Quantitative acoustic contrast tomography reveals unique multiscale physical fluctuations during aflatoxin synthesis in Aspergillus parasiticus.

Fungal pathogens need regulated mechanical and morphological fine-tuning for pushing through substrates to meet their metabolic and functional needs. Currently very little is understood on how coordinated colony level morphomechanical modifications regulate their behavior. This is due to an absence of a method that can simultaneously map, quantify, and correlate global fluctuations in physical properties of the expanding fungal colonies. Here, we show that three-dimensional ultrasonic reflections upon decoding can render acoustic contrast tomographs that contain information on material property and morphology in the same time scale of one important phytopathogen, Aspergillus parasiticus, at multiple length scales. By quantitative analysis of the changes in acoustic signatures collected as the A. parasiticus colony expands with time, we further demonstrate that the pathogen displays unique acoustic signatures during synthesis and release of its hepatocarcinogenic secondary metabolite, aflatoxin, suggesting an involvement of a multiscale morphomechanical reorganization of the colony in this process. Our studies illustrate for the first time, the feasibility of generating in any invading cell population, four-dimensional maps of global physical properties, with minimal physical perturbation of the specimens. Our developed method that we term quantitative acoustic contrast tomography (Q-ACT), provides a novel diagnostic framework for the identification of in-cell molecular factors and discovery of small molecules that may modulate pathogen invasion in a host.

An electrophysiological investigation of the effects of social rejection on self control.

Previous studies have shown that social rejection leads to impaired performance on a variety of tasks that require self control, including the Stroop color-word interference task; however, mechanisms underlying the effect remain to be elucidated. We attempted to clarify the effects of social rejection on self control resources by measuring event-related potentials (ERPs) during a computerized Stroop test. Stroop performance and ERPs from 54 participants in rejected, control, and accepted groups were analyzed. A significant difference in the pattern of results for the N450 ERP was found, with rejected participants showing less negativity on incongruent trials and more on congruent trials compared to accepted participants and controls. The results suggest social rejection reduces the engagement of cognitive control mechanisms, and are more consistent with a limited strength resource model than with limited capacity resource models that focus on limitations in attention.

Comparing Perika St. John's Wort and Sertraline for Treatment of Posttraumatic Stress Disorder in Mice.

Posttraumatic stress disorder (PTSD) is a serious mental health condition that affects some individuals who have witnessed or experienced a life-threatening or traumatic event. An enhanced or exaggerated acoustic startle response (ASR), reflecting heightened sensitivity to unexpected, loud sound, is a hallmark symptom of PTSD. Antidepressant medications, such as sertraline, are first-line pharmacotherapeutic agents in the treatment of PTSD, but concerns about potential side effects or taking synthetic drugs prompt discovery of naturalistic therapeutic agents. This study examined the relative effectiveness of a compound containing St. John's Wort (SJW), an herb widely prescribed for depression in Europe and sold as a dietary supplement in the United States, compared to sertraline (Zoloft) in a mouse model of PTSD. Thirty-six mice were tested for baseline ASR, then they were exposed to rats in a predator exposure paradigm known to induce PTSD-like symptoms. Mice were randomly divided into three groups for treatment (control, sertraline, SJW), and ASR was retested one week later. One-way ANOVAs found no significant group differences in ASR amplitude at baseline but a significant effect of Treatment Group after predator exposure, F(2, 33) = 5.645, p = .008, n2 = .225, when SJW-treated mice had ASR amplitudes that were significantly lower than sertraline-treated mice (by 27%) and controls (by 26%). Fecal boli counts showed a similar pattern, with lowest counts in SJW-treated mice. These results suggest SJW could be considered for studies of PTSD treatment in humans as well.

Activation of Aflatoxin Biosynthesis Alleviates Total ROS in Aspergillus parasiticus.

