Systemic health effects of noise exposure.

Noise, any unwanted sound, is pervasive and impacts large populations worldwide. Investigators suggested that noise exposure not only induces auditory damage but also produces various organ system dysfunctions. Although previous reviews primarily focused on noise-induced cardiovascular and cerebral dysfunctions, this narrow focus has unintentionally led the research community to disregard the importance of other vital organs. Indeed, limited studies revealed that noise exposure impacts other organs including the liver, kidneys, pancreas, lung, and gastrointestinal tract. Therefore, the aim of this review was to examine the effects of noise on both the extensively studied organs, the brain and heart, but also determine noise impact on other vital organs. The goal was to illustrate a comprehensive understanding of the systemic effects of noise. These systemic effects may guide future clinical research and epidemiological endpoints, emphasizing the importance of considering noise exposure history in diagnosing various systemic diseases.

Noise Stress Abrogates Structure-Specific Endonucleases within the Mammalian Inner Ear.

Nucleotide excision repair (NER) is a multistep biochemical process that maintains the integrity of the genome. Unlike other mechanisms that maintain genomic integrity, NER is distinguished by two irreversible nucleolytic events that are executed by the xeroderma pigmentosum group G (XPG) and xeroderma pigmentosum group F (XPF) structure-specific endonucleases. Beyond nucleolysis, XPG and XPF regulate the overall efficiency of NER through various protein-protein interactions. The current experiments evaluated whether an environmental stressor could negatively affect the expression of Xpg (Ercc5: excision repair cross-complementing 5) or Xpf (Ercc4: excision repair cross-complementing 4) in the mammalian cochlea. Ubiquitous background noise was used as an environmental stressor. Gene expression levels for Xpg and Xpf were quantified from the cochlear neurosensory epithelium after noise exposure. Further, nonlinear cochlear signal processing was investigated as a functional consequence of changes in endonuclease expression levels. Exposure to stressful background noise abrogated the expression of both Xpg and Xpf, and these effects were associated with pathological nonlinear signal processing from receptor cells within the mammalian inner ear. Given that exposure to environmental sounds (noise, music, etc.) is ubiquitous in daily life, sound-induced limitations to structure-specific endonucleases might represent an overlooked genomic threat.

Oral intake of carboxy alkyl ester improves attention: A randomized double-blind cross-over placebo-controlled study.

OBJECTIVE: To test the null hypothesis that oral intake of the dietary supplement carboxy alkyl ester (CAE) would have no effect on attention as revealed by mean rapid visual information processing (RVIP) scores. METHODS: In a randomized double-blind cross-over placebo-controlled trial, healthy participants (age 19-66 years) of both sexes were randomly assigned to consume 700 mg of CAE or 700 mg of placebo. They received baseline attention testing via the RVIP task. Then they consumed CAE or placebo followed by RVIP testing. Participants were then given a washout period where they did not consume CAE or placebo. Afterward, individuals who initially consumed CAE were given the placebo and those who initially consumed the placebo were given CAE. Finally, all participants were tested again via RVIP. RESULTS: A priori statistical computation revealed that 30-day oral intake of CAE improved mean RVIP test scores (t = 2.4, p < .05) relative to that at baseline, which resulted in a rejection of the null hypothesis. CONCLUSIONS: Daily oral intake of the CAE dietary supplement may boost attention and further research is now needed to confirm this observation.

Abnormal neural adaptation consequent to combined exposure to jet fuel and noise.

