Longitudinal study of seafood and fish oil supplement intake and risk of persistent tinnitus

Abstract

Background

Persistent tinnitus is common, disabling, and difficult to treat. Diet has been implicated in tinnitus etiology, but studies are inconsistent, and longitudinal data are scarce. Seafood intake is associated with a lower risk of hearing loss, but the longitudinal association with tinnitus is unknown.

Objectives

We examined the independent associations of seafood intake, fish oil supplement use, and risk of developing persistent tinnitus.

Methods

This prospective cohort study followed 73,482 females in the Nurses’ Health Study II from 1991 to 2021. Diet was assessed using a validated food frequency questionnaire every 4 y. Multivariable-adjusted Cox proportional hazards regression was used to evaluate independent associations between total seafood intake, specific types of fish, shellfish, fish oil supplements, and risk of persistent tinnitus (defined as tinnitus experienced daily).

Results

After 1,998,421 person-y of follow-up, 9362 cases of incident persistent tinnitus were reported. Seafood intake was independently associated with a lower risk of developing persistent tinnitus. Compared with participants who never or rarely consumed seafood, the multivariable-adjusted hazard ratios (MVHRs; 95% confidence interval) for tinnitus were 0.87 (0.78, 0.95) among participants who consumed 1 serving/wk, 0.77 (0.68, 0.86) for 2–4 servings/wk, and 0.79 (0.64, 0.96) for 5+/servings/wk (P-trend < 0.0001). Examined individually, higher intakes of tuna fish, light-meat fish and shellfish were associated with lower risk. Compared with participants who never or rarely consumed the specific type, the MVHRs for consumption of 1+ servings/wk were 0.84 (0.78, 0.90) (P-trend < 0.0001) for tuna fish, 0.91 (0.83, 0.99) (P-trend = 0.04) for light-meat fish, and 0.82 (0.72, 0.93) (P-trend < 0.0001) for shellfish. A higher risk for dark-meat fish intake was suggested [MVHR: 1.09 (0.99, 1.21) (P-trend = 0.04)]. Fish oil supplement use (yes/no) was associated with higher risk [MVHR: 1.12 (1.06, 1.19)].

Conclusions

Regular consumption of tuna fish, light-meat fish, or shellfish is associated with a lower risk of developing persistent tinnitus in females. Fish oil supplement use is associated with higher risk.

Introduction

Tinnitus is the perception of sound in the absence of an external stimulus [1]. The perception of tinnitus can vary among individuals and is commonly described as a ring, buzz, roar, whistle, hum, click, hiss, or squeal. The phantom sound can be intermittent or constant, may vary in volume and pitch, and may be perceived in 1 or both ears or in the head. Persistent tinnitus can be disabling, leading to impaired sleep, concentration, work and daily function, and reduced quality of life [2]. Approximately 50 million adults in the United States suffer from tinnitus, among whom 3 million are severely disabled by it [3], and the economic burden of tinnitus is substantial [4]. There is no cure for tinnitus, and the effectiveness of available treatments is generally uncertain [5]. The etiology of persistent tinnitus is often unclear, and there are few long-term longitudinal investigations of factors that influence risk of its development [6,7]. Although tinnitus may be precipitated by pathologic alterations anywhere along the auditory pathway, the persistence of the tinnitus perception likely results from subsequent changes in the central nervous system. Identifying whether there are modifiable factors that influence risk of persistent tinnitus could aid in prevention and inform targeted treatment strategies for this often intractable condition.

Dietary intake may influence risk of developing persistent tinnitus, but findings from cross-sectional studies have been inconsistent, and longitudinal data are limited [[8], [10]]. Previous studies demonstrate that higher seafood intake is associated with a lower risk of hearing loss [11] and other neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease [12], but the longitudinal association of seafood intake and risk of developing persistent tinnitus is unclear. One cross-sectional study in the UK Biobank found modestly lower odds of prevalent persistent tinnitus among participants who reported eating “non-oily” or “oily” fish, but no associations were observed for bothersome tinnitus or transient tinnitus [8]. An important limitation of that study was that diet information was obtained from a nonvalidated questionnaire with a relatively small set of food questions that did not allow assessment of simultaneous adjustment for overall dietary intake. To further investigate whether seafood intake may influence the risk of developing persistent tinnitus, we longitudinally examined the relation of seafood intake, as well as intake of specific types of fish and shellfish, and the risk of incident persistent tinnitus in a well-characterized cohort of 73,482 United States females, who were followed for up to 30 y.