An aspect of mycotoxin biosynthesis that remains unclear is its relationship with the cellular management of reactive oxygen species (ROS). Here we conduct a comparative study of the total ROS production in the wild-type strain (SU-1) of the plant pathogen and aflatoxin producer, Aspergillus parasiticus, and its mutant strain, AFS10, in which the aflatoxin biosynthesis pathway is blocked by disruption of its pathway regulator, aflR. We show that SU-1 demonstrates a significantly faster decrease in total ROS than AFS10 between 24 h to 48 h, a time window within which aflatoxin synthesis is activated and reaches peak levels in SU-1. The impact of aflatoxin synthesis in alleviation of ROS correlated well with the transcriptional activation of five superoxide dismutases (SOD), a group of enzymes that protect cells from elevated levels of a class of ROS, the superoxide radicals (O2-). Finally, we show that aflatoxin supplementation to AFS10 growth medium results in a significant reduction of total ROS only in 24 h cultures, without resulting in significant changes in SOD gene expression. Our findings show that the activation of aflatoxin biosynthesis in A. parasiticus alleviates ROS generation, which in turn, can be both aflR dependent and aflatoxin dependent.

Electrophysiological correlates of progressive sensorineural pathology in carboplatin-treated chinchillas.

Carboplatin produces progressive damage to auditory nerve fibers, spiral ganglion neurons (SGNs) and inner hair cells (IHC) in the chinchilla cochlea but leaves outer hair cells intact. Within 1 h after injection, many afferent terminals beneath IHCs and myelin lamellae surrounding SGN processes are vacuolated. One day after injection, approximately half of the nerve fibers are missing. IHCs are intact at 2 days, but 20-30% are missing at 3 days. We studied the electrophysiological correlates of this progressive morphological damage by recording cochlear microphonics (CM), distortion product otoacoustic emissions (DPOAE), summating potentials (SP), compound action potentials (CAP) and midbrain evoked potentials (IC-EVP) before and 1 h, 12 h, 1 days, 3 days, 5 days, 7 days and 14 days after carboplatin injection (75 mg/kg IP) in four chinchillas. CM and DPOAEs tended to be unchanged or enhanced. CAP and SP showed little change until Day 3, when amplitudes were reduced in all animals and CAP thresholds were elevated by 9 dB; amplitudes declined further between Days 3 and 5 but not thereafter. IC-EVP amplitudes decreased on Days 3 or 5 but thresholds were relatively unchanged. All animals showed some recovery of IC-EVP between Days 7 and 14, including one with 70% enhancement on Day 14. The results indicate that threshold and amplitude measures fail to detect peripheral pathology until some relatively high threshold level of damage has been exceeded. This has important implications for monitoring peripheral damage and interpreting electrophysiological test results in animals and humans.

Disgusted but not afraid: Feelings toward same-sex kissing reveal subtle homonegativity.

Overt sexual prejudice is declining, but heterosexuals who report little to no prejudice may still harbor subtle biases against gay men and lesbians. We examined implicit prejudice in a sample of 37 heterosexual college students who reported little or no sexual prejudice, using the Affect Misattribution Procedure (AMP) and psychophysiological measures of affect. Skin conductance, heart rate, and facial electromyographic responses were recorded as participants viewed photos of mixed- and same-sex couples kissing and rated them on valence, arousal, and disgustingness. Sexual prejudice was evident in implicit (AMP) ratings and explicit ratings of valence and disgustingness, but not in psychophysiological responses. Results suggest that implicit prejudice harbored by young adults who endorse low levels of sexual prejudice is more cognitively than emotionally based, unlike the fear-based reactions commonly described for racism. Limitations and future directions for research are discussed.

Multi-institutional Analysis Shows that Low PCAT-14 Expression Associates with Poor Outcomes in Prostate Cancer.