A fundamental property of first-order sensory neurons is the ability to alter their response properties as a function of change in the statistical parameters of an input signal. Such neural adaptation shapes the performance features of contiguous neural circuits that ultimately drive sensory discrimination. The current study focused on whether combined exposure to jet fuel and noise might alter the capacity of the auditory nerve to adapt to stimulus presentation speed. Young hooded Long-Evans 4-5 weeks old male rats were grouped and used in the current experiment. One group was exposed via inhalation to 1000 mg/m3 of jet propulsion fuel for 6 hr per day, 5 days per week for 4 weeks. Another group was exposed to a 5.5-11.3 kHz band-pass noise at 85 dB SPL for 6 hr per day, 5 days per week for 4 weeks. An additional group was simultaneously exposed to both jet fuel and noise. An age-matched group served as control and was not exposed to either jet fuel or noise. After experimental exposures, animals were given 4 weeks to recover and then assessed for neural adaptation. Both slow and fast rectangular voltage pulses were employed to elicit neuroelectric activity from the animals. Data demonstrated significant neural adaptation (1.46 µV shift) among controls, where neural activity decreased as the stimulus presentation speed rose from 10 to 100 per sec. This effect might also be observed in animals in the jet fuel treated and rats in the noise-exposed group. However, animals who were simultaneously exposed to both jet fuel and noise failed to exhibit neural adaptation. This abnormality appeared to be masked because independent slow and fast stimuli produced similar neural activity between controls and rats exposed to both jet fuel and noise. Therefore, neural adaptation assays may further be developed to unmask silent neurotoxicity consequent to physiochemical exposures.

Degenerate brainstem circuitry after combined physiochemical exposure to jet fuel and noise.

Degenerate neural circuits exhibit "different" circuit properties yet produce similar circuit outcomes (many-to-one) which ensures circuit robustness and complexity. However, neuropathies may hijack degeneracy to yield robust and complex pathological circuits. The aim of the current study was to test the hypothesis that physiochemical exposure to combined jet fuel and noise might induce degeneracy in the brainstem. The auditory brainstem of pigmented rats was used as a model system. The animals were randomized into the following experimental groups: Fuel+Noise, fuel-only, noise-only, and control. Ascending volume conductance from various auditory brainstem regions were evaluated simultaneously with peripheral nervous system (PNS) input to brainstem circuitry. Data demonstrated normal PNS inputs for all groups. However, the Fuel+Noise exposure group produced different caudal brainstem circuit properties while rostral brainstem circuitry initiated outputs that were similar to that of control. This degenerative effect was specific to Fuel+Noise exposure, since neither noise-alone or fuel-alone produced the same result. Degeneracy in the auditory brainstem is consistent with perceptual abnormalities, such as poor speech discrimination (hear but not understand), tinnitus (ringing in the ear), hyperacusis (hypersensitivity to even low-level sound), and loudness intolerance. Therefore, a potential consequence of Fuel+Noise exposure among military and civilian populations may be evidenced as increased rates of super-threshold auditory perceptual abnormalities. This is particularly important because to date, the ototoxic profile of Fuel+Noise exposure has remained unresolved.

Effects of acute noise exposure on DNA damage response genes in the cochlea, cortex, heart and liver.

Noise as a systemic stressor induces various organ dysfunctions and the underlying molecular pathology is unknown. Previous studies have shown that noise exposure results in the accumulation of DNA damage in auditory and non-auditory organs. The DNA damage response (DDR) is a global protective mechanism that plays a critical role in maintaining DNA integrity. However, the role of DDR genes in noise induced systemic (non-auditory) pathology has not been investigated. The current pilot study was designed to test the hypothesis that an acute noise exposure would alter the normal expression of DDR genes (e.g., ATM, p53 & XPC) in auditory (cochlea) and non-auditory organs, such as the cortex, heart and liver. Mice were used as subjects in this study and consisted of a baseline group, a one-hour noise exposure (@105 dB) group, and a four-hour noise exposure (@105 dB) group. ATM, p53 and XPC expression levels were quantified through end-point polymerize chain reactions. The current study demonstrated that noise exposure failed to elicit statistically significant changes in DDR genes (relative to baseline) across the various organs. The failure of the cochlea, heart, cortex and liver to upregulate protective DDR genes during acute noise exposure might help to explain their susceptibility to noise-induced DNA damage. This suggests that, biomedical interventions to upregulate DDR genes may need to be implemented before noise exposure or during the early stages of noise exposure.

A broad filter between call frequency and peripheral auditory sensitivity in northern grasshopper mice (Onychomys leucogaster).

