Serum Estradiol Correlates With Benign Paroxysmal Positional Vertigo in Postmenopausal Women.

BACKGROUND: A high incidence of benign paroxysmal positional vertigo (BPPV) is reported in postmenopausal women, and the association between estradiol (E2) deficiency and the occurrence of BPPV was investigated. METHODS: Postmenopausal women with and without BPPV were included from 2016 to 2019, and 1-year follow-up was performed. Serum otolin-1 and E2 levels were assayed before the canalith repositioning treatment. Bone mineral density (BMD) was measured with a dual-energy x-ray absorptiometry scan. Receiver operating characteristic analysis was performed to determine the occurrence of BPPV, and Pearson analysis was performed to indicate the correlation between E2, otolin-1, and BMD. RESULTS: Eighty-six postmenopausal women with BPPV and 80 age-, demographics-, and clinical characteristics-matched normal postmenopausal women were enrolled. Decreased E2 levels, increased otolin-1 levels, and decreased BMD were observed in postmenopausal women with BPPV, and increased BMD and decreased otolin-1 levels were observed in patients with higher levels of serum E2. Receiver operating characteristic analysis revealed that E2, otolin-1, and BMD showed low sensitivity and moderate specificity to determine the occurrence of BPPV. On the other hand, a low correlation coefficient was found between E2 and otolin-1, or BMD. It is worth noting that low E2 levels were found in the relapsed patients with BPPV after a 1-year follow-up. CONCLUSION: E2 deficiency is correlated with the occurrence of BPPV, which may be a potential risk biomarker for postmenopausal women.

Prestin and otolin-1 proteins in the hearing loss of adults chronically exposed to lead.

BACKGROUND: Some studies in animal models and humans suggest that exposure to lead is associated with hearing loss. Lead can reach the inner ear through the blood circulation; evidence suggests that lead could accumulate in the inner ear, causing inner ear damage. AIM: To evaluate prestin and otolin-1 protein levels and their relationship with an increased hearing threshold in participants exposed to lead. METHODS: We conducted a cross-sectional study with 315 participants from Tlaxcala, Mexico. Blood lead levels (BPb) were evaluated by graphite furnace atomic absorption spectrometry. Serum prestin and otolin-1 were quantified using ELISA. Auditory function at frequencies of 0.125 to 8 kHz was evaluated in a soundproof chamber. RESULTS: Participants were classified according to BPb: group I (<10 µg/dL) had a median BPb of 6 µg/dL and prestin levels of 11.06 ng/mL. While participants in group II (≥10 µg/dL) had a median of BPb 20.7 µg/dL (p < 0.05) and prestin levels of 0.15 ng/mL (p < 0.001). Participants in both groups showed a normal hearing. Otolin-1 levels were higher for participants with normal hearing and lower for participants with hearing loss in both groups, p > 0.05. Multiple linear regression models predict an average decrease of 0.17 to 0.26 ng/mL in prestin levels per decibel increase for the frequencies evaluated. CONCLUSIONS: Participants with high BPb showed an increase in hearing threshold, and prestin levels decreased proportionally to the hearing threshold increase. This is the first study to evaluate prestin as a potential biomarker for hearing damage, evaluated by audiometry, in participants with lead exposure.

Natural Mutations Affect Structure and Function of gC1q Domain of Otolin-1.

Otolin-1 is a scaffold protein of otoliths and otoconia, calcium carbonate biominerals from the inner ear. It contains a gC1q domain responsible for trimerization and binding of Ca2+. Knowledge of a structure-function relationship of gC1q domain of otolin-1 is crucial for understanding the biology of balance sensing. Here, we show how natural variants alter the structure of gC1q otolin-1 and how Ca2+ are able to revert some effects of the mutations. We discovered that natural substitutions: R339S, R342W and R402P negatively affect the stability of apo-gC1q otolin-1, and that Q426R has a stabilizing effect. In the presence of Ca2+, R342W and Q426R were stabilized at higher Ca2+ concentrations than the wild-type form, and R402P was completely insensitive to Ca2+. The mutations affected the self-association of gC1q otolin-1 by inducing detrimental aggregation (R342W) or disabling the trimerization (R402P) of the protein. Our results indicate that the natural variants of gC1q otolin-1 may have a potential to cause pathological changes in otoconia and otoconial membrane, which could affect sensing of balance and increase the probability of occurrence of benign paroxysmal positional vertigo (BPPV).