Methods

Study population

The Conservation of Hearing Study (CHEARS) investigates risk factors for auditory disorders, including hearing loss and tinnitus, among participants in several large ongoing prospective cohort studies, including the Nurses’ Health Study II. Nurses’ Health Study II was established in 1989 with the enrollment of 116,408 female registered nurses aged 25–42 y. Participants completed questionnaires at baseline and every 2 y regarding a wide range of demographic, health, diet, and lifestyle factors, including detailed information on medication use (questionnaires can be accessed at: https://www.nurseshealthstudy.org/participants/questionnaires). The follow-up rate over >30 y exceeds 90% of eligible person-time [13]. Participants with tinnitus at baseline for this study in 1991 (the first year that dietary information was assessed) were excluded (n = 1958), allowing us to examine the longitudinal association of dietary intake and subsequent development of incident tinnitus. We also excluded participants who reported cancer (other than nonmelanoma skin cancer) due to potential exposure to ototoxic chemotherapy (n = 1130), a history of stroke (n = 176), had missing information on tinnitus (n = 24,223), date of tinnitus onset (n = 4222), participants who reported implausible energy intake (defined as <600 or >3500 kcal/d) or missing information on diet at baseline (n = 11,217) [[14], [15], [16]]. In our primary analysis, 73,482 participants were included in the analytic sample (Supplemental Figure 1). The study protocol was approved by the institutional review board of Brigham and Women’s Hospital. Participants provided implied consent by virtue of returning their questionnaires, which is accepted by the Brigham and Women’s Hospital Institutional Review Board as informed consent.

Ascertainment of seafood intake

Dietary intake was assessed by using a validated semiquantitative food frequency questionnaire (SFFQ) that included >130 items and was first administered in 1991 and then every 4 y thereafter [[14], [15], [16]]. The SFFQ included 4 questions about finfish and shellfish intake, with common units or portion sizes for each item: 1) canned tuna fish (3–4 oz); 2) dark-meat fish, such as tuna steak, mackerel, salmon, sardines, bluefish, and swordfish (3–5 oz); 3) light-meat (other) fish, such as cod, haddock, and halibut (3–5 oz); and 4) shrimp, lobster, scallops, and clams as a main dish. For each item, participants were asked “how often, on average,” they had consumed a given quantity during the preceding year. Nine response options were provided, ranging from “almost never” to “6 or more per day.” For clarity, the term “seafood” will include the total intake of fish and shellfish, whereas individual seafood types will be described as dark-meat fish, light-meat fish, canned tuna fish, and shellfish. Seafood intake was assessed by totaling the participant’s response to the finfish plus shellfish items. To assess long-term intake and to minimize misclassification, we calculated cumulative average intake so that fish, shellfish, and other dietary intake in a given time period represented the average intake of previous and current time periods [17]. The SFFQ also collected information on dietary supplement use, including fish oil supplements. The reproducibility and validity of the SFFQ as an instrument for ranking individuals by fish intakes have been demonstrated in several validation studies in this and similar cohorts [[14], [15], [16]].

Ascertainment of tinnitus

Information on tinnitus was collected on the 2009, 2013, 2017, and 2021 biennial questionnaires. Participants were asked, “In the past 12 mo, have you had ringing, roaring, or buzzing in your ears or head?” Information was also collected on how often the symptoms occur (ranging from never to every day), how long symptoms last (“a few seconds,” “<5 min,” “5 min to an hour,” “several hours,” or “all the time”), and the age at which the symptoms first began. Consistent with methods used previously in this and other cohorts [[18], [19], [20]], we defined persistent tinnitus as tinnitus occurring daily to evaluate associations among those with the most severe tinnitus. In additional analyses, we examined alternative definitions of tinnitus, including tinnitus occurring several days per week.

Assessment of covariates

In multivariable-adjusted analyses, we included factors potentially associated with fish and shellfish intake and tinnitus using updated information (the most recent information available from each subsequent questionnaire). On the 1989 questionnaire, participants responded to a question about their major ancestry. The response options provided were Southern European/Mediterranean, Scandinavian, Other Caucasian, African American, Hispanic, Asian, and Other. Participants could mark >1 response. Factors included were age (years, continuous), major ancestry (self-identified categories), BMI (in kg/m²) (<21, 21–22, 23–24, 25–29, 30–31, ≥32), waist circumference (<70, 71–79, 80–88, >88 cm), physical activity (quintiles, metabolic equivalents from recreational and leisure-time activities), smoking (never, past, current), hypertension (yes/no), diabetes mellitus (yes/no), depression (defined as the use of antidepressants in the past 2 y or self-reported diagnosis, yes/no), anxiety (using the phobic anxiety scale of the Crown-Crisp Experiential Index) [21], aspirin use (number of days per week), ibuprofen use (number of days per week), acetaminophen use (number of days per week), caffeine intake (<150, 150–299, 300–449, 450–599, ≥600 mg/d), alcohol intake (<1, 1–4.9, 5–14.9, 15–29.9, 30–34.9, 35–39.9, 40–44.9, ≥45 g/wk), dietary intake (quintiles, using the Alternate Mediterranean dietary adherence score without fish and alcohol) [22], total energy intake (calories per day) and self-reported hearing status (no hearing loss, mild hearing loss, moderate or worse hearing loss). Covariate information on many of these factors has been validated [13,[23], [24], [25], [26]]. Information on dietary intake and other time-varying covariates was updated at the beginning of each time period based on information obtained from the most recent available questionnaire cycle.

