Abstract
Background Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants linked to adverse health effects. Recent epidemiological data suggest an association between PFAS exposure and hearing impairment, but underlying mechanisms remain unclear. This study examined PFAS-induced auditory dysfunction using Ldlr(-)/(-) mice on a C57BL/6J background exposed for seven weeks to a mixture of five PFAS compounds (2 mg/L each) in drinking water. PFAS exposure significantly elevated hearing thresholds by 18-33 dB across multiple frequencies, indicative of auditory impairment. Functional assessments revealed impaired outer hair cell (OHC) function, and immunohistochemical analysis identified ~ 24% OHC loss in the basal turn of the cochlea. In addition, PFAS exposure reduced wave-I amplitudes and increased latencies, suggesting cochlear synaptopathy. Immunohistochemistry further demonstrated a significant decrease in ribbon synapse numbers (CtBP2 and GluR2 markers) per inner hair cell and a ~ 53% reduction in spiral ganglion cell density. Overall, PFAS exposure induced cochlear synaptopathy and high-frequency hearing loss in mice. The findings also indicated that cochlear OHCs, ribbon synapses, and spiral ganglions are potential targets in PFAS-induced hearing loss. Together, these data suggest that PFAS exposure elicits a multifaceted ototoxic response, affecting both sensory and neural elements of the cochlea.