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

Abstract

Copper/zinc superoxide dismutase (Cu/Zn SOD) is a first-line defense against free radical damage in the cochlea and other tissues. To determine whether 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 measurable Cu/Zn SOD activity (homozygous knockout mice), (b) 50% reduction of Cu/Zn SOD (heterozygous knockout mice), and (c) normal levels of Cu/Zn SOD (wild-type mice). ABRs were obtained by using 4-, 8-, 16-, and 32-kHz tone bursts. Cochleas were harvested immediately after testing, and separate counts were made of inner and outer hair cells. Compared with wild-type mice, homozygous and heterozygous knockout mice exhibited significant threshold elevations and greater hair cell loss. Phenotypic variability was higher among heterozygous knockout mice than among wild-type or homozygous knockout mice. Separate groups of wild-type and homozygous knockout mice were examined for loss of spiral ganglion cells and eighth nerve fibers. At 13 months of age, both wild-type and knockout mice had significantly fewer nerve fibers than 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 2-month-old wild-type mice. The results indicate that Cu/Zn SOD deficiencies increase the vulnerability of the cochlea to damage associated with normal aging, presumably through metabolic pathways involving the superoxide radical.