| Summary: | 博士 === 國立臺灣大學 === 臨床醫學研究所 === 100 === Background：Age-related hearing impairment (ARHI) is a complex disease, and could be affected by genetic and environmental factors. Previous studies showed that
obesity-related co-morbidities, such as: dyslipidemia, diabetes mellitus, and hypertension, were associated with ARHI. But, it is still unclear whether obesity per sec could lead to ARHI. On the other hand, hypoxia, oxidative stress, mitochondrial dysfunction, cochlear cell apoptosis, etc, were supposed to be the mechanisms of ARHI and were also associated with obesity. But, the detailed mechanisms of obesity-related hearing degeneration are still unclear.
Purpose：To investigate the relationship of obesity, plasma adiponectin levels, oxidative stress and ARHI, and to investigate the detailed mechanisms of obesity-related hearing degeneration.
Hypothesis：Waist circumference (WC) or central obesity was a novel independent risk factor for ARHI. Plasma adiponectin concentration might be negatively associated with hearing thresholds in humans. Plasma reactive oxygen species concentrations were positively associated with hearing thresholds in humans. Obesity might exacerbate hearing degeneration via enhancing hypoxia, inflammation, caspase-dependent and –independent apoptosis signaling pathways.
Clinical significance: If the hypotheses were true, we will find novel risk factors for ARHI, and we also offer a brand new avenue for the research in ARHI. We expect that our studies could make a contribution on the prevention and treatment for hearing degeneration.
Methods:
Part one: Association of WC and hearing thresholds in humans.
By cross-sectional design, we invited subjects, who were older than 40 years old, from the Health department of National Taiwan University Hospital and volunteer helpers from Buddhist Dalin Tzu Chi General Hospital. All eligible subjects received medical questionnaire, physical examination, audiometry, and blood biochemistric study. Nine hundred and fifty-four subjects with normal or symmetric sensorineural hearing impairment, but without personal or family histories of early-onset hearing loss, obvious cognitive dysfunction, high occupational noise exposure, were included in this study. Association of WC and hearing thresholds were analyzed. The hearing thresholds were presented with age- and sex-independent Z-scores of low (250 and 500 Hz), middle (1000 Hz and 2000 Hz) and high (4000 Hz and 8000 Hz) frequencies, which were transformed from individual pure tone thresholds.
Part two: Association of plasma adiponectin concentration and hearing thresholds in humans.
This part was a subsequent study of Part one. The association between plasma adiponectin concentration and hearing thresholds was analyzed in the same study population of Part one.
Part three: Association of plasma reactive oxygen species (ROS) concentration and hearing thresholds in humans.
This part was also a subsequent study of Part one. The association between plasma ROS concentrations, which were detected by chemiluminescence method, and hearing thresholds was analyzed in 302 subjects within the study population of Part one.
Part four: Effects and mechanisms of diet-induced obesity on hearing degeneration.
Sixty 4-weeks-old male CD/1 mice with auditory brainstem response (ABR) thresholds lower than 50 decibel sound pressure level (dB SPL) by 8000 Hz tone burst were randomly and equally divided into two groups. Diet-induced obesity (DIO) group fed with high fat diet and control group fed with normal diet for 16 weeks. Morphometry, biochemistry, ABR thresholds, omental fat weight and histopathology of the cochlea were compared at the end of study.
Results：
Part one: Association of WC and hearing thresholds in humans.
There were 954 subjects (535 were female; 419 were male) in this study. The mean age of all subjects were 56.5 years old (standard deviation was 8.7). After adjusting for coronary artery disease (CAD), diabetes mellitus (DM), hypertension (HTN), dyslipidemia, chronic kidney disease (CKD), smoking, drinking, noise exposure and even body mass index (BMI), WC still showed significant positive association with Z scores of middle or high frequencies. In other words, the larger the WC is, the worser the hearing of middle and high frequencies is.
Part two: Association of plasma adiponectin concentration and hearing thresholds in humans.
The general characteristics of subjects were the same as those in Part one. The mean concentration of plasma adiponectin was 10.2 μg/ml (standard deviation was 5.0). After adjusting for CAD, DM, HTN, dyslipidemia, CKD, smoking, drinking, noise exposure, and even WC, the plasma adiponectin concentration still showed significant negative association with Z scores of high frequencies. In other words, the larger the plasma adiponectin concentration is, the better the hearing of high frequencies is. In addition, the risk of hearing impairment for high frequencies (pure tone average≧25 dB hearing level) decreased by 0.965-fold for every 1 unit increase in adiponectin concentration, after adjusting for age, gender, WC, systemic diseases, and smoking, alcohol consumption, and noise exposure.
Part three: Association of plasma ROS concentration and hearing thresholds in humans.
Luminol-dependent chemiluminescence signals, which reflect hydrogen peroxide (H2O2), hypochlorite (HOCl/OCl–), and hydroxyl radicals (•OH) levels, showed significant positive association with Z-low, Z-middle, or Z-high after adjusting central obesity, systemic diseases, habits, and noise exposure. Lucigenin-dependent chemiluminescence signals, which mainly reflect superoxide anion (O2‧–) level, showed significant positive association with Z-low, but not with Z-middle or Z-high after adjusting other variables.
Part four: Effects and mechanisms of diet-induced obesity on hearing degeneration.
Compared to control group, the diet-induced obesity (DIO) group had significant higher body weight, fasting plasma triglyceride concentration, and omental fat weight after ICR/CD1 mice were fed with high fat diet for 16 weeks. The auditory brainstem response thresholds at 16000 Hz and 32000 Hz were significantly higher in the DIO group than the control group. But, the fasting plasma sugar and high-density lipoprotein cholesterol concentration were not significantly different in both groups.
Cohlear H&E stain showed that DIO group had thinner diameter with higher vessel wall to radius ratio in the stria vascularis of cochlear basal turn. The cell density of spiral ganglion or spiral ligament was significantly lower in the DIO group than in the control group. But, the degeneration of Organ of Corti was similar in both groups.
Cohlear immunohistochemistric stain showed that hypoxia-induced factor-1α, tumor necrosis factor α, nuclear factor-kappa B, caspase 3, poly(adenosine diphosphate-ribose) polymerase-1, apoptosis inducing factor stains were significantly denser in the DIO group than in the control group.
Conlcusions: Waist circumference or central obesity was a novel independent risk factor for age-related hearing impairment. Plasma adiponectin concentration showed negative association with hearing of of high frequencies. Adiponectin might play a protective role on hearing, especially for high frequencies. Plasma ROS levels were associated with severity of age-related hearing impairment in humans. Various ROS might have differential impacts on auditory dysfunctions. Diet-induced obesity could exacerbate the hearing degeneration in CD/1 mice. The most notable histological findings were narrower blood vessels in the stria vascularis, increased inflammatory responses, increased cell loss of spiral ganglion and spiral ligament. And, the high fat diet could increase cell apoptosis of spiral ganglion and spiral ligament via activation of both caspase-dependent and caspase-independent apoptosis signaling pathways.
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