Cu/Zn SOD deficiency potentiates hearing loss and cochlear pathology in aged 129,CD-1 mice

Copper/zinc superoxide dismutase (Cu/Zn SOD) is a first-line defense agains t free radical damage in the cochlea and other tissues. To determine whethe r deficiencies in Cu/Zn SOD increase age-related hearing loss and cochlear pathology, we collected auditory brainstem responses (ABRs) and determined cochlear hair cell loss in 13-month-old 129/CD-1. mice with (a) no measurab le Cu/Zn SOD activity (homozygous knockout mice), (b) 50% reduction of Cu/Z n SOD (heterozygous knockout mice), and (c) normal levels of Cu/Zn SOD (wil d-type mice). ABRs were obtained by using 4-, 8-, 16-, and 32-kHz tone burs ts. Cochleas were harvested immediately after testing, and separate counts were made of inner and outer hair cells. Compared with wild-type mice, homo zygous and heterozygous knockout mice exhibited significant threshold eleva tions and greater hair cell loss. Phenotypic variability was higher among h eterozygous knockout mice than among wild-type or homozygous knockout mice. Separate groups of wild-type and homozygous knockout mice were examined fo r loss of spiral ganglion cells and eighth nerve fibers. At 13 months of ag e, both wild-type and knockout mice had significantly fewer nerve fibers th an did 2-month-old wild-type mice, with significantly greater loss in aged knockout mice than in aged wild-type mice. Thirteen-month-old knockout mice also had a significant loss of spiral ganglion cells compared with 8-month -old wild-type mice. The results indicate that Cu/Zn SOD deficiencies incre ase the vulnerability of the cochlea to damage associated with normal aging , presumably through metabolic pathways involving the superoxide radical. J . Comp. Neurol. 413:101-112, 1999. (C) 1999 Wiley-Liss, Inc.