Acoustic communication is a fundamental component of mate and competitor recognition in a variety of taxa and requires animals to detect and differentiate among acoustic stimuli (Bradbury and Vehrencamp in Principles of animal communication, 2nd edn., Sinauer Associates, Sunderland, 2011). The matched filter hypothesis predicts a correspondence between peripheral auditory tuning of receivers and properties of species-specific acoustic signals, but few studies have assessed this relationship in rodents. We recorded vocalizations and measured auditory brainstem responses (ABRs) in northern grasshopper mice (Onychomys leucogaster), a species that produces long-distance calls to advertise their presence to rivals and potential mates. ABR data indicate the highest sensitivity (28.33 ± 9.07 dB SPL re: 20 µPa) at 10 kHz, roughly corresponding to the fundamental frequency (11.6 ± 0.63 kHz) of long-distance calls produced by conspecifics. However, the frequency range of peripheral auditory sensitivity was broad (8-24 kHz), indicating the potential to detect both the harmonics of conspecific calls and vocalizations of sympatric heterospecifics. Our findings provide support for the matched filter hypothesis extended to include other ecologically relevant stimuli. Our study contributes important baseline information about the sensory ecology of a unique rodent to the study of sound perception.

Functional consequences of inducible genetic elements from the p53 SOS response in a mammalian organ system.

In response to DNA damage from ultraviolet (UV) radiation, bacteria deploy the SOS response in order to limit cell death. This bacterial SOS response is characterized by an increase in the recA gene that transactivates expression of multiple DNA repair genes. The current series of experiments demonstrate that a mammalian organ system (the cochlea) that is not evolutionarily conditioned to UV radiation can elicit SOS responses that are reminiscent of that of bacteria. This mammalian SOS response is characterized by an increase in the p53 gene with activation of multiple DNA repair genes that harbor p53 response elements in their promoters. Furthermore, the experimental results provide support for the notion of a convergent trigger paradox, where independent SOS triggers facilitate disparate physiologic sequelae (loss vs. recovery of function). Therefore, it is proposed that the mammalian SOS response is multifunctional and manipulation of this endogenous response could be exploited in future biomedical interventions.

Background Noise Contributes to Organic Solvent Induced Brain Dysfunction.

Occupational exposure to complex blends of organic solvents is believed to alter brain functions among workers. However, work environments that contain organic solvents are also polluted with background noise which raises the issue of whether or not the noise contributed to brain alterations. The purpose of the current study was to determine whether or not repeated exposure to low intensity noise with and without exposure to a complex blend of organic solvents would alter brain activity. Female Fischer344 rats served as subjects in these experiments. Asynchronous volume conductance between the midbrain and cortex was evaluated with a slow vertex recording technique. Subtoxic solvent exposure, by itself, had no statistically significant effects. However, background noise significantly suppressed brain activity and this suppression was exacerbated with solvent exposure. Furthermore, combined exposure produced significantly slow neurotransmission. These abnormal neurophysiologic findings occurred in the absence of hearing loss and detectable damage to sensory cells. The observations from the current experiment raise concern for all occupations where workers are repeatedly exposed to background noise or noise combined with organic solvents. Noise levels and solvent concentrations that are currently considered safe may not actually be safe and existing safety regulations have failed to recognize the neurotoxic potential of combined exposures.

Inhalation of Hydrocarbon Jet Fuel Suppress Central Auditory Nervous System Function.

More than 800 million L/d of hydrocarbon fuels is used to power cars, boats, and jet airplanes. The weekly consumption of these fuels necessarily puts the public at risk for repeated inhalation exposure. Recent studies showed that exposure to hydrocarbon jet fuel produces lethality in presynaptic sensory cells, leading to hearing loss, especially in the presence of noise. However, the effects of hydrocarbon jet fuel on the central auditory nervous system (CANS) have not received much attention. It is important to investigate the effects of hydrocarbons on the CANS in order to complete current knowledge regarding the ototoxic profile of such exposures. The objective of the current study was to determine whether inhalation exposure to hydrocarbon jet fuel might affect the functions of the CANS. Male Fischer 344 rats were randomly divided into four groups (control, noise, fuel, and fuel + noise). The structural and functional integrity of presynaptic sensory cells was determined in each group. Neurotransmission in both peripheral and central auditory pathways was simultaneously evaluated in order to identify and differentiate between peripheral and central dysfunctions. There were no detectable effects on pre- and postsynaptic peripheral functions. However, the responsiveness of the brain was significantly depressed and neural transmission time was markedly delayed. The development of CANS dysfunctions in the general public and the military due to cumulative exposure to hydrocarbon fuels may represent a significant but currently unrecognized public health issue.

