure to noise alone. An equivalent carbon monoxide exposure in a 'quiet' environment did not produce any change in auditory detection thresholds. The potentiation of noise-induced threshold shifts by carbon monoxide provides additional support for the hypothesized role of metabolic exhaustion or bloodflow impairment in noise-induced hearing loss. It also suggests a possible interpretation of clinical findings of auditory impairment associated with carbon monoxide exposure.

Animals↗
PubMed1987

Neurotoxicity of prenatal carbon monoxide exposure.

Despite the very wide recognition that carbon monoxide (CO) is a significant neurotoxicant, the level at which subtle effects occur, and the existence of sensitive periods in development for such toxicity, has been undetermined. In terms of risk to the fetus, a potentially susceptible sub-population, there is concern, first, that the level of exposure at which neurotoxicity occurs may be different from the adult, and second, that the site of toxic action and subsequent neurotoxic effects of CO may be different in the immature and mature brain. The investigator studied the susceptibility of the developing brain to moderate levels of CO maintained chronically through the period of neuronal proliferation, and into the period of synapse formation. Carbon monoxide may be thought of as both a prototypical hypoxic agent, and a significant public health hazard in its own right. Carbon monoxide is a ubiquitous toxic agent that accounts for large numbers of deaths and significant morbidity in human populations. Subtle neurotoxic effects of this agent may be even more common, but they may go largely undetected, or fail to be associated with CO exposure. We have shown that prenatal CO exposure at moderate levels can produce significant neurotoxic effects in rats. The data obtained from the cerebellum and neostriatum, in particular, suggest that chronic, moderate perinatal CO exposure may disrupt neuronal proliferation and, perhaps, may disrupt certain markers for neurochemical transmission.

Animals↗
PubMed1986

Trimethyltin exposure produces an unusual form of toxic auditory damage in rats.

A single injection of trimethyltin chloride (TMT; 2, 4, or 6 mg/kg) is shown to produce a frequency-specific, dose-dependent auditory impairment, as well as to decrease the amplitude of the acoustically elicited startle response, in exposed rats. This finding stands in contrast to data presented earlier on the effects of triethyltin bromide (TET), which produces changes in startle response without affecting auditory acuity. Animals intoxicated with TMT at moderate doses appear to recover their auditory acuity over the course of several weeks. This slow recovery of auditory function, which is uncharacteristic for chemical ototoxicity, suggests that TMT may be a useful model agent for studying ototoxic mechanisms.

Acoustic Stimulation↗
PubMed1986

Trimethyltin ototoxicity: evidence for a cochlear site of injury.

The environmental contaminant, trimethyltin (TMT), produces a profound elevation in tone intensity necessary to inhibit the acoustic startle reflex in laboratory animals which recovers over a prolonged period except at very high frequencies. The recovery that is observed does not begin until 3 to 5 weeks after a single acute administration depending upon dosage. As opposed to the very temporary threshold shifts by the salicylates and loop diuretics or the permanent and progressive ototoxicity resulting from aminoglycoside antibiotics the time course for recovery of acoustic startle reflex inhibition after TMT appears to be an anomaly for a chemical ototoxicant. In terms of the duration of loss only, this pattern appears similar to that sometimes observed after noise exposure. The current investigation replicates the finding that recovery of acoustic startle reflex inhibition after TMT is frequency related in that only the highest frequency impairment appears to be permanent. While this frequency dependence suggests a cochlear locus of injury, both the known neurotoxic effects of TMT and the time course of the behavioral impairment suggest a more central locus of injury. Compound action potential and cochlear microphonic recordings made from the round window in the current study confirm a preferential high frequency effect of TMT and demonstrate a significant cochlear component to the ototoxic effects of this agent.

Action Potentials↗
PubMed1986

Postnatal alterations in cerebellar GABA content, GABA uptake and morphology following exposure to carbon monoxide early in development.

Rats were exposed to either 0, 75, 150 or 300 ppm carbon monoxide (CO) from the day of conception until 10 days after birth. Exposure to CO resulted in significant deficits in cerebellar weight and deficits in total cerebellar content of gamma-aminobutyric acid (GABA) among rats at 10 days and 21 days after birth. Total cerebellar high-affinity 3H-GABA uptake was decreased among rats exposed to 300 ppm at 21 days of age, while total high-affinity 3H-glutamate uptake was unaffected. Moreover, cerebella of rats exposed to 300 ppm had fewer fissures, although major fissures were of normal depth, when examined histologically at 21 days of age. These results identify developmental processes involving GABAergic neuronal maturation and foliation of the cerebellum as vulnerable to early CO exposure.

Animals↗
PubMed1985

Moderate prenatal carbon monoxide exposure produces persistent, and apparently permanent, memory deficits in rats.

The effects of moderate (150 +/- 2 ppm) prenatal carbon monoxide (CO) exposure (maternal HbCO concentrations of 15.6 +/- 1.1%) on learning and memory were assessed in young and aged adult rats using a two-way active avoidance paradigm. In experiment 1, the prenatal CO-exposed rats at 120 days of age acquired a conditioned avoidance response equally well as control animals in a 100-trial session. However, following a 24-hr interval the CO-exposed rats failed to demonstrate significant retention of the task as indicated by the absence of significant improvement in performance over the indicated by the absence of significant improvement in performance over the previous day; control subjects did show significant retention. In experiment 2, in which 120-day-old animals received 50 training trials per day until a criterion of ten consecutive avoidance responses was met, the prenatal CO-exposed subjects again acquired the task as well as control animals. When tested for retention 28 days later, a significant memory impairment was again observed in terms of trials required to reattain the avoidance criterion as well as in total percent avoidance responding. In neither experiment did an analysis of initial or average latency to escape the footshock stimulus reveal any significant alterations. These latter results suggest that the observed performance impairment reflected a memory deficit and not a disruption of sensory, motor, or motivational factors. In experiment 3, prenatal CO-exposed rats approximately 1 year of age (300-360 days of age) showed impairment relative to air-exposed controls in both the original learning and retention of the two-way avoidance response. Again, however, there was no evidence for alterations in performance factors per se. Collectively these data indicate that while young adult rats prenatally exposed to 150 ppm CO demonstrate an associative deficit restricted to memory impairment, aged adults similarly exposed during the prenatal period display a more pronounced deficit similar to that recently reported for animals tested as juveniles. The importance of parametric manipulations in uncovering long-term toxicity is also discussed.

Aging↗
PubMed1985

Brain manganese, catecholamine turnover, and the development of startle in rats prenatally exposed to manganese.

Manganese (Mn) can be neurotoxic when present in high concentrations. Neonatal animals show differential absorption, accumulation, and excretion of Mn relative to adults. If similar kinetic differences exist during gestation, then fetal animals may be susceptible to Mn neurotoxicity. The objective of this study was to examine maternal-fetal Mn transfer and the susceptibility of prenatal animals to Mn neurotoxicity. This was approached by studying the ability of Mn to cross the placenta and reach the fetal central nervous system using radiotracer and atomic absorption spectroscopy techniques. Manganese is thought to disrupt catecholamine neurotransmission in the central nervous system. This was examined in newborn rats by alpha-methyl-para-tyrosine induced catecholamine turnover and the development of the acoustic startle response. The results suggest that there are limits on fetal Mn accumulation under conditions of both normal and excessive dietary Mn levels. Manganese accumulation in the fetal brain after exposure to increased dietary Mn does not alter either dopamine or norepinephrine turnover or the development of the acoustic startle response. Excess Mn does not appear to be neurotoxic to fetal rats in spite of its limited accumulation in nervous tissue after gestational exposure.

Acoustic Stimulation↗