Hearing vulnerability after noise exposure in a mouse model of reactive oxygen species overproduction

Abstract

Previous studies have convincingly argued that reactive oxygen species (ROS) contribute to the development of several major types of sensorineural hearing loss, such as noise-induced hearing loss (NIHL), drug-induced hearing loss, and age-related hearing loss. However, the underlying molecular mechanisms induced by ROS in these pathologies remain unclear. To resolve this issue, we established an in vivo model of ROS overproduction by generating a transgenic (TG) mouse line expressing the human NADPH oxidase 4 (NOX4, NOX4-TG mice), which is a constitutively active ROS-producing enzyme that does not require stimulation or an activator. Overproduction of ROS was detected at the cochlea of the inner ear in NOX4-TG mice, but they showed normal hearing function under baseline conditions. However, they demonstrated hearing function vulnerability, especially at high-frequency sounds, upon exposure to intense noise, which was accompanied by loss of cochlear outer hair cells (OHCs). The vulnerability to loss of hearing function and OHCs was rescued by treatment with the antioxidant Tempol. Additionally, we found increased protein levels of the heat-shock protein 47 (HSP47) in models using HEK293 cells, including H O treatment and cells with stable and transient expression of NOX4. Furthermore, the up-regulated levels of Hsp47 were observed in both the cochlea and heart of NOX4-TG mice. Thus, antioxidant therapy is a promising approach for the treatment of NIHL. Hsp47 may be an endogenous antioxidant factor, compensating for the chronic ROS overexposure in vivo, and counteracting ROS-related hearing loss.

Nox3-Derived Superoxide in Cochleae Induces Sensorineural Hearing Loss

“…Twomonth-old control, Nox3-Cre +/− ;tdTomato +/+ , and Nox3-Cre +/+ ;tdTomato +/+ (Nox3-KO) mice were anesthetized as described and exposed to octave-band noise at 120 dB SPL centered at 8 kHz for 3 h inside a sound chamber. The condition of NE to induce a permanent threshold shift was determined based on our previous report (Morioka et al, 2018). Each animal was placed in a cage in the sound chamber, which was fitted with a speaker (300 HT; FOSTEX, Akishima, Japan) driven by a noise generator (SF-06; RION, Kokubunji, Japan) and power amplifier (DAD-M100proHT;…”

“…There are seven isoforms in humans (NOX1-5, DUOX1-2), and previous studies have demonstrated that ROS contribute to ARHL, DIHL, and NIHL ( Kamogashira et al, 2015 ). Recently, we reported a transgenic mouse line that expresses NOX4 , which produces low levels of ROS without stimulation, exhibits hearing vulnerability after noise exposure (NE) ( Morioka et al, 2018 ), further indicating that ROS contribute to SNHL.…”

The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia

“…Four-week-old DIA1 TG/TG mice and littermate control WT mice were anesthetized with the anesthetic cocktail and exposed to octave-band-noise, centered at 8 kHz, for 1 h at 105 dB SPL in a sound chamber, as described previously 57 . Each animal was placed in the center of the chamber.…”

Key Signaling Pathways Regulate the Development and Survival of Auditory Hair Cells

“…ROS-induced oxidative stress has been reported to play a key role in several systems and in cochlear damage [132][133][134][135][136]. Numerous studies have demonstrated that the accumulation of ROS and subsequent apoptosis induction promote several major types of SNHL, including noise-induced hearing loss, drug-induced hearing loss, and age-related hearing loss [137][138][139][140][141][142]. ROS are considered to be toxic products of cell metabolism and are signaling molecules that regulate a variety of physiological processes.…”