Abstract
The prevalence of noise-induced hearing loss (NIHL) continues to increase, with limited therapies available for individuals with cochlear damage. We have previously established that the transcription factor FOXO3 is necessary to preserve outer hair cells (OHCs) and hearing thresholds up to two weeks following mild noise exposure in mice. The mechanisms by which FOXO3 preserves cochlear cells and function are unknown. In this study, we analyzed the immediate effects of mild noise exposure on wild-type, Foxo3 heterozygous (Foxo3+/−), and Foxo3 knock-out (Foxo3−/−) mice to better understand FOXO3’s role(s) in the mammalian cochlea. We used confocal and multiphoton microscopy to examine well-characterized components of noise-induced damage including calcium regulators, oxidative stress, necrosis, and caspase-dependent and caspase-independent apoptosis. Lower immunoreactivity of the calcium buffer Oncomodulin in Foxo3−/− OHCs correlated with cell loss beginning 4 h post-noise exposure. Using immunohistochemistry, we identified parthanatos as the cell death pathway for OHCs. Oxidative stress response pathways were not significantly altered in FOXO3’s absence. We used RNA sequencing to identify and RT-qPCR to confirm differentially expressed genes. We further investigated a gene downregulated in the unexposed Foxo3−/− mice that may contribute to OHC noise susceptibility. Glycerophosphodiester phosphodiesterase domain containing 3 (GDPD3), a possible endogenous source of lysophosphatidic acid (LPA), has not previously been described in the cochlea. As LPA reduces OHC loss after severe noise exposure, we treated noise-exposed Foxo3−/− mice with exogenous LPA. LPA treatment delayed immediate damage to OHCs but was insufficient to ultimately prevent their death or prevent hearing loss. These results suggest that FOXO3 acts prior to acoustic insult to maintain cochlear resilience, possibly through sustaining endogenous LPA levels.
Highlights
Noise-induced hearing loss (NIHL) is a pervasive health threat
By 24 h post-noise (HPN), many OCM+/CytC+ cells were lost and fewer outer hair cells (OHCs) nuclei remained in the Foxo3−/− (Fig. 2H–H′′, white arrows)
About one-third of Foxo3−/− OHCs were lost from the basal cochlea without any IHC loss [20]
Summary
Noise-induced hearing loss (NIHL) is a pervasive health threat. In 2017, the NIDCD estimated that despite increased awareness and access to protective equipment, nearly 40 million American adults had signs of NIHL [1]. Individuals have varying susceptibilities to noise damage, partially due to differences in gene expression crucial for hearing recovery and cochlear preservation [2]. Transcriptional regulators comprise a class of NIHL susceptibility genes, including Forkhead Box O-3 (FOXO3) [3]. It has previously been shown that 4 h following a stressor, evidence of the two-step induction of FOXO3 by AMPK used for transcription was present in glutamate-exposed neurons [19]. These neuronal observations suggest that FOXO3 is capable of driving gene transcription in stressed, damaged, or dysfunctional cells. ROS accumulation in Received: 10 March 2021 Revised: June 2021 Accepted: June 2021
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