BACKGROUND: Long noncoding RNAs (lncRNAs) are an emerging class of relatively underexplored oncogenic molecules with biological and clinical significance. Current inadequacies for stratifying patients with aggressive disease presents a strong rationale to systematically identify lncRNAs as clinical predictors in localized prostate cancer. OBJECTIVE: To identify RNA biomarkers associated with aggressive prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Radical prostatectomy microarray and clinical data was obtained from 910 patients in three published institutional cohorts: Mayo Clinic I (N=545, median follow-up 13.8 yr), Mayo Clinic II (N=235, median follow-up 6.7 yr), and Thomas Jefferson University (N=130, median follow-up 9.6 yr). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary clinical endpoint was distant metastasis-free survival. Secondary endpoints include prostate cancer-specific survival and overall survival. Univariate and multivariate Cox regression were used to evaluate the association of lncRNA expression and these endpoints. RESULTS AND LIMITATIONS: An integrative analysis revealed Prostate Cancer Associated Transcript-14 (PCAT-14) as the most prevalent lncRNA that is aberrantly expressed in prostate cancer patients. Down-regulation of PCAT-14 expression significantly associated with Gleason score and a greater probability of metastatic progression, overall survival, and prostate cancer-specific mortality across multiple independent datasets and ethnicities. Low PCAT-14 expression was implicated with genes involved in biological processes promoting aggressive disease. In-vitro analysis confirmed that low PCAT-14 expression increased migration while overexpressing PCAT-14 reduced cellular growth, migration, and invasion. CONCLUSIONS: We discovered that androgen-regulated PCAT-14 is overexpressed in prostate cancer, suppresses invasive phenotypes, and lower expression is significantly prognostic for multiple clinical endpoints supporting its significance for predicting metastatic disease that could be used to improve patient management. PATIENT SUMMARY: We discovered that aberrant prostate cancer associated transcript-14 expression during prostate cancer progression is prevalent across cancer patients. Prostate cancer associated transcript-14 is also prognostic for metastatic disease and survival highlighting its importance for stratifying patients that could benefit from treatment intensification.

Auditory processing disorder in children diagnosed with nonverbal learning disability.

PURPOSE: To determine whether children with a nonverbal learning disability (NVLD) have a higher incidence of auditory processing disorder (APD), especially in the tolerance-fading memory type of APD, and what associations could be found between performance on neuropsychological, intellectual, memory, and academic measures and APD. METHOD: Eighteen children with NVLD ranging in age from 6 to 18 years received a central auditory processing test battery to determine incidence and subtype of APD. Psychological measures for assessment of NVLD included the Wechsler Scales, Wide Range Assessment of Memory and Learning, and Wechsler Individual Achievement Test. Neuropsychological measures included the Category Test, Trails A and B, the Tactual Performance Test, Grooved Pegs, and the Speech Sounds Perception Test. Neuropsychological test scores of the NVLD+APD and NVLD groups were compared using analysis of covariance procedures, with Verbal IQ and Performance IQ as covariates. RESULTS: Sixty-one percent of the children were diagnosed with APD, primarily in the tolerance-fading memory subtype. The group of children with APD and NVLD had significantly lower scores on Verbal IQ, Digit Span, Sentence Memory, Block Design, and Speech Sounds Perception than children without APD. An ancillary finding was that the incidence of attention deficit/hyperactivity disorder was significantly higher in children with NVLD (with and without APD) than in the general population. CONCLUSION: The results indicate that children with NVLD are at risk for APD and that there are several indicators on neuropsychological assessment suggestive of APD. Collaborative, interdisciplinary evaluation of children with learning disorders is needed in order to provide effective therapeutic interventions.

Ameliorative effects of exposing DBA/2J mice to an augmented acoustic environment on histological changes in the cochlea and anteroventral cochlear nucleus.

DBA/2J (D2) mice, which exhibit very early progressive sensorineural hearing loss, were treated nightly with an augmented acoustic environment (AAE) initiated before the onset of hearing, and consisting of repetitive bursts of a 70-dB sound pressure level (SPL), 4-25 kHz noise band. At 55 days of age, AAE-treated mice exhibited less elevation of auditory brainstem response thresholds, fewer missing hair cells, and greatly reduced loss of anteroventral cochlear nucleus (AVCN) volume and neuron number compared to untreated control mice. It was hypothesized that the central neuroprotective effect was associated with increased afferent input to AVCN neurons evoked by the AAE as well as a healthier cochlea.

Dietary vitamin C supplementation reduces noise-induced hearing loss in guinea pigs.

Vitamin C (ascorbate) is a water-soluble, low molecular weight antioxidant that works in conjunction with glutathione and other cellular antioxidants, and is effective against a variety of reactive oxygen species, including superoxide and hydroxyl radicals that have been implicated in the etiology of noise-induced hearing loss (NIHL). Whereas most animals can manufacture their own vitamin C, humans and a few other mammals such as guinea pigs lack the terminal enzyme for vitamin C synthesis and must obtain it from dietary sources. To determine if susceptibility to NIHL could be influenced by manipulating dietary levels of vitamin C, albino guinea pigs were raised for 35 days on a diet with normal, supplemented or deficient levels of ascorbate, then exposed to 4 kHz octave band noise at 114 dB SPL for 6 h to induce permanent threshold shifts (PTS) of the scalp-recorded auditory brainstem response. Animals that received the highest levels of dietary ascorbate developed significantly less PTS for click stimuli and 4, 8, 12, and 16 kHz tones than animals on normal and deficient diets. Outer hair cell loss was minimal in all groups after noise exposure, but permanent damage to stereocilia were observed in noise-exposed ears. The results support the hypothesis that dietary factors influence individual susceptibility to hearing loss, and suggest that high levels of vitamin C may be beneficial in reducing susceptibility to NIHL.

Thyroparathyroidectomy procedures and thyroxine levels in the chinchilla.

Thyroid and embedded parathyroid glands were surgically removed (thyroparathyroidectomized) from adult chinchillas (Chinchilla laniger) to create an animal model of hypothyroidism. Thyroxine (T4) levels were measured at the time of surgery and one or two times after surgery from 10 thyroparathyroidectomized chinchillas and five sham controls to establish baseline serum T4 levels and to assess the degree and duration of hypothyroidism in this animal model. Baseline T4 levels ranged from 3.4 to 6.4 microg/dl (mean +/- 1 standard deviation, 5.25 +/- 0.84 microg/dl), with no differences between male and female chinchillas (5.4 +/- 0.6 microg/dl versus 5.2 +/- 1.0 microg/dl, respectively). T4 levels were significantly reduced in 80% of thyroparathyroidectomized chinchillas when measured 6 to 14 days after surgery, but reductions were variable, ranging from 9 to 89% in individual animals. There was rapid regrowth of thyroid tissue and a return of T4 levels to the baseline range in five of the seven animals followed for 1 to 2 months after surgery. T4 levels increased significantly in the sham-operated chinchillas, indicating a nonspecific effect of surgery. The results establish surgical procedures for creating a model of variable, transient hypothyroidism in the chinchilla. We also summarize published basal T4 values for various laboratory animals, to provide a convenient reference.

Calpain immunoreactivity and morphological damage in chinchilla inner ears after carboplatin.

Carboplatin produces an unusual pattern of damage in the chinchilla inner ear, characterized by early destruction of type I afferent fibers and preferential loss of type I hair cells in the vestibular end organs and inner hair cells (IHCs) in the cochlea. In the present study, we investigated a potential role of calpains, a family of calcium-activated proteases, in carboplatin ototoxicity. Chinchillas received carboplatin (100 mg/kg IP) and were sacrificed 12, 24, 48, or 72 h later for morphological evaluation or immunocytochemistry. Nerve fibers and myelin were the initial sites of increased calpain immunoreactivity (IR) and morphological damage. At 12 h, granular immunoreactive puncta were present within nerve fibers and their myelin sheaths in the spiral ganglion. In the habenula perforata, dense reaction product was present in large vacuoles in the myelin surrounding the nerve fibers. At 24 h, nerve fibers and myelin were destroyed in the habenula, and those in the spiral ganglion showed increased calpain IR and morphological damage. At 72 h, nerve fibers and myelin were completely destroyed. Calpain IR was not a prominent feature of IHCs, type I vestibular hair cells, or ganglion cells at any time after carboplatin. The results show a correlation between calpain IR and carboplatin-induced axon and myelin degeneration. We propose that calpain-induced axonopathy and myelinopathy are primary features of carboplatin ototoxicity in chinchilla.

Time course of efferent fiber and spiral ganglion cell degeneration following complete hair cell loss in the chinchilla.

Ethacrynic acid (EA) is known to interact with aminoglycoside antibiotics such as gentamicin (GM). In the chinchilla, co-administration of GM and EA can produce hair cell lesions ranging from a small loss of outer hair cells (OHCs) in the base of the cochlea to complete destruction of all hair cells, depending on dosing parameters. Although hair cell loss has been characterized, little is known about the fate of efferent fibers or spiral ganglion neurons (SGNs) in this model. To study the time course of efferent fiber and SGN loss, chinchillas were injected with GM (125 mg/kg IM) followed immediately by EA (40 mg/kg IV). Estimates of efferent fiber loss and density changes were made after 3 days or 1, 2, 3, or 4 weeks of survival. Estimates of SGN loss and density changes were made after 15 days or 1, 2, 4, or 6 months of survival. Cochlear function was rapidly abolished and all cochlear hair cells were missing within 24 h after treatment. Inner hair cells (IHCs) in the middle turn of the cochlea died earlier than cells in the apex or base, and OHCs in Rows 1 and 2 died earlier than OHCs in Row 3. Degeneration of efferent nerve fibers began 3-7 days post-injection, versus 15-30 days for SGNs, and the loss of efferent fibers was essentially complete within 1 month, versus 2-4 months for SGNs. The rapid time course of efferent fiber and SGN loss in the chinchilla may make it a practical model for studying mechanisms of neural loss and survival in the mammalian inner ear.

Gamma-aminobutyric acid circuits shape response properties of auditory cortex neurons.

Neurons containing gamma aminobutyric acid (GABA) are widely distributed throughout the primary auditory cortex (AI). We investigated the effects of endogenous GABA by comparing response properties of 110 neurons in chinchilla AI before and after iontophoresis of bicuculline, a GABA(A) receptor antagonist, and/or CGP35348, a GABA(B) receptor antagonist. GABA(A) receptor blockade significantly increased spontaneous and driven discharge rates, dramatically decreased the thresholds of many neurons, and constricted the range of thresholds across the neural population. Some neurons with 'non-onset' temporal discharge patterns developed an onset pattern that was followed by a long pause. Interestingly, the excitatory response area typically expanded on both sides of the characteristic frequency; this expansion exceeded one octave in a third of the sample. Although GABA(B) receptor blockade had little effect alone, the combination of CGP35348 and bicuculline produced greater increases in driven rate and expansion of the frequency response area than GABA(A) receptor blockade alone, suggesting a modulatory role of local GABA(B) receptors. The results suggest that local GABA inhibition contributes significantly to intensity and frequency coding by controlling the range of intensities over which cortical neurons operate and the range of frequencies to which they respond. The inhibitory circuits that generate nonmonotonic rate-level functions are separate from those that influence other response properties of AI neurons.

Late dosing with ethacrynic acid can reduce gentamicin concentration in perilymph and protect cochlear hair cells.

A key factor in the well-known interaction between ethacrynic acid (EA) and aminoglycoside antibiotics (AABs) is disruption of the blood-labyrinth barrier (BLB), leading to rapid entry of EA and AABs into the cochlear fluids. The idea that the blood-labyrinthine fluid concentration gradient might be utilized in a protective manner was tested in the current experiment. We hypothesized that administering EA when gentamicin (GM) levels are higher in the cochlea than in the blood might actually reduce cochlear damage by permitting efflux of GM from the cochlear fluids into the bloodstream, down a concentration gradient and across a temporarily disrupted BLB. Guinea pigs received 1, 11, 14 or 20 injections of GM (125 mg/kg i.m.). Approximately half of the animals also received a single injection of EA (40 mg/kg i.v.) either concurrently or 12-18 h after the last GM injection. Concurrent injection of EA significantly increased GM concentration in serum and perilymph at all time points sampled (2.5, 5-8, and 12 h post injection). Compared to animals that received GM only, animals that received a delayed injection of EA had a significantly lower GM concentration in perilymph, lower thresholds of the compound action potential, and less outer hair cell loss. Collectively, the evidence suggests that EA can reduce GM ototoxicity if it is administered 12-18 h after GM, but the mechanism remains to be elucidated. The results may have implications for the clinical management of aminoglycoside ototoxicity in humans, as well as for understanding the mechanisms underlying AAB/EA interactions.

Ethacrynic acid rapidly and selectively abolishes blood flow in vessels supplying the lateral wall of the cochlea.

The mechanisms underlying the ototoxicity of ethacrynic acid (EA) are not fully understood. Previous studies have focused on morphologic and enzymatic changes in the stria vascularis. The current experiment shows that one of the earliest effects of EA is ischemia, resulting from impaired blood flow in vessels supplying the lateral wall of the cochlea. Inner ear microcirculation, endocochlear potentials, compound action potentials (CAP), cochlear microphonics (CM) and summating potentials (SP) were monitored over time in chinchillas following a single injection of EA (40 mg/kg i.v.). At all times after EA injection, blood vessels supplying the spiral lamina, modiolus, and vestibular end organs appeared normal. In contrast, lateral wall (spiral ligament and stria vascularis) vessels were poorly stained with eosin 2 min after EA injection, and devoid of red blood cells at 30 min post EA. Decline, but not recovery, of CAP, CM and SP followed the microcirculation changes in the lateral wall. Reperfusion was delayed in stria vascularis arterioles relative to other lateral wall vessels. The ischemia-reperfusion caused by EA would be expected to generate large quantities of free radicals, which may trigger or contribute to the cellular, enzymatic, and functional pathologies that have been described in detail previously.

Noise-induced hearing loss in chinchillas pre-treated with glutathione monoethylester and R-PIA.

The protective effects of glutathione monoethylester (GEE) and GEE in combination with R-N6-phenylisopropyladenosine (R-PIA) were evaluated in the chinchilla when exposed to impulse (145 dB pSPL) or continuous (105 dB SPL, 4 kHz OB) noise. Six groups of 10 chinchillas were used as subjects. Before exposure to noise, the subjects were anesthetized, a 30 microl drop of drug was placed on the round window (GEE [50, 100, 150 mM], GEE 50 mM and R-PIA). Forty minutes later the subject was exposed to either impulse or continuous noise. The 50 mM treatment provided significant protection from impulse noise, but not from continuous noise exposure. The combination provided significant protection from both the continuous and impulse noise. In a separate set of experiments, glutathione (GSH) levels were measured in the perilymph. All the drug treatments elevated GSH levels. The results are discussed in terms of antioxidant treatments as a prophylactic measure against noise-induced hearing loss.

Chinchilla models of selective cochlear hair cell loss.

Although it is well known that ethacrynic acid (EA) can enhance gentamicin (GM) ototoxicity, there has been no systematic study of the relationship between dosing parameters and inner ear pathology. We examined the effects of two parameters, GM dose and time delay between GM and EA administration, on cochlear and vestibular hair cell loss in chinchillas. 'No delay' groups received one injection of GM (125, 40, 20, or 10 mg/kg i.m.) followed immediately by EA (40 mg/kg i.v.); 'delay' groups received GM (10 mg/kg i.m.) followed by EA 1 or 1.5 h later. Animals were sacrificed 7 days later for evaluation of hair cell loss in the cochlea and vestibular end organs (cristae, saccule and utricle). Vestibular function was assessed prior to sacrifice by measuring the duration of nystagmus induced by cold caloric stimulation. No delay groups had approximately 100% loss of outer hair cells and dose-dependent losses of inner hair cells, ranging from approximately 100% to 58%. In 1 and 1.5 h delay groups, inner hair cell losses were approximately 19% and 0%, outer hair cell losses were approximately 74% and 47%, and outer hair cell loss followed a typical base to apex gradient. Two results were remarkable. First, the three groups with partial inner hair cell loss showed an atypical lesion pattern in which losses were substantially greater in the apical half than in the basal half of the cochlea. Second, there was no vestibular pathology in any group. The results establish dosing parameters that can be used to produce animal models with defined patterns and magnitudes of cochlear hair cell damage, but normal vestibular function and morphology.

Evidence of a Common Pathway in Noise-Induced Hearing Loss and Carboplatin Ototoxicity.

In spite of the differences in the nature of the insult, the hearing loss from ototoxic drugs and noise exposure share a number of similarities in cochlear pathology. This paper explores the common factors between noise-induced hearing loss and ototoxicity by experimentally manipulating cochlear glutathione (GSH). In the first experiment, chinchillas were treated with a drop of saline (50 &mgr;l) on the round window of one ear and a drop of buthionine sulfoximine (BSO, 50 &mgr;l of 200 mM) on the other ear. BSO is a drug that blocks GSH synthesis and it was hypothesised that GSH-depressed ears would be more vulnerable to noise. Six hours after treatment, the animals were exposed to a 105 dB 4 kHz octave band noise for 4 hours, then a second dose of BSO was applied 2 hours later. The BSO treated ears showed more temporary threshold shifts and reduced GSH staining at day 4 post exposure, but there was no BSO effect in terms of greater permanent threshold shift (PTS) or hair cell loss. In the second experiment, chinchillas were pretreated with BSO and 3 days later were given either a single dose of carboplatin (25 mg/kg i.p.), a double dose (day 3 and 7) or only BSO. Chinchillas that received BSO and the double dose of carboplatin had significantly greater loss of inner and outer hair cells than the carboplatin chinchillas. In addition, the BSO and carboplatin chinchillas also had larger decreases in evoked response amplitudes suggesting that GSH depletion potentiated the ototoxicity of carboplatin. These results are discussed in terms of the role of reactive oxygen species in creating hearing loss and the potential protective role of glutathione.

The Influence of Superoxide Dismutase and Glutathione Peroxidase Deficiencies on Noise-Induced Hearing Loss in Mice.

One consequence of noise exposure is increased production of reactive oxygen species (ROS), such as superoxide, hydrogen peroxide, and hydroxyl radicals, in the cochlea. ROS can cause oxidative damage to diverse cellular components, including membranes, proteins, and DNA, if they are not "neutralised" by antioxidant defences. Two important enzymes of the cochlear antioxidant defense system are cytosolic copper/zinc superoxide dismutase (SOD1) and selenium-dependent glutathione peroxidase (GPx1). These metalloenzymes work together to regulate ROS production in virtually every cell in the body, and they may be important for limiting cochlear damage associated with aging and acoustic overexposure. In this chapter, we describe a series of experiments using mice with targeted deletions of Sod1 or Gpx1, the mouse genes that code for SOD1 and GPx1, respectively, to study the cellular mechanisms underlying noise-induced hearing loss (NIHL). The results from Sod1 and Gpx1 knockout mice provide insights into the link between endogenous levels of antioxidant enzymes and susceptibility to NIHL.