Exposure to low levels of jet-propulsion fuel impairs brainstem encoding of stimulus intensity.

Jet propulsion fuel-8 (JP-8) is a kerosene-based fuel that is used in military jets. The U.S. Armed Services and North Atlantic Treaty Organization countries adopted JP-8 as a standard fuel source and the U.S. military alone consumes more than 2.5 billion gallons annually. Preliminary epidemiologic data suggested that JP-8 may interact with noise to induce hearing loss, and animal studies revealed damage to presynaptic sensory cells in the cochlea. In the current study, Long-Evans rats were divided into four experimental groups: control, noise only, JP-8 only, and JP-8 + noise. A subototoxic level of JP-8 was used alone or in combination with a nondamaging level of noise. Functional and structural assays of the presynaptic sensory cells combined with neurophysiologic studies of the cochlear nerve revealed that peripheral auditory function was not affected by individual exposures and there was no effect when the exposures were combined. However, the central auditory nervous system exhibited impaired brainstem encoding of stimulus intensity. These findings may represent important and major shifts in the theoretical framework that governs current understanding of jet fuel and/or jet fuel + noise-induced ototoxicity. From an epidemiologic perspective, results indicate that jet fuel exposure may exert consequences on auditory function that may be more widespread and insidious than what was previously shown. It is possible that a large population of military personnel who are suffering from the effects of jet fuel exposure may be misidentified because they would exhibit normal hearing thresholds but harbor a "hidden" brainstem dysfunction.

Emerging and established therapies for chemotherapy-induced ototoxicity.

PURPOSE: Ototoxicity is considered a dose-limiting side effect of some chemotherapies. Hearing loss, in particular, can have significant implications for the quality of life for cancer survivors. Here, we review therapeutic approaches to mitigating ototoxicity related to chemotherapy. METHODS: Literature review. CONCLUSIONS: Numerous otoprotection strategies are undergoing active investigation. However, numerous challenges exist to confer adequate protection while retaining the anti-cancer efficacy of the chemotherapy. IMPLICATIONS FOR CANCER SURVIVORS: Ototoxicity can have significant implications for cancer survivors, notably those receiving cisplatin. Clinical translation of multiple otoprotection approaches will aid in limiting these consequences.

Dynamic compartmentalization of DNA repair proteins within spiral ganglion neurons in response to noise stress.

ABSTRACT In response to stress, spiral ganglion neurons may remodel intracellular pools of DNA repair proteins. This hypothesis was addressed by determining the intracellular location of three classic DNA excision repair proteins (XPA, CSA, and XPC) within the neurons under normal conditions, one day after noise stress (105 dB/4 hr) and following DNA repair adjuvant therapy with carboxy alkyl esters (CAEs; 160 mg/kg/28 days). Under normal conditions, three intracellular compartments were enriched with at least one repair protein. These intracellular compartments were designated nuclear, cytoplasmic, and perinuclear. After the noise stress each repair protein aggregated in the cytoplasm. After CAE therapy each intracellular compartment was enriched with the three DNA repair proteins. Combining noise stress with CAE therapy resulted in the enrichment of at least two repair proteins in each intracellular compartment. The combined results suggest that in response to noise stress and/or otoprotective therapy, spiral ganglion neurons may selectively remodel compartmentalized DNA repair proteins.

Nondeterministic nature of sensorineural outcomes following noise trauma.

Over 1.1 billion individuals are at risk for noise induced hearing loss yet there is no accepted therapy. A long history of research has demonstrated that excessive noise exposure will kill outer hair cells (OHCs). Such observations have fueled the notion that dead OHCs underlie hearing loss. Therefore, previous and current therapeutic approaches are based on preventing the loss of OHCs. However, the relationship between OHC loss and hearing loss is at best a modest correlation. This suggests that in addition to the death of OHCs, other mechanisms may regulate the type and degree of hearing loss. In the current study, we tested the hypothesis that permanent noise-induced-hearing loss is consequent to additional mechanisms beyond the noise dose and the death of OHCs. Hooded male rats were randomly divided into noise and control groups. Morphological and physiological assessments were conducted on both groups. The combined results suggest that beyond OHC loss, the surviving cochlear elements shape sensorineural outcomes, which can be nondeterministic. These findings provide the basis for individualized ototherapeutics that manipulate surviving cellular elements in order to bias cochlear function towards normal hearing even in the presence of dead OHCs.