Serum Prestin and Otolin-1 Levels in Pilots of Helicopter-Based Emergency Medical Services: Potential Markers for Ear Injury.

INTRODUCTION: Occupational noise exposure is a major public health concern, impacting a large workforce worldwide. In this study, we sought to evaluate the serum concentrations of prestin, a cochlear protein that diminishes following noise exposure, and otolin-1, a protein secreted into the bloodstream subsequent to inner ear damage, among three diverse professional categories, each exposed to varying degrees of noise. Helicopter emergency medical service (HEMS) pilots and construction workers were considered high-risk groups due to their elevated exposure to occupational noise, whereas office workers were regarded as a low-risk group, reflecting their comparatively minimal noise exposure. METHODS: The study sample included 60 males, encompassing helicopter pilots, construction laborers, and office workers (n=20, each). Recruitment occurred during standard occupational health visits, with all participants presenting normal clinical audiograms. Serum levels of prestin and otolin-1 were measured in duplicate using commercially available immunoassays and compared across the three professional categories. RESULTS: HEMS pilots had the lowest mean serum prestin level at 211±27 pg/mL, followed by construction workers at 234±29 pg/mL, and office workers at 269±42 pg/mL (p<0.001, one-way analysis of variance), with all inter-group differences statistically significant (p<0.05, Tukey's post hoc tests). For otolin-1, HEMS pilots showed the highest mean at 216±20 pg/mL, with construction workers at 196±22 pg/mL, and office workers at 181±20 pg/mL (p<0.001, one-way analysis of variance). Statistically significant differences were found between HEMS pilots and both other groups for otolin-1 levels (p<0.05, Tukey's post hoc tests), but not between construction workers and office workers. CONCLUSIONS:  Serum concentrations of prestin and otolin-1 may differ among healthy individuals according to their occupational noise exposure and have the potential to act as indicators of subclinical inner ear injury. To substantiate these preliminary observations, incorporating exposure assessment, especially via direct measurements of noise and vibration exposure, would markedly improve the reliability of our findings.

Otolin-1, an otolith- and otoconia-related protein, controls calcium carbonate bioinspired mineralization.

BACKGROUND: Otoliths and otoconia are calcium carbonate biomineral structures that form in the inner ear of fish and humans, respectively. The formation of these structures is tightly linked to the formation of an organic matrix framework with otolin-1, a short collagen-like protein from the C1q family as one of its major constituents. METHODS: In this study, we examined the activity of recombinant otolin-1 originating from Danio rerio and Homo sapiens on calcium carbonate bioinspired mineralization with slow-diffusion method and performed crystals characterization with scanning electron microscopy, two-photon excited fluorescence microscopy, confocal laser scanning microscopy and micro-Raman spectroscopy. RESULTS: We show that both proteins are embedded in the core of CaCO3 crystals that form through the slow-diffusion mineralization method. Both of them influence the morphology but do not change the polymorphic mineral phase. D.rerio otolin-1 also closely adheres to the crystal surface. GENERAL SIGNIFICANCE: The results suggest, that otolin-1 is not a passive scaffold, but is directly involved in regulating the morphology of the resulting calcium carbonate biocrystals.

N'-terminal- and Ca2+-induced stabilization of high-order oligomers of full-length Danio rerio and Homo sapiens otolin-1.

Otolin-1 is a C1q family member and a major component of the organic matrix of fish otoliths and human otoconia. To date, the protein molecular properties have not been characterized. In this work, we describe biochemical characterization and comparative studies on saccular-specific otolin-1 derived from Danio rerio and Homo sapiens. Due to the low abundance of proteins in the otoconial matrix, we developed a production and purification method for both recombinant homologues of otolin-1. Danio rerio and Homo sapiens otolin-1 forms higher-order oligomers that can be partially disrupted under reducing conditions. The presence of Ca2+ stabilizes the oligomers and significantly increases the thermal stability of the proteins. Despite the high sequence coverage, the oligomerization of Danio rerio otolin-1 is more affected by the reducing conditions and presence of Ca2+ than the human homologue. The results show differences in molecular behaviour, which may be reflected in Danio rerio and Homo sapiens otolin-1 role in otolith and otoconia formation.

Association between otolin-1 and benign paroxysmal positional vertigo: A meta-analysis.

