Galectin-3 protects auditory function in female mice

Sex differences in the development of sensorineural hearing loss have been recognized in various inner ear disorders, but the molecular basis for such differences is poorly understood. Autosomal genes have been shown to cause sex differences in disease susceptibility, but many genes exerting sex-dependent effects on auditory function remain to be identified. Galectin-3 (Gal-3), a protein encoded by the autosomal gene Lgals3, is a member of the β-galactoside-binding protein family, and has been linked to multiple biological processes, including immune responses, apoptosis, and cell adhesion. Here, we investigated auditory function and hair cell integrity in Gal-3 knockout (KO, Lgals3^-/-) and wild-type (WT, Lgals3^+/+) mice from age 1 to 6 months. KO mice show a more rapid age-related increase in ABR thresholds compared to WT mice. Noticeably, the threshold deterioration in female KO mice is significantly greater than in the male KO and WT mice. The ABR threshold elevation manifests over a broad frequency range in female KO mice, whereas the threshold elevations are confined to high frequencies in the male KO and WT mice. Moreover, DPOAE input/output functions reveal a similar pattern of auditory dysfunction, with the female KO mice displaying a significantly greater reduction in DPOAE amplitudes than male KO mice and WT mice of both sexes. Finally, age-related outer hair cell loss is greater for female KO mice compared to male KO mice and WT mice of both sexes. Together, these results indicate that Gal-3 deficiency exacerbates age-related cochlear degeneration and auditory dysfunction in female mice. Our study identifies Gal-3 as a sex-dependent molecule for maintaining female cochlear integrity.