The underlying mechanisms of lead exposure-induced cochlear spiral ganglion neurons (SGNs) injury are not yet clear. This study explored whether ferroptosis is involved in lead-induced SGNs injury and investigated the mechanism of lead-induced iron overload in SGNs. A primary culture cell model of lead acetate-induced SGNs damage was established. The changes in levels of iron ions, reactive oxygen species, lipid peroxides, and glutathione in SGNs were measured after lead acetate intervention and ferroptosis inhibitors pre-treatment. The morphology of mitochondria was also observed, and the expression of ferroptosis marker genes glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), as well as iron metabolism-related proteins transferrin receptor protein 1 (TFR1), nuclear receptor coactivator 4 (NCOA4), heme oxygenase-1 (HO-1), and ferroportin (FPN) were detected. Results showed that lead acetate exposure induced SGNs injury in a time- and dose-dependent manner. Intracellular iron accumulation, increased levels of reactive oxygen species and lipid peroxide with decreased level of antioxidant capacity were occurred in SGNs after lead exposure. Meanwhile, decreased expressions of GPX4 and SLC7A11 and increased expressions of iron metabolism-related proteins (TFR1, NCOA4, and HO-1) were also found. Lead acetate intervention also caused mitochondrial shrinkage with blurred and fragmented morphology. Pre-treatment with ferroptosis inhibitors (Fer-1 and DFOM) significantly ameliorated lead-induced SGNs injury. In summary, lead exposure can induce ferroptosis in SGNs, the antioxidant defense system and iron metabolism disorder are involved in lead-induced SGNs ferroptosis. Thus, inhibiting ferroptosis may be a new strategy for preventing and treating lead exposure-related hearing loss.
Keywords: Ferroptosis; Hearing loss; Iron metabolism; Lead exposure; Spiral ganglion neurons.
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