Background: There is increasing research on the potential of inner ear proteins as serum biomarkers for the diagnosis and prognosis of various inner ear diseases. Among them, benign paroxysmal positional vertigo (BPPV) is the most common vestibular disease. Notably, otolin-1, an inner ear-specific protein, is detectable in the serum of most patients with BPPV patients. Therefore, we found a need to conduct this meta-analysis to determine the relationship between otolin-1 in serum and BPPV. Methods: This meta-analysis was conducted by searching PubMed, EMBASE, Cochrane Library, Google Scholar, and China Network Knowledge Infrastructure databases for the eligible original studies in Chinese or English published between January 2010 and February 2022. Data were collected and pooled by using the mean differences (MDs) corresponding to 95% confidence intervals (CIs). Heterogeneity among these studies was assessed by using I2 statistics and the adopted fixed or random-effect mode thereafter. Egger's and Begg's tests were also used to assess the publication bias. Results: This meta-analysis included six articles with a total of 585 participants. Serum otolin-1 levels were remarkably increased in patients with BPPV as compared to that in healthy controls (MD: 165.38, 95% CI: 110.13-220.64, p < 0.00001). However, Egger's and Begg's tests have indicated no publication bias, and the results were reliable based on the sensitivity analysis. Conclusion: This meta-analysis indicated that there is a higher serum level of otolin-1 in patients with BPPV than in healthy controls. Therefore, otolin-1 may serve as a biomarker for the onset of BPPV.

A potential serological biomarker for inner ear pathologies: OTOLIN-1.

Objective: The goal of the study was to determine whether the level of OTOLIN-1, a protein whose expression is highly restricted to the inner ear,is increased in the body fluids of patients with inner ear disorders in comparison to healthy subjects. Methods: In the preliminary part of the study, OTOLIN-1 levels were measured in the serum, urine, and saliva of patients with an acute onset of Ménière´s disease and in healthy individuals. Subsequently, only serum OTOLIN-1 levels were taken into account and were compared between patients with acute onset of Ménière´s disease, sudden hearing loss, vestibular neuritis and healthy subjects. Results: The most reliable diagnostic parameter was OTOLIN-1 levels in serum. Serum samples of patients with Ménière's disease and sudden hearing loss showed significantly higher OTOLIN-1 levels than those from healthy individuals. In addition, there was no significant difference between the serum concentration of OTOLIN-1 in patients with vestibular neuritis and the control group. Conclusions: Serum levels of OTOLIN-1 can potentially be used as a biomarker for acute onset of inner ear disorders due to its significant increase in patients with acute Meniere´s disease and sudden hearing loss in comparison to healthy individuals.

High Serum Levels of Otolin-1 in Patients With Benign Paroxysmal Positional Vertigo Predict Recurrence.

Background: Otolin-1 is an inner ear-specific protein that is exclusively expressed in otoconia and vestibule and cochlea cells. Recent investigations reported that otolin-1 can cross the blood-labyrinthine barrier and that the levels in serum well-reflected otolith status. Serum otolin-1 levels in patients with benign paroxysmal positional vertigo (BPPV) are significantly elevated compared with healthy controls. We aimed to explore whether otolin-1 can also serve as a biomarker for predicting BPPV recurrence. Method: Patients at our institution with new-onset of idiopathic BPPV between May, 2017 and May, 2018 were recruited and followed up for 2 years. All demographic data of the patients were collected, and serum levels of otolin-1 and other laboratory indicators were measured and compared according to the recurrence status. Results: A total of 74 patients, who met the inclusion criteria were enrolled in this study, of which 27 (36.5%) patients had suffered one or more episodes of recurrence after undergoing canal repositioning treatments during the study. The serum levels of otolin-1 in patients with recurrent BPPV were significantly higher than those in patients without recurrent BPPV (363.9 vs. 309.8 pg/ml, p = 0.001). In multivariate analysis comparing the second to fourth quartiles (Q2-Q4) against the first quartile (Q1) of otolin-1, the level of otolin-1 in Q4 could significantly predict BPPV recurrence, and the odds ratio (OR) was elevated by approximately 812% (OR = 9.12; 95% confidence interval [CI]: 1.44-57.9; p = 0.019). Conclusion: High serum levels of otolin-1 were associated with an increased risk of BPPV recurrence, and further investigation is required to confirm this association and clarify the exact mechanism.

An evaluation of serum Otolin-1 & Vitamin-D in benign paroxysmal positional vertigo.

