Exposure-duration-associated auditory dysfunction and cochlear presynaptic ribbon alterations during simulated high-altitude hypobaric hypoxia in mice

High-altitude hypobaric hypoxia can alter auditory function, but the temporal relationships among cochlear dysfunction, hair-cell integrity, inner-hair-cell presynaptic ribbons, and redox-bioenergetic disturbances remain unclear.

Eighty male C57BL/6J mice were assigned to an ambient-pressure control group in Xining, China (approximately 2,260 m), or to nominal 3-, 15-, or 30-day simulated hypobaric-hypoxia exposure groups (n = 20 per group). Chamber entry was staggered, and terminal assessments and tissue collection were completed within a period of less than 24 h. Separate animal subsets were used for auditory brainstem response (ABR) recording and hematological assessment. ABR thresholds, wave I latency, and wave I peak-to-trough amplitude were evaluated. Hair-cell survival and CtBP2-positive presynaptic ribbons were assessed by confocal microscopy. Hematological indices, 4-hydroxynonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine-related immunoreactivity, whole-cochlear ATP content, and JC-1-defined mitochondrial polarization were also assessed.

Red blood cell count, hemoglobin concentration, and hematocrit were increased at all exposure durations. Exposure group was associated with altered ABR thresholds and wave I measures. Control-focused comparisons showed prolonged wave I latency at 4 and 8 kHz in all hypoxia groups, whereas wave I amplitude at 90 dB SPL was lower at both frequencies only after 15 days. OHC survival did not differ significantly among groups, and no overt IHC loss was observed. CtBP2-positive puncta were reduced in the basal turn after 3 days and in all cochlear turns after 15 days. 4-HNE immunoreactivity increased at all time points, whereas 8-OHdG-related immunoreactivity increased after 3 and 15 days. Whole-cochlear ATP content was reduced at all time points. At 30 days, JC-1 analysis indicated a shift toward mitochondrial depolarization in mixed cochlear-cell suspensions.

Simulated high-altitude hypobaric-chamber exposure was associated with an exposure-duration-associated and endpoint-specific cochlear phenotype. Auditory abnormalities and presynaptic ribbon alterations occurred without substantial hair-cell loss and were accompanied by oxidative and bioenergetic disturbances. The pattern of abnormalities varied across exposure groups and endpoints.