Statistical methods

Descriptive analyses for baseline characteristics in 1991 were examined by categories of seafood intake. All analyses were prospective, using information on the intake of fish and shellfish that was collected before the date of tinnitus onset. We computed the person-time of follow-up for each participant from the study baseline to the date of reported tinnitus, report of cancer (other than nonmelanoma skin cancer), or end of follow-up. Seafood consumption was divided into 5 categories (<1 serving/mo, 1–3 servings/mo, 1 serving/wk, 2–4 servings/wk, and 5+ servings/wk), with the lowest category as the referent group. Based on the number of cases, consumption of specific fish types was divided into 3 categories (<1 serving/mo, 1–3 servings/mo, ≥1 serving/wk). In our primary analyses, to better represent long-term dietary intake and reduce measurement error, we calculated seafood intake as a cumulative average of intake from all available dietary questionnaires up to the start of each follow-up interval [27]. Cox proportional hazard regression models adjusted for potential confounders were used to estimate the multivariable-adjusted hazard ratios (MVHR) for persistent tinnitus by category of intake compared with the lowest category of intake. The proportional hazards assumption was evaluated and found to be valid (P > 0.5 for all tests). To test for a linear trend across categories of intake, we modeled the category medians as a continuous variable. We used restricted cubic splines with knots at the 5th, 35th, 65th, and 95th percentiles [28] to evaluate the dose-response relationship between seafood intake and risk of incident tinnitus. To examine whether the association between seafood intake and risk of tinnitus differed among those with and without self-reported hearing loss, we conducted analyses stratified by hearing status. We used the Anderson-Gill data structure, with a new data record created for each biennial questionnaire cycle in which the participant was at risk, with covariates set to represent the value from the latest returned questionnaire to handle time-varying covariates efficiently. We stratified by age and calendar time in all models. Missingness of the potential confounders was handled by the missing-indicator method; for data on covariates for which we did not have information due to the information being missing or reported as “unknown,” a missing/unknown category was included in the multivariable model using an indicator variable for each covariate [29]. For all hazard ratios, we calculated 95% confidence intervals (CIs). All P values are 2-tailed. Statistical tests were performed with SAS statistical software, version 9.4 (SAS Institute Inc).

Results

Characteristics of participants at baseline (1991) according to the category of seafood intake are shown in Table 1. Baseline characteristics are presented to provide representative values, but updated information was used for the analyses. At baseline, 78.9% of the participants consumed seafood at least once per week. Participants with frequent seafood intake were more likely to identify as Black or Asian, were more physically active, and had slightly higher total energy and alcohol intake. There were no large differences in the 1991 baseline characteristics or in seafood consumption or fish oil supplement use between participants who were included and those who were not included in the study (Supplemental Table 1).

TABLE 1.

Age-standardized baseline (1991) characteristics of females in the Nurses’ Health Study II, according to seafood intake.

Characteristic	Seafood intake (servings)
	<1/mo	1–3/mo	1/wk	2–4/wk	5+/wk
	N = 5403	N = 10,131	N = 44,858	N = 10,577	N = 2513
Age, y1	35.9 (4.8)	36.1 (4.7)	36.2 (4.6)	36.5 (4.6)	36.6 (4.6)
BMI, kg/m2	24.4 (5.3)	24.3 (5.2)	24.4 (5.1)	24.9 (5.4)	25.0 (5.5)
Waist circumference,2 cm	78.1 (13.0)	78.1 (12.8)	77.7 (12.3)	78.5 (13.0)	77.8 (12.6)
White,3 %	94.0	94.2	94.0	92.9	89.1
Black,3 %	0.8	0.9	1.2	1.5	2.4
Hispanic,3 %	0.8	1.1	1.0	1.1	0.9
Asian,3 %	1.2	0.9	1.2	1.6	3.8
Mixed/other,3 %	3.3	2.9	2.7	2.9	3.8
Physical activity, METS/wk4	18.2 (25.3)	17.8 (24.2)	20.3 (25.7)	24.4 (29.4)	31.6 (38.4)
Total energy intake (cal/d)	1585 (524)	1624 (507)	1790 (526)	1975 (545)	2133 (580)
AMED score (without fish)	3.3 (1.7)	3.3 (1.6)	3.8 (1.6)	4.3 (1.5)	4.7 (1.5)
Caffeine intake, mg/d	238.1	243.9	242.9	240.8	243.7
Alcohol intake, g/d	2.2 (5.2)	2.4 (5.5)	3.3 (6.1)	3.6 (6.4)	4.1 (7.1)
Never smoker, %	69.7	69.2	66.2	64.0	62.4
Past smoker, %	19.2	20.0	22.4	24.7	25.3
Current smoker, %	10.9	10.7	11.2	11.1	12.0
Hypertension, %	6.6	5.7	5.6	7.3	8.1
Diabetes, %	0.8	0.9	0.9	1.0	1.1
Depression, %	13.6	13.1	12.3	12.8	12.6
Anxiety, crown-crisp score2	2.3 (1.9)	2.3 (1.9)	2.2 (1.9)	2.3 (1.9)	2.3 (2.0)
Aspirin use
None, %	83.9	84.5	84.0	83.9	82.6
1 d/wk, %	2.2	2.2	2.4	2.2	2.2
≥2 d/wk, %	6.0	5.5	6.2	6.0	6.6
Acetaminophen use5
None, %	46.8	43.8	43.0	43.0	45.0
1 d/wk, %	36.0	38.9	40.0	40.0	36.6
≥2 d/wk, %	13.3	13.3	13.3	13.0	13.5
Ibuprofen use5
None, %	34.3	33.4	32.6	32.2	34.3
1 d/wk, %	37.3	38.4	38.8	40.0	36.0
≥2 d/wk, %	24.1	24.1	24.6	23.5	24.6
No hearing loss,6 %	96.9	97.4	97.4	97.5	97.6
Mild hearing loss,6 %	1.9	1.7	1.6	1.5	1.4
Moderate or worse hearing loss,6 %	1.2	1.0	1.0	0.9	1.0
Fish oil supplement, regular use,7 %	0.3	0.4	0.5	0.6	1.2