BACKGROUND: Serum otolin-1 is an inner ear protein exclusively expressed in otoconia and cells of vestibule and cochlea. Serum otolin-1 is found to be quantifiable in patients with BPPV. Low Vitamin-D is associated with pathogenesis of BPPV. Since otoconia degeneration contributes to BPPV, lack of Vitamin-D may impact otoconia structure and integrity. OBJECTIVE: We aimed at studying the s.otolin-1 as biomarker and significance of vit-D in BPPV. MATERIAL AND METHOD: 23 patients in test and control groups respectively were chosen within the age of 20 to 65 years. All the patients were diagnosed using Dix Hallpike menouver and head roll test, patients were treated with appropriate Canal Reposition Menouver (CRM). RESULTS: Serum Otolin-1 levels among the test ranged from 366 to 882 pg/mL with mean of 585.17 pg/mL whereas in control group ranged from 223 to 462 pg/mL with mean of 335.26 pg/mL. Mean Vitamin-D levels among the test group was 22.67 ng/mL (Range = 6.3-68.4) and that of control 15.43 pg/mL (Range = 5.4-27.7) respectively. The relationship between the serum Otolin-1 and Vitamin-D was not statistically significant. CONCLUSION: Otolin-1 levels is increased in BPPV patients and is sensitive in BPPV, specificity needs to be validated. Role of vitamin-D with respect to inner ear proteins needs further investigation.

Increased Otolin-1 in Serum as a Potential Biomarker for Idiopathic Benign Paroxysmal Positional Vertigo Episodes.

Objective: Otolin-1, a main specific otoconia matrix protein, passes through the labyrinth-blood barrier and is detectable in peripheral blood. Serum otolin-1 levels differ between patients with benign paroxysmal positional vertigo (BPPV) and healthy controls and are significantly age-related, increasing in healthy controls with age, suggesting that serum otolin-1 levels reflect otolith status. The aim of this study was to determine whether otolin-1 levels change during vertigo episodes in patients with BPPV and whether any change is specific and sensitive enough for BPPV episodes. Method: Patients diagnosed with de novo idiopathic BPPV during an acute episode were included in the study from May 2017 to May 2018. Blood samples were drawn before patients were treated with canalith-repositioning maneuvers. Serum otolin-1 levels were compared between 78 patients and 121 age- and sex-matched healthy individuals. Results: There were no significant differences between the groups in the age distribution, sex ratio, body mass index, clinical history, routine blood parameters, or total protein, albumin, uric acid, creatinine, blood urea nitrogen and lipid profiles (P > 0.05). Serum levels of otolin-1 were significantly higher in BPPV patients than in healthy controls (P < 0.001). Receiver operating characteristic analysis revealed that a serum otolin-1 value of 299.45 pg/ml was the optimal cut-off value to discriminate patients with BPPV from healthy controls (area under the curve 0.757, 95% CI 0.687~0.826) with a sensitivity of 67.9% and a specificity of 72.7%. Conclusion: Serum levels of otolin-1 may be a potential biomarker for BPPV episodes.

[Changes of serum E2 and Otolin-1 levels in postmenopausal women with BPPV].

Objective:To investigate the changes of serum estradiol（E2） and otolith structural protein Otolin-1 levels in postmenopausal women with benign paroxysmal positional vertigo（BPPV）. Method:Forty postmenopausal women diagnosed as primary BPPV were selected as the experimental group. Meanwhile, 40 postmenopausal women without vertigo during the same time were selected as the control group. 4 ml of fasting peripheral venous blood was extracted in the morning, and E2 and Otolin-1 protein levels in serum of the two groups were detected by electrochemiluminescence（ECL） and ELISA, respectively. Result:①The serum level of E2 in the experimental group was（29.11±15.11） pg/ml, which was lower than that in the control group（37.18±12.24） pg/ml（P=0.010）. ②The serum level of Otolin-1 in the experimental group was（361.55±186.14） pg/ml, which was significantly higher than that in the control group（282.61±139.98） pg/ml（P=0.035）. ③Spearman correlation analysis was carried out on the serum levels of Otolin-1 and E2 in the experimental group and the control group, respectively, and no correlation was found between them（P=0.403 and 0.363, respectively）. ④In the control group, age was negatively correlated with serum E2 level（P=0.044, r=-0.320）, suggesting that age was only weakly correlated with E2 level. However, in the experimental group, there was no correlation between the two（P=0.148）. ⑤There was no correlation between age and serum Otolin-1 level in the two groups（P=0.705 and 0.076, respectively）. Conclusion:Compared with postmenopausal patients without vertigo, the level of E2 in postmenopausal BPPV patients decreased, but the level of Otolin-1 increased significantly. Therefore, the serum level of Otolin-1 may be used as a bio-marker to assist the diagnosis and efficacy evaluation of postmenopausal women with BPPV.