Age-related and noise-induced hearing loss alters grasshopper mouse (Onychomys) vocalizations.

Age-related and noise-induced hearing loss disorders are among the most common pathologies affecting Americans across their lifespans. Loss of auditory feedback due to hearing disorders is correlated with changes in voice and speech-motor control in humans. Although rodents are increasingly used to model human age- and noise-induced hearing loss, few studies have assessed vocal changes after acoustic trauma. Northern grasshopper mice (Onychomys leucogaster) represent a candidate model because their hearing sensitivity is matched to the frequencies of long-distance vocalizations that are produced using vocal fold vibrations similar to human speech. In this study, we quantified changes in auditory brainstem responses (ABRs) and vocalizations related to aging and noise-induced acoustic trauma. Mice showed a progressive decrease in hearing sensitivity across 4-32 kHz, with males losing hearing more rapidly than females. In addition, noise-exposed mice had a 61.55 dB SPL decrease in ABR sensitivity following a noise exposure, with some individuals exhibiting a 21.25 dB recovery 300-330 days after noise exposure. We also found that older grasshopper mice produced calls with lower fundamental frequency. Sex differences were measured in duration of calls with females producing longer calls with age. Our findings indicate that grasshopper mice experience age- and noise- induced hearing loss and concomitant changes in vocal output, making them a promising model for hearing and communication disorders.

Real-time quantification of Xeroderma pigmentosum mRNA from the mammalian cochlea.

OBJECTIVE: Human mutations in the DNA repair genes, Xeroderma pigmentosum (XP)-C and XPA result in hearing loss, which has fueled the hypothesis that there is a significant demand for these genes in protecting cochlear genetic material. Therefore, we quantified the level of XPC and XPA mRNA in the mammalian cochlea. DESIGN: XPC and XPA mRNAs were purified from the cochlea of 15 Fischer344 rats and quantified using SYBR Green chemistry. Another 15 Fischer344 rats were sacrificed for immunolocalization of XPC and XPA polypeptides in the cochlea and kidney (control organ). RESULTS: XP mRNA levels were up to 95% (XPA) and 69% (XPC) of the respective maximum expression capacity of each gene. In addition, these cochlear levels were up to sixfold (XPC) and threefold (XPA) greater than that of the kidney, which is known to exhibit XP-DNA repair activity that is greater than most organs of the body. Immunohistochemistry revealed that most kidney and cochlear cells were immunopositive. CONCLUSION: These data suggest that under normal conditions the cochlea is experiencing persistent genomic stress that helps to explain the hypersensitivity of the cochlea to exogenous stressors (ototoxic xenobiotics and/or acoustic-overexposure) as well as provide a basis to interpret hearing loss among patients with XP.

Preincision complex-I from the excision nuclease reaction among cochlear spiral limbus and outer hair cells.

The excision nuclease reaction defends the genome from endogenous and exogenous mutagens. The rate-limiting step in the reaction is facilitated by preincision complex-1 (PIC-1). PIC-1 is maintained by xeroderma pigmentosum A and C (XPA and XPC) through protein-protein interactions and DNA binding. XPA and XPC exhibit high-affinity for DNA adducts from the anticancer molecule, cisplatin. Systemic cisplatin treatment results in ubiquitous DNA adducts in the cochlea. Cochleae harvested from patients treated with cisplatin reveal dead outer hair cells among normal spiral limbus cells. Such discrepancy, suggest differences in genome defense repertoire among cochlear cells. The purpose of this study was to use cisplatin as a stimulus to examine XPA and XPC immunoreactivity among outer hair cells and spiral limbus cells. Fischer344 rats were treated with either one or two cycles of cisplatin, where each cycle lasted four days and separated by a 10 day rest period. Cochleae were harvested after each treatment cycle and four days after the second treatment cycle then processed for immunohistochemistry. Unlike spiral limbus cells, outer hair cells failed to acclimate to the cisplatin treatment cycles by regulating XPA and XPC immunoreactivity. These results imply that outer hair cells may have a limited capacity to mobilize PIC-I beyond basal demand.