Values are means (SD) or medians for continuous variables, percentages or N’s, or both for categorical variables and are standardized to the age distribution of the study population.

Values of polytomous variables may not sum to 100% due to rounding.

Abbreviations: AMED, alternate Mediterranean diet; METS, metabolic equivalents of task; SD, standard deviation.

¹Value is not age-adjusted.

²Measured in 1993.

³On the 1989 questionnaire, participants responded to a question about their major ancestry. The response options provided were Southern European/Mediterranean, Scandinavian, Other Caucasian, African American, Hispanic, Asian, and Other. Participants could mark >1 response.

⁴Metabolic equivalents from recreational and leisure-time activities.

⁵Assessed in 1995.

⁶Hearing status was self-reported on the biennial questionnaire.

⁷Fish oil supplement use on a regular basis.

Seafood intake

After 1,998,421 person-y of follow-up, 9362 cases of incident persistent tinnitus (tinnitus experienced daily) were reported. After adjustment for potential confounders, more frequent seafood intake was inversely associated with the risk of developing persistent tinnitus and the magnitude of the inverse association was greater with increasing frequency of intake (Table 2). In comparison with participants who never or rarely consumed seafood (<1 serving/mo), the MVHR, 95% CI for persistent tinnitus was 0.87 (0.78, 0.95) among participants who consumed 1 serving/wk, 0.77 (0.68, 0.86) for 2–4 servings/wk, and 0.79 (0.64, 0.96) for 5+ servings/wk (P-trend < 0.0001). We observed a linear relationship between the increasing number of servings of seafood consumed per week and the risk of incident persistent tinnitus (P-for-linearity < 0.0001) (Figure 1). In analyses stratified by hearing status, the association between seafood intake and risk of incident tinnitus was similar among those with and without self-reported hearing loss (Supplemental Table 2).

TABLE 2.

Seafood intake and risk of incident persistent tinnitus in the Nurses’ Health Study II (1991–2021) (n = 73,482).

Seafood intake (servings)	n of cases	Person-y	Age-adjusted HR (95% CI)	MVHR1 (95% CI)	MVHR2 (95% CI) (Further adjusted for hearing loss)
<1/mo	447	95,230	1.00 (reference)	1.00 (reference)	1.00 (reference)
1–3/mo	1911	378,320	0.94 (0.85, 1.04)	0.92 (0.83, 1.02)	0.93 (0.84, 1.04)
1/wk	5855	1,241,812	0.88 (0.80, 0.97)	0.85 (0.77, 0.94)	0.87 (0.78, 0.95)
2–4/wk	1029	247,375	0.76 (0.68, 0.85)	0.74 (0.66, 0.83)	0.77 (0.68, 0.86)
5+/wk	120	35,684	0.71 (0.58, 0.86)	0.76 (0.62, 0.93)	0.79 (0.64, 0.96)
P-for-trend			<0.0001	<0.0001	<0.0001

Cox proportional hazard models were used to calculate age- and MVHRs and 95% CIs. Linear trends were assessed by using servings per week as a continuous variable in the age-adjusted and multivariable-adjusted models.

Abbreviations: AMED, alternate Mediterranean diet; CI, confidence interval; HR, hazard ratio; MVHR, multivariable-adjusted hazard ratio.

¹MVHR adjusted for age, major ancestry, BMI, waist circumference, physical activity, smoking, hypertension, diabetes, depression, anxiety, alcohol intake, total energy intake, caffeine intake, aspirin use, ibuprofen use, acetaminophen use, AMED dietary adherence score without fish and alcohol, and fish oil supplement use.