Effect of calcium ions on structure and stability of the C1q-like domain of otolin-1 from human and zebrafish.

Otolin-1 is a collagen-like protein expressed in the inner ear of vertebrates. It provides an organic scaffold for otoliths in fish and otoconia in land vertebrates. In this study, the expression and purification procedure of C1q-like domain of otolin-1 from human and zebrafish was developed. The structure and stability of the proteins were investigated. The results of sedimentation velocity analytical ultracentrifugation and small-angle X-ray scattering indicated that the C1q-like domain of otolin-1 forms stable trimers in solution in the presence of calcium ions. It was also observed that calcium ions influenced the secondary structure of the proteins. C1q-like domains were stabilized by the calcium ions. The human variant was especially affected by the calcium ions. The results indicate the importance of the C1q-like domain for the assembly of the organic matrix of otoliths and otoconia.

Correlation between the expression of serum estradiol and otolin-1 and the recurrence of postmenopausal benign paroxysmal positional vertigo / 中国医师杂志

Objective:To explore the correlation between the expression levels of serum estradiol and otolin-1 and the recurrence of postmenopausal benign paroxysmal positional vertigo (BPPV).Methods:A total of 116 postmenopausal female patients who were diagnosed with primary BPPV in the Vertigo Treatment Center of Beijing Geriatric Hospital from January 2018 to December 2019 were selected as the research objects. They were divided into recurrence group (27 cases) and the non-recurrence group (89 cases) according to the recurrence during follow-up. The basic data, laboratory indexes and complications of the two groups were compared. The serum estradiol level was detected by electrochemiluminescence and the serum otolin-1 level was detected by enzyme-linked immunosorbent assay. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of serum estradiol and otolin-1 in the recurrence of postmenopausal BPPV patients; Multivariate logistic regression was used to analyze the risk factors of recurrence in postmenopausal BPPV patients.Results:The proportion of severe cough in the recurrence group was higher than that in the non-recurrence group ( P<0.05); the level of estradiol in the recurrence group was significantly lower than that in the non-recurrence group ( P<0.05), and the level of otolin-1 was significantly higher ( P<0.05); ROC results showed that the areas under the curve (AUCs) of serum estradiol and otolin-1 for predicting the recurrence of postmenopausal BPPV patients were 0.852 (95% CI: 0.774-0.911) and 0.722 (95% CI: 0.631-0.801) respectively, and the cut-off values were 18.09 pg/ml and 361.79 pg/ml respectively; Multivariate logistic regression analysis showed that severe cough, estradiol ≤18.09 pg/ml, and otolin-1 >361.79 pg/ml were independent risk factors for recurrence in postmenopausal BPPV patients ( P<0.05). Conclusions:The serum estradiol level of patients with postmenopausal BPPV recurrence decreases, and the level of otolin-1 increases. The abnormal level is an independent risk factor affecting the recurrence of patients with postmenopausal BPPV.

Spatial Expression of Otolith Matrix Protein-1 and Otolin-1 in Normally and Kinetotically Swimming Fish.

Kinetosis (motion sickness) has been repeatedly shown to affect some fish of a given clutch following the transition from 1g to microgravity or from hypergravity to 1g. This susceptibility to kinetosis may be correlated with irregular inner ear otolith growth. Otoliths are mainly composed of calcium carbonate and matrix proteins, which play an important role in the process of otolith mineralization. Here, we examine the morphology of otoliths and the expression pattern of the major otolith proteins OMP-1 and otolin-1 in a series of hypergravity experiments. In the utricle, OMP-1 is present in centripetal (medial) and centrifugal (lateral) regions of the meshwork area. In the saccule, OMP-1 was expressed within a dorsal and a ventral narrow band of the meshwork area opposite to the periphery of the sulcus acusticus. In normal animals, the spatial expression pattern of OMP-1 reaches more posteriorly in the centrifugal aspect and is considerably broader in the centripetal portion of the utricle compared to kinetotic animals. However, otolin-1 was not expressed in the utricule. In the saccule, no differences were observed for either gene when comparing normal and kinetotically behaving fish. The difference in the utricular OMP-1 expression pattern between normally and kinetotically swimming fish indicates a different otolith morphology and thus a different geometry of the otoliths resting on the corresponding sensory maculae. As the utricle is the endorgan responsible for sensing gravity, the aberrant morphology of the utricular otoliths, based on OMP-1 expression, likely leads to the observed kinetotic behavior.