Kk. Ohlemiller et al., Targeted deletion of the cytosolic Cu/Zn-superoxide dismutase gene (Sod1) increases susceptibility to noise-induced hearing loss, AUDIOL NEUR, 4(5), 1999, pp. 237-246
Reactive oxygen species (ROS) such as superoxide, peroxide and hydroxyl rad
icals are generated during normal cellular metabolism and are increased in
acute injury and in many chronic disease states. When their production is i
nadequately regulated, ROS accumulate and irreversibly damage cell componen
ts, causing impaired cellular function and death. Antioxidant enzymes such
as superoxide dismutase (SOD) play a vital role in minimizing ROS levels an
d ROS-mediated damage. The cytosolic form of Cu/Zn-SOD appears specialized
to remove superoxide produced as a result of injury. 'Knockout' mice with t
argeted deletion of Sod1, the gene that codes for Cu/Zn-SOD, develop normal
ly but show enhanced susceptibility to central nervous system injury. Since
loud noise is injurious to the cochlea and is associated with elevated coc
hlear ROS, we hypothesized that Sod? knockout mice would be more susceptibl
e to noise-induced permanent threshold shifts (PTS) than wild-type and hete
rozygous control mice. Fifty-nine mice (15 knockout, 29 heterozygous and 15
wild type for Sod?) were exposed to broad-band noise (4.0-45.0 kHz) at 110
dB SPL for 1 h. Hearing sensitivity was evaluated at 5, 10, 20 and 40 kHz
using auditory brainstem responses before exposure and 1, 14 and 28 days af
terward. Cu/Zn-SOD deficiency led to minor (0-7 dB) threshold elevations pr
ior to noise exposure, and about 10 dB of additional noise-induced PTS at a
ll test frequencies, compared to controls. The distribution of thresholds a
t 10 and 20 kHz at 28 days following exposure contained three modes, each s
howing an effect of Cu/Zn-SOD deficiency. Thus another factor, possibly an
additional unlinked gene, may account for the majority of the observed PTS.
Our results indicate that genes involved in ROS regulation can impact the
vulnerability of the cochlea to noise-induced hearing loss.