²MVHR adjusted for all covariates in MVHR¹ plus hearing loss.

FIGURE 1.

Total seafood intake and risk of incident persistent tinnitus in the Nurses’ Health Study II (n = 73,482 females). Cubic spline curve describing the association between total seafood intakes and risk of incident persistent tinnitus in the nurses’ health study II (n = 73,482 females). Hazard ratios and 95% CIs are based on Cox proportional hazards models with age as the underlying timescale, adjusted for major ancestry, BMI, waist circumference, physical activity, smoking, hypertension, diabetes, depression, anxiety, alcohol intake, total energy intake, caffeine intake, aspirin use, ibuprofen use, acetaminophen use, AMED dietary adherence score without fish and alcohol, hearing loss and fish oil supplement use. The P value for nonlinearity was obtained using the likelihood ratio test. AMED, alternate Mediterranean diet; CI, confidence interval.

Specific types of fish and shellfish

We also examined the relationship between the consumption of specific types of fish or shellfish and the risk of persistent tinnitus (Table 3). When examined individually, higher intakes of canned tuna fish, light-meat fish, and shellfish were associated with lower risk. Compared with participants who never or rarely consumed the specific type, the MVHRs were 0.84 (0.78, 0.90) among those who consumed 1 or more servings per week of canned tuna (P-trend < 0.0001); 0.91 (0.83, 0.99) for light-meat fish (P-trend = 0.04); and 0.82 (0.72, 0.93) for shellfish (P-trend < 0.0001). There was a suggestion that dark-meat fish intake was associated with higher risk [MVHR: 1.09 (0.99, 1.21)] (P-trend = 0.04) for 1 serving/wk or more.

TABLE 3.

Specific type of seafood intake and risk of incident persistent tinnitus in the Nurses’ Health Study II (1991–2021) (n = 73,482).

Seafood intake (servings)	n of cases	Person-y	Age-adjusted HR (95% CI)	MVHR1 (95% CI)	MVHR2 (95% CI) (Further adjusted for hearing loss)
Canned tuna fish
<1/mo	1678	336,674	1.00 (reference)	1.00 (reference)	1.00 (reference)
1–3/mo	5476	1,098,778	0.93 (0.88, 0.99)	0.91 (0.86, 0.97)	0.92 (0.87, 0.97)
1+/wk	2207	562,419	0.83 (0.78, 0.88)	0.83 (0.78, 0.89)	0.84 (0.78, 0.90)
P-for-trend			<0.0001	<0.0001	<0.0001
Dark-meat fish
<1/mo	5301	1,220,555	1.00 (reference)	1.00 (reference)	1.00 (reference)
1–3/mo	3536	666,721	1.03 (0.98, 1.07)	1.05 (1.00, 1.10)	1.05 (1.00, 1.10)
1+/wk	524	109,201	0.95 (0.87, 1.04)	1.09 (0.98, 1.20)	1.09 (0.99, 1.21)
P-for-trend			0.8	0.03	0.04
Light-meat fish
<1/mo	2989	633,781	1.00 (reference)	1.00 (reference)	1.00 (reference)
1–3/mo	5522	1,114,915	0.99 (0.95, 1.04)	1.01 (0.97, 1.07)	1.02 (0.97, 1.07)
1+/wk	846	247,938	0.82 (0.76, 0.88)	0.90 (0.82, 0.98)	0.91 (0.83, 0.99)
P-for-trend			<0.0001	0.04	0.04
Shellfish
<1/mo	4861	1,009,063	1.00 (reference)	1.00 (reference)	1.00 (reference)
1–3/mo	4214	912,835	0.89 (0.85, 0.92)	0.89 (0.85, 0.93)	0.90 (0.86, 0.94)
1+/wk	286	75,734	0.76 (0.68, 0.86)	0.82 (0.72, 0.93)	0.82 (0.72, 0.93)
P-for-trend			<0.0001	<0.0001	<0.0001

Cox proportional hazard models were used to calculate age- and MVHRs and 95% CIs. Linear trends were assessed by using servings per week as a continuous variable in the age-adjusted and multivariable-adjusted models.

Abbreviations: AMED, alternate Mediterranean diet; CI, confidence interval; HR, hazard ratio; MVHR, multivariable-adjusted hazard ratio.

¹MVHR adjusted for age, major ancestry, BMI, waist circumference, physical activity, smoking, hypertension, diabetes, depression, anxiety, alcohol intake, total energy intake, caffeine intake, aspirin use, ibuprofen use, acetaminophen use, AMED dietary adherence score without fish and alcohol, the other individual fish types, and fish oil supplement use.

²MVHR adjusted for all covariates in MVHR¹ plus hearing loss.