Aminoglycoside induced ototoxicity.

Aminoglycosides are bactericidal aminoglycosidic aminocyclitols. They are cost effective and therefore widely used, however ototoxicity is a prominent dose-limiting side effect. Aminoglycoside induced ototoxicity leads to permanent bilaterally severe, high-frequency sensorineural hearing loss and temporary vestibular hypofunction. The permanent hearing loss is accompanied by degeneration of hair cells and neurons in the cochlea. An iron-aminoglycoside complex is believed to potentiate ROS-induced cellular degeneration in the cochlea. The development of aminoglycoside otoprotective strategies is a primary goal in ototoxicity research. Animal experiments have provided encouraging evidence for the protection of cochlear hair cells and neurons from aminoglycoside toxicity. However, the extent to which such protection, generalize to human ototoxicity remains unresolved.

Cisplatin induces cytoplasmic to nuclear translocation of nucleotide excision repair factors among spiral ganglion neurons.

Genomic DNA is a high-affinity target for the antineoplastic molecule cisplatin. Cell survival from cisplatin DNA damage is dependent on removal of cisplatin-DNA adducts by nucleotide excision repair (NER) pathways. The rate-limiting steps in the NER pathways are DNA damage identification and verification. These steps are accomplished by xeroderma pigmentosum complementation group C and A (XPC and XPA) and RNA polymerase II. Unlike RNA polymerase II, XPC and XPA have no known cellular function beyond DNA repair. Cisplatin is known to damage spiral ganglion neurons at the basal coil of the cochlea therefore it was posited that cisplatin may target their DNA and mobilize XPC and XPA. Female Fisher344 rats were given two, four day cycles of cisplatin (2mg/kg) or saline, separated by a 10day rest period. A 2 x 3 x 2 factorial design, consisting of two treatment conditions (cisplatin and saline treatment), three survival times (5, 19 and 22 days) and two analysis methods (quantitative RT-PCR and immunohistochemistry) was employed to evaluate the expression and distribution of XPC and XPA. Quantitative RT-PCR revealed statistically significant differences in cochlear XPC and XPA mRNA levels after cisplatin treatment at all times except day 22 for XPA. Immunohistochemistry revealed that a proportion ( approximately 50%) of spiral ganglion neurons in control rats showed cytoplasmic expression of XPC and XPA. After cisplatin treatment, a similar proportion ( approximately 50%) of spiral ganglion neurons showed increased nuclear expression of XPC and XPA, which appears to represent translocation from the cytoplasm. Basal coil spiral ganglion neurons translocated XPC and XPA at later treatment cycles and with less magnitude than apical coil neurons after cisplatin treatment. Therefore, it is suggested that cisplatin treatment induces nuclear translocation of NER proteins among spiral ganglion neurons and that this nuclear translocation is less efficient at the base relative to the apex.

Noise Induced DNA Damage Within the Auditory Nerve.

An understanding of the molecular pathology that underlies noise induced neurotoxicity is a prerequisite to the design of targeted therapies. The objective of the current experiment was to determine whether or not DNA damage is part of the pathophysiologic sequela of noise induced neurotoxicity. The experiment consisted of 41 hooded Long-Evans rats (2 month old males) that were randomized into control and noise exposed groups. Both the control and the noise group followed the same time schedule and therefore started and ended the experiment together. The noise dose consisted of a 6000 Hz noise band at 105 dB SPL. Temporal bones from both groups were harvested, and immunohistochemistry was used to identify neurons with DNA damage. Quantitative morphometric analyses was then employed to determine the level of DNA damage. Neural action potentials were recorded to assess the functional impact of noise induced DNA damage. Immunohistochemical reactions revealed that the noise exposure precipitated DNA damage within the nucleus of auditory neurons. Quantitative morphometry confirmed the noise induced increase in DNA damage levels and the precipitation of DNA damage was associated with a significant loss of nerve sensitivity. Therefore, DNA damage is part of the molecular pathology that drives noise induced neurotoxicity. Anat Rec, 300:520-526, 2017. © 2016 Wiley Periodicals, Inc.