Biomedical subjects

Laurence D Fechter

Publications and source records attributed to Laurence D Fechter.

9 recordsLinked to original sources

PubMed2005

Acrylonitrile potentiates hearing loss and cochlear damage induced by moderate noise exposure in rats.

The diversity of chemical and drugs that can potentiate noise-induced hearing loss (NIHL) has impeded efforts to predict such interactions. We have hypothesized that chemical contaminants that disrupt intrinsic antioxidant defenses hold significant risk for potentiating NIHL. If this is true, then acrylonitrile (ACN) would be expected to potentiate NIHL. ACN, one of the 50 most commonly used chemicals in the United States, is metabolized via two pathways that are likely to disrupt intrinsic reactive oxygen species (ROS) buffering systems: (1) it conjugates glutathione, depleting this important antioxidant rapidly; (2) a second pathway involves the formation of cyanide, which can inhibit superoxide dismutase. We hypothesized that moderate noise exposure, that does not produce permanent hearing loss by itself, could initiate oxidative stress and that ACN could render the inner ear more sensitive to noise by disrupting intrinsic antioxidant defenses. Temporary and persistent effects of ACN alone (50 mg/kg, sc 5 days), noise alone (95 or 97 dB octave band noise, 4 h/day for 5 days), or ACN in combination with noise were determined using distortion product otoacoustic emissions (DPOAEs) and compound action potential (CAP) amplitudes. Histopathological damage to hair cells resulting from these treatments was also investigated using surface preparations of the organ of Corti. Individually, neither ACN nor noise exposures caused any permanent hearing or hair cell loss; only a reversible temporary threshold shift was measured in noise-exposed animals. However, when given in combination, ACN and noise induced permanent threshold shifts (13-16 dB between 7 and 40 kHz) and a decrease in DPOAE amplitudes (up to 25 dB at 19 kHz), as well as significant outer hair cell (OHC) loss (up to 20% in the first row between 13 and 47 kHz). This investigation demonstrates that ACN can potentiate NIHL at noise levels that are realistic in terms of human exposure, and that the OHCs are the main target of toxicity. While the exact mechanism is unknown, the results are consistent with the hypothesis of ROS involvement in NIHL at moderate levels.

Acrylonitrile↗

PubMed2005

Ototoxicity.

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Environmental Exposure↗

PubMed2004

JP-8 jet fuel exposure induces inflammatory cytokines in rat skin.

The Department of Defense (DoD) has identified that one of the main complaints of personnel exposed to JP-8 jet fuel is irritant dermatitis. The purpose of this investigation is to describe the JP-8-induced inflammatory cytokine response in skin. JP-8 jet fuel or acetone control (300 microl) was applied to the denuded skin of rats once a day for 7 days. Skin samples from the exposed area were collected 2 and 24 h after the final exposure. Histological examination of skin biopsies showed neutrophilic inflammatory infiltrate. Reverse transcription-polymerase chain reaction (RT-PCR) was performed utilizing skin total RNA to examine the expression of various inflammatory cytokines. The CXC chemokine GROalpha was significantly upregulated at both time points, whereas GRObeta was only increased 2 h post final exposure. The CC chemokines MCP-1, Mip-1alpha, and eotaxin were induced at both time points, whereas Mip-1beta was induced only 24 h post exposure. Interleukins-1beta and -6 (IL-1beta and IL-6) mRNAs were significantly induced at both time points, while TNFalpha was not significantly different from control. Enzyme-linked immunosorbent assay (ELISA) of skin protein confirmed that MCP-1, TNFalpha, and IL-1beta were modulated as indicated by PCR analysis. However, skin IL-6 protein content was not increased 2 h post exposure, whereas it was significantly upregulated by jet fuel after 24 h. Data from the present study indicate that repeated (7 days) JP-8 exposure induces numerous proinflammatory cytokines in skin. The increased expression of these cytokines and chemokines may lead to increased inflammatory infiltrate in exposed skin, resulting in JP-8-induced irritant dermatitis.

Animals↗

PubMed2003

Acrylonitrile potentiates noise-induced hearing loss in rat.

Acrylonitrile, one of the 50 most commonly produced industrial chemicals, has recently been identified as a promoter of noise-induced hearing loss (NIHL). This agent has the potential to produce oxidative stress through multiple pathways. We hypothesize that acrylonitrile potentiates NIHL as a consequence of oxidative stress. The objectives of this study were to characterize acrylonitrile exposure conditions that promote permanent NIHL in rats and determine the ability of this nitrile to produce auditory dysfunction by itself. Additionally, we sought to determine whether a spin-trap agent that can form adducts with ROS would protect against the effects of acrylonitrile. Acrylonitrile administration produced significant elevation in NIHL detected as a loss in compound action potential sensitivity. The effect was particularly robust for high-frequency tones and particularly when acrylonitrile and noise were given on repeated occasions. Acrylonitrile by itself did not disrupt threshold sensitivity. Administration of the spin-trap agent phenyl- N- tert-butylnitrone (PBN), given to rats prior to acrylonitrile and noise, did block the elevation of NIHL by acrylonitrile. However, PBN at the dose and time interval given was ineffective in protecting auditory function in subjects exposed to noise alone. The results suggest that oxidative stress may play a role in the promotion of NIHL by acrylonitrile.

Acrylonitrile↗

PubMed2003

Acrylonitrile produces transient cochlear function loss and potentiates permanent noise-induced hearing loss.

There is growing evidence that agents that produce oxidative stress in the cochlea have significant ototoxic potential by themselves and can potentiate noise-induced hearing loss as well. Acrylonitrile (ACN) metabolism entails conjugation with glutathione, resulting in rapid and pronounced depletion of this important antioxidant in many organs including brain, liver, and kidney. ACN metabolism also results in cyanide (CN) formation through a secondary oxidative pathway. The results of two physiological experiments are reported here. First, the acute effects of ACN (50 mg/kg sc) on auditory sensitivity are assessed using a within subject study. In the second study, persistent effects of ACN alone (50 mg/kg, sc and 2 x 50 mg/kg, sc) and ACN in combination with noise exposure (8 h, 108 dB octave-band noise) are evaluated using threshold sensitivity as the dependent measure. Auditory threshold shift and absolute thresholds were determined using the compound action potential (CAP) amplitude. Acute ACN administration produces a loss in auditory threshold sensitivity that reached a maximum 10-20 min following sc injection. Auditory thresholds returned to control levels 75-100 min following exposure. In the study of permanent auditory threshold shifts, ACN plus noise increased auditory threshold impairment relative to rats receiving noise only when thresholds were assessed 3 weeks following exposure. ACN by itself did not produce permanent threshold impairment 3 weeks following administration. Assays were undertaken in separate groups of rats to track the elevation in blood CN and the depletion of total glutathione in cochlea, brain, and liver following ACN treatment. Systemic blood CN levels were not significantly elevated until 60-120 min following injection, and cochlear glutathione levels showed significant depletion as little as 15 min after injection and remained depressed for about 4 h. The results confirm the prediction that ACN is acutely ototoxic and can enhance noise-induced hearing loss.

Acrylonitrile↗

PubMed2003

The relationship between noise-induced hearing loss and hair cell loss in rats.

Noise-induced hearing loss (NIHL) and hair cell loss are known to show only a moderate correlation. One reason for this is that NIHL may reflect not only the sum of dead hair cells, but also the sum of impaired but still living hair cells. This report compares hair cell loss in different cochlear regions in rats with noise-induced compound action potential (CAP) threshold elevation at corresponding frequencies. CAP threshold elevation and hair cell loss were determined 4 weeks after noise exposure. In the apical turn (<35% from the apex) there was no hair cell loss even when a 60 dB CAP threshold elevation was induced. In the region of 40-60% from the apex in the middle turn, significant hair cell loss was not observed until CAP threshold elevation exceeded about 40-50 dB. This critical level decreased towards the basal turn. In the basal turn, outer hair cell (OHC) loss was observed in almost all of the noise-exposed rats, even in some cases without detectable NIHL, but inner hair cell (IHC) loss was still not observed until 50 dB threshold elevation. In the region of 75-90% from the apex related to the highest frequencies tested in this study (30-40 kHz), a linear NIHL/OHC loss relationship was observed. The results of this paper suggest that the high frequency hair cells in rat cochlea may die relatively rapidly after injury, leading to a linear relation between NIHL and hair cell loss, but that the low frequency hair cells may survive without auditory function.

Acoustic Stimulation↗

PubMed2002

The relationship of particle size to olfactory nerve uptake of a non-soluble form of manganese into brain.