Fish oil supplements

At baseline (1991), the use of fish oil supplements use was uncommon (∼1%), but supplement use increased over the course of follow-up. In 2011, ∼25–40% of participants reported fish oil supplement use. The characteristics of the participants according to fish oil supplement use (yes/no) in 2011 are shown in Supplemental Table 3. No large differences were observed. Fish oil supplement use was independently associated with a higher risk of persistent tinnitus (Table 4). After adjustment for total seafood intake and the other covariates, compared with never users, the MVHR was 1.12 (1.06, 1.19) among fish oil supplement users.

TABLE 4.

Fish oil supplement use and risk of persistent tinnitus in females in the Nurses’ Health Study II (1991–2021).

Fish oil supplement Use1	Number of cases	Person-y	Age-adjusted HR (95% CI)	Multivariable-adjusted HR2 (95% CI)
No	7670	1,797,036	1.00 (reference)	1.00 (reference)
Yes	1692	201,385	1.30 (1.23, 1.37)	1.12 (1.06, 1.19)

Cox proportional hazard models were used to calculate age- and MVHRs and 95% CIs.

Abbreviations: AMED, alternate Mediterranean diet; CI, confidence interval; HR, hazard ratio; MVHR, multivariable-adjusted hazard ratio.

¹Fish oil supplement use on a regular basis.

²MVHR adjusted for age, major ancestry, BMI, waist circumference, physical activity, smoking, hypertension, diabetes, depression, anxiety, alcohol intake, total energy intake, caffeine intake, aspirin use, ibuprofen use, acetaminophen use, AMED dietary adherence score without fish and alcohol, hearing loss, and dark-meat fish, light-meat fish, canned tuna fish, and shellfish intake.

Discussion

In this large prospective study of >73,000 females, we observed a lower risk of developing incident persistent tinnitus among participants who consumed seafood regularly. Notably, we found a linear, direct association between the number of servings of total seafood consumed per week and the risk of incident tinnitus. However, the magnitude of the association depended on the frequency and type of seafood consumed. Regular consumption of tuna fish, light-meat fish, and shellfish were each associated with lower risk, whereas there was a suggestion that dark-meat fish consumption was associated with higher risk. These findings indicate that dietary factors may be important in the pathogenesis of tinnitus. Adjustment for hearing loss did not alter the magnitude of the associations between fish intake and tinnitus, suggesting the potential influence of fish intake on tinnitus is independent of hearing status. Of note, fish oil supplement use may increase the risk of developing tinnitus.

Fish and shellfish are recognized as important contributors to an overall healthy diet. They are the major sources of long-chain omega (ω)-3 PUFAs and are rich in vitamin D, several B vitamins, folic acid, and minerals such as selenium, iron, zinc, iodine, magnesium, and potassium, high in protein and low in saturated fat [30,31]. Previous studies show the benefits of eating fish once or twice a week, including reduced risk of cardiovascular disease, depression, neurodegenerative disease, and other chronic conditions [[32], [33], [34], [35]]. The antioxidative, anti-inflammatory, neuroprotective, and cardioprotective properties of the ω-3 PUFAs and other nutrients found in seafood may help protect against persistent tinnitus by maintaining vascular health and attenuating cerebrovascular disease [36], reducing neuroinflammation [37], promoting neuronal health [[38], [39], [40]], and possibly by moderating symptoms of depression or other mood-related disorders [41]. The influence of dietary intake on circulating metabolite profiles associated with the development of cardiovascular disease, type 2 diabetes, depression, and neurodegenerative disease has been shown [42,43]; plausibly, diet may also influence the persistence of tinnitus [[44], [45], [46], [47]]. Similar to findings for other neurodegenerative disorders, our recent metabolomics findings indicate that metabolic dysregulation may play a contributing role to tinnitus [20].

Evidence suggests persistent tinnitus can be precipitated by cochlear dysfunction and reduced auditory nerve output that initiates a neurobiological signaling cascade that triggers central neuroplastic changes [48] and altered limbic, autonomic, and reticular activity [49,50]. Once triggered, factors that influence neuroinflammation, neural transmission, and neuroplasticity may all contribute to tinnitus persistence [50]. Seafood consumption may help maintain adequate cochlear blood flow and protect against ischemic injury. Cochlear vascular compromise can disrupt the maintenance of the endocochlear potential, ion transport, endolymphatic fluid balance, and the integrity of the blood-labyrinth barrier in the stria vascularis [51]. Seafood consumption could also reduce the risk of tinnitus by reducing the burden of cerebrovascular risk factors and neuroinflammation [34,37,38]. A population-based study in France found that higher fish intake was associated with a lower magnetic resonance imaging burden of cerebrovascular disease [52]. ω-3 PUFAs and other nutrients in commonly consumed fish and shellfish were shown to have anti-inflammatory and neuroprotective benefits [31,53]. Both fish and shellfish are abundant in nicotinamide adenine dinucleotide [31], which may play a protective role in neurodegenerative disorders by mitigating oxidative stress, inflammation, and mitochondrial dysfunction [54,55].

