Electron Microscopy Reveals Abnormal Otoconia in a Hypercalcemic Mouse Model of Primary Hyperparathyroidism

Mice with chronic hypercalcemia have smaller otoconia and altered surface morphology when compared with controls.

Serum calcium dysregulation may contribute to otoconial degeneration and has been linked to benign paroxysmal positional vertigo (BPPV), but direct evidence is scarce.

Four female transgenic mice modeling hypercalcemic primary hyperparathyroidism (PHPT) and 4 female age-matched wild-type mice were studied. Utricular otoconia were extracted under sodium cacodylate solution, gold-coated, and imaged by Zeiss Sigma scanning electron microscope. Otoconia were hand-measured using ImageJ to quantify major axis, minor axis, and area. Statistical analysis included linear mixed-effects modeling and Mann-Whitney testing across 3 size categories (small, medium, and large). Fractured otoconia were quantified to assess structural stability.

Transgenic PHPT mice exhibited smaller otoconia than control mice across the major axis (5.15±0.05 µm vs. 9.09±0.16 µm), minor axis (2.79±0.02 µm vs. 4.55±0.07 µm), and area (13.24±0.28 µm2 vs. 39.98±1.55 µm2). The linear mixed-effects model showed a significant interaction between group (control vs. transgenic mice) and otoconial size category. Subgroup analysis showed the greatest between-group differences among large otoconia for major axis (P=0.039), minor axis (P=0.038), and area (P=0.032). Otoconia fracture frequency was low but there was a 4.4-fold increase in cracks within the hypercalcemic mice.

Mice with chronic hypercalcemia and PHPT have smaller otoconia when compared with normal mice, with increased frequency of fractured otoconia, consistent with a potential role of chronic calcium dysregulation in otoconial degeneration and potentially BPPV.