The essential element, manganese, can produce chronic neuromotor impairment related to basal ganglia (BG) damage when it is presented in excessive quantities. The uptake and elimination patterns of manganese following ingestion have been well studied and, under normal conditions, excretion appears to keep manganese levels under tight control. Less is known about inhalation exposure, but it has been proposed that the lung might serve as a long-term reservoir for manganese transport into blood. Recent data suggest that a third route of exposure, transport by the olfactory nerve directly to the brain, might have importance in toxicology since such a route would bypass liver uptake and biliary excretion of manganese. In this study, we sought to determine how particle size and the use of a poorly soluble form of manganese might influence net systemic absorption of manganese dust and the potential role of the olfactory nerve in transport of manganese dioxide. Rats were exposed in nose-only exposure chambers to manganese dioxide (MnO2) aerosols of 1.3 and 18 microm mass median aerodynamic diameter (MMAD). The concentration of aerosols was kept constant at 3 mg/m3 as Mn. Following 15 days of exposure (five times per week for 3 weeks), rats were euthanized and tissues harvested for manganese determination carried out by graphite furnace atomic absorption spectroscopy. Small-particle MnO2 exposure resulted in an elevation in olfactory bulb manganese concentration, presumably through uptake by the olfactory nerve, but the effect was highly variable. While small increases in cortical and neostriatal manganese levels were also observed in these rats, they did not reach statistical significance. By contrast, there was no evidence of olfactory nerve MnO2 uptake in rats receiving the large-particle exposure.

Administration, Inhalation↗

PubMed2002

Potentiation of noise-induced hearing loss by low concentrations of hydrogen cyanide in rats.

Noise-induced hearing loss is the most prevalent occupational injury in the United States despite the adoption of clear permissible exposure limits and protocols for hearing conservation. This study identifies low-level chemical asphyxiant exposure as a risk factor capable of potentiating noise-induced hearing loss. Rats were exposed to 10, 30, and 50 ppm hydrogen cyanide (HCN) alone for 3.5 h (n = 28) or in combination with 2 h octave band noise exposure (100 dB(lin); n = 28). Additional groups received noise exposure alone (n = 16) and no treatment other than placement in an inhalation chamber with clean air and quiet (n = 16). Pure tone compound action potential (CAP) thresholds were determined 4 weeks following the exposure in order to assess pure tone auditory sensitivity and permanent threshold impairment. Cochleae from an additional 13 subjects were processed for light microscopy to permit assessment of hair cell loss. The results demonstrate that the noise exposure alone impaired CAP threshold by about 10 dB, averaged between 12-40 kHz, and produced a 5% loss of outer hair cells at the base of the cochlea, but no inner hair cell loss. The combined exposure to noise and HCN caused a cyanide dose-dependent CAP threshold impairment that exceeds the noise exposure alone. This effect reached statistical significance at a HCN level of 30 ppm. Combined exposure also produced more outer hair cell loss than noise alone. HCN alone did not cause significant hearing loss or hair cell loss. A risk assessment analysis was conducted for the auditory threshold data using benchmark dose software published by the U. S. EPA (BMDS version 1.3). A continuous model showed that the data could be described by a linear function. For a benchmark response corresponding to a 5 dB increase in auditory threshold above the effect of noise alone, the lower bound on the 95% confidence interval for the benchmark dose was 9 ppm. The benchmark dose that impaired auditory threshold 10% above the effect of noise alone had a lower bound of 2 ppm. The lower bound to the HCN dose that produced a 1 SD elevation in noise-induced hearing loss was 16 ppm. These exposure levels provide a range of concentrations below to slightly above the short-term exposure limit for HCN. However, if these levels are adjusted for an 8 h time-weighted average (TWA), the resulting levels are below the permissible exposure level (PEL) for HCN.

Animals↗

PubMedDate not supplied

Promotion of noise-induced hearing loss by chemical contaminants.

Recent studies have underscored the ability of a wide range of chemical agents to potentate noise-induced hearing loss. Given the ubiquitous nature of noise exposure particularly in many work settings, the high rate of noise-induced hearing loss, the limited degree to which auditory function can recover following damage to the inner ear, and the disparate chemical structures that appear capable of impairing hearing, this issue appears to have great public health significance. A compendium of chemicals known to potentiate noise induced hearing loss is presented along with a hypothesis that might explain at least one basis for potentiation of noise-induced hearing loss by certain chemical toxicants. The use of benchmark dose analysis to undertake a risk assessment for promotion of noise-induced hearing loss by both carbon monoxide and hydrogen cyanide is described.

Auditory Threshold↗