The association between seafood intake and risk of incident tinnitus was similar among those with and without hearing loss. It is noteworthy that most individuals with hearing loss do not report persistent tinnitus [[56], [57]]. A recent genome-wide association study meta-analysis showed that although tinnitus and hearing loss share a large number of variants, there is also a distinct genetic architecture of tinnitus with higher polygenicity and a large proportion of variants that do not overlap with hearing loss. Further, unlike hearing loss, investigators found tissue-expression analysis for tinnitus inferred broad enrichment across most brain tissues, indicating that tinnitus as a disorder is distinct from hearing loss [58].

The central nervous system plays a major role in the pathophysiology of tinnitus [[57], [59], [60]], and dysfunction of the noise-canceling system may contribute to the persistence of chronic tinnitus [[61], [62], [63]]. Possibly, neuroprotective constituents in seafood could help prevent aging-related neurodegenerative changes that increase susceptibility to tinnitus persistence. A study of fish consumption and age-related brain gray matter loss demonstrated that dietary fish intake was related to larger gray matter volumes, particularly in the orbital frontal cortex, anterior cingulate gyrus, hippocampus, and posterior cingulate gyrus [35], regions that have also been implicated in tinnitus persistence and tinnitus distress [[61], [64], [65]]. Among individuals with persistent tinnitus, fMRI findings indicate disruptions in functional connectivity patterns involving these regions and brain auditory, prefrontal, visual, and default mode networks [66].

Findings from previous studies have been inconclusive. A cross-sectional study in the UK Biobank, using a nonvalidated set of questions about commonly eaten food groups, observed modest inverse odds for consumption once per week or more of “non-oily fish” [odds ratio (OR): 0.91; 95% CI: 0.87, 0.94] or “oily fish” (OR: 0.95; 95% CI: 0.91, 0.99) and persistent tinnitus, but no association for bothersome tinnitus [8]. Although a small hospital-based case-control study in Italy using a single assessment of diet found no significant association between fish intake and tinnitus [67], the findings were suggestive of an inverse association (OR: 0.75; 95% CI: 0.41, 1.40) for fish consumption 2 or more times per week. Whereas other studies of diet and tinnitus suggested that dietary intake may influence tinnitus risk [[9], [10], [68], [69]], to our knowledge, our report is the first large longitudinal study to examine fish and shellfish intake and risk of incident persistent tinnitus using a well-validated food frequency questionnaire with prospectively collected repeated measures of dietary intake along with extensive and updated information on tinnitus and potentially related factors.

Our findings that dark-meat fish and fish oil supplements were not associated with a lower risk of persistent tinnitus were unexpected. Possibly, these findings could indicate that there are nutrients in seafood other than the ω-3 PUFAs that are more important in protecting against tinnitus or that components present in dark-meat fish or fish oil supplements offset the benefits that ω-3 PUFAs provide. Light-meat fish and shellfish tend to have less fat and more protein than dark-meat fish. All are good sources, although in differing amounts, of ω-3 PUFAs, phosphorus, selenium, niacin, vitamin B-12, and other B vitamins. Several types of shellfish are also sources of iron, zinc, magnesium, copper, iodine, and other trace minerals. Nutrient content is influenced by factors such as habitat and feeding, leading to wide variation within specific seafood types. Notably, certain types of dark-meat fish, such as shark, swordfish, king mackerel, and tilefish, may be high in mercury or other contaminants. Reduced hearing sensitivities and prolonged auditory brainstem responses following mercury exposure have been shown in humans and in animals [[70], [71], [72]]. Fish may absorb contaminants that are persistent, bioaccumulative, and toxic, such as polychlorinated biphenyls (PCBs), per- and polybrominated diphenyl ethers, dioxins, chlorinated pesticides and per- and polyfluoroalkyl substances [[73], [74]]. Studies in Europe, Asia and the United States have shown significant associations between seafood consumption and higher plasma polyfluoroalkyl substances burden [[75], [76], [77], [78], [79]]. The influence of specific seafood species on risk of tinnitus merits further investigation.

Our findings showed that fish oil supplement use did not reduce risk of tinnitus; indeed, a modest, significantly higher risk of tinnitus was observed among fish oil supplement users. Although substantial evidence supports the health benefits of eating seafood rich in ω-3 PUFAs, research into the benefits of fish oil supplement use has produced mixed results [[80], [81]]. Clinical trials investigating marine ω-3 PUFA supplementation and several neurodegenerative or cardiovascular health outcomes have been inconsistent, with insufficient or no evidence supporting the reduced risk of major cardiovascular disease outcomes [[81], [82]], cognitive decline [[83], [84]], cancer [82], or pain prevalence or severity [85]. A systematic review of antenatal ω-3 PUFA intake from different sources (seafood, fish, overall diet, and supplementation) with perinatal depression, anxiety, and psychological distress found dietary ω-3 PUFA intake during pregnancy was associated with better perinatal mental health, but ω-3 PUFA supplementation was not [86]. Meta-analyses have shown that ω-3 PUFA supplements were associated with an increased risk for atrial fibrillation [87], coagulopathy, and bleeding [88]. To our knowledge, this is the first large longitudinal study to evaluate the influence of fish oil supplements on the risk of persistent tinnitus. The UK Biobank recorded the use of dietary supplements, but the formulation of supplements was not recorded, and fish oil supplement use was not evaluated [69]. Notably, fish oil supplements are not Food and Drug Administration (FDA) approved as over-the-counter medications and have no FDA-approved clinical indications. In contrast to the rigorous regulatory standards for the safety, efficacy, and manufacturing of prescription and over-the-counter medications, dietary supplements (including fish oil) are classified by the FDA as food. Concerns regarding nonprescription fish oil supplements include demonstrated variability in content, inconsistencies in labeling, low product quality, and impurities [89]. Substantial heterogeneity in the doses of individual ω-3 fatty acids in available supplements was demonstrated, with potential variability in safety and efficacy between supplements [90]. The quality of fish oil supplements derived from fish by-products depends on the source of the raw materials and processing methods and may contain higher concentrations of potentially neurotoxic or ototoxic environmental contaminants and pesticides than the whole fish from which they originated. For example, lipid-soluble organochlorine contaminants, such as PCBs, may become more concentrated in the oil fraction during processing [91]. The adverse influence of PCBs on central auditory function has been shown in animals [[92], [93]] and in humans [94]. Extracted fish oils were shown to be a source of lipophilic persistent organic pollutants, including halogenated contaminants such as PCBs, organochlorinated pesticides, and per- and polybrominated diphenyl ethers [91], and of mineral oil saturated and aromatic hydrocarbons [95]. Further studies that evaluate fish oil supplements with known content and quality would be informative.

Our study has several strengths, including its large size and long duration of follow-up. We collected detailed and regularly updated information on diet, permitting investigation of a broad range of intake. We asked distinct questions about specific fish and shellfish; thus, we were able to examine these individually. We obtained dietary data prospectively before the onset of tinnitus. To account for long-term intake and changes in participants’ patterns of use over several years, we evaluated cumulative average intake over time. Our study also had limitations. Subjective tinnitus is perceived only by the individual; thus, diagnosis must rely on self-report [96]. Definitions of tinnitus used in previous epidemiologic studies have varied greatly [97]; however, when we examined alternative definitions of tinnitus in additional analyses, the results were similar. We did not have information on the diagnosed causes of tinnitus in the full cohort. However, in a subcohort of ∼33,000 who completed an online hearing and tinnitus supplemental questionnaire [19], the frequency of known causes of tinnitus, such as Meniere’s disease (0.9%), vestibular schwannoma (<0.1%), and otosclerosis (<0.1%), were low. Although residual confounding could have influenced the results, the analyses were carefully adjusted for potentially confounding variables. We did not have information on seafood preparation methods. We examined the risk of developing tinnitus, so we cannot comment on whether increasing seafood intake might improve symptoms in individuals with tinnitus. The study population included predominantly White female healthcare professionals, which enhanced the validity of collected health-related information and reduced variability in education and socioeconomic status, but research in additional populations is warranted.

In conclusion, regular seafood consumption, particularly tuna fish, light-meat fish, and shellfish, was associated with a lower risk of persistent tinnitus in females. Fish oil supplement use was associated with higher risk. Seafood intake, but not fish oil supplement use, may help protect against the development of persistent tinnitus.

Acknowledgments

We thank Elaine Coughlan-Gifford for her computer programming support on this project.

Author contributions

The authors’ responsibilities were as follows– SGC: formulated the study question and designed the research (project conception, development of overall research plan, and study oversight), contributed to the data acquisition, conducted the statistical analyses, interpreted the results, wrote and revised the manuscript, and has primary responsibility for the final content; GCC: contributed to the study conception, design, data acquisition, interpretation of the results, and critical revision of the manuscript; OAZ: contributed to the interpretation of the results and critical revision of the manuscript. All authors had access to the data and participated in the preparation of the manuscript; and all authors: read and approved the final manuscript.

Data availability

The data described in this manuscript will be made available from the corresponding author upon reasonable request.

Funding

This research was supported by grants U01 DC010811, UO1 CA176726, and R21 DC020777 from the NIH. The supporting source had no involvement in the study design, collection, analysis, or interpretation of data, writing of the manuscript, or restrictions regarding publication.

Conflict of interest

SGC received an investigator-initiated grant from GlaxoSmithKline Biologicals SA. GCC serves as a consultant to OM1, Atom Bioscience, and receives royalties from UpToDate for being an author and Section Editor. All other authors report no conflicts of interest.

Appendix A. Supplementary data

The following is the Supplementary data to this article: