Mercury is a ubiquitous neurotoxin that exists in elemental, organic, and inorganic forms in nature [1
]. The mechanism involved in methylmercury toxicity are inhibition of protein synthesis, alteration of protein phosphorylation, and microtubule disruption, resulting in increased intracellular Ca2+ concentration that leads to alteration of neurotransmitter function and neuronal death [3
]. Humans incur the highest mercury levels from consumption of seafood because, while methylmercury is accumulated from plankton to humans at high absorption rates, mercury’s excretion rate from the human body is very low and its retention time is long [1
]. Exposure to mercury, in its effect on the nervous system, increases the risk of psychiatric symptoms [3
]. An epidemic outbreak of methylmercury poisoning was first reported in 1956 among residents around Minimata Bay in Japan, the symptoms being severe behavioral dysfunction, deterioration of cognitive function, changes in mood levels, and paralysis, resulting, eventually, in some cases, in death [5
]. Moreover, among Iraq residents in 1972, consumption of methylmercury-treated wheat flour led to neurological deficits, symptoms of depression and anxiety, loss of co-ordination and hearing, as well as slurred speech and blindness [6
Fish is one of the major food sources of polyunsaturated fatty acids (PUFA) such as omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [7
]. In humans, EPA and DHA are synthesized from alpha-linolenic acid (ALA), which in turn is obtained from diets [10
]. According to the American Cancer Society (ACS) and the American Heart Association (AHA), consumption of fish at least two times a week is recommended [11
]. The omega-3 fatty acid is an essential nutrient; it has been suggested, in fact, that sufficient consumption of fish has a protective effect against cardiovascular disease (CVD) and mental illness such as depression [7
]. Omega-3 fatty acid deficiency leads to impairment of serotoninergic and dopaminergic neurotransmitters and, thereby, altered inflammatory status of neurological functions [12
]. According to the Birth Cohort Study in Finland, inappropriate PUFA consumption incurs a higher risk of depression among women [14
]. Methylmercury, a principle type of organic mercury, accumulates in the human body through fish intake, and more than 99% of blood mercury level is known to be due to fish consumption [15
]. Several studies have revealed that higher intake of fish is significantly associated with increased risk of mercury exposure [1
Studies of blood mercury levels have shown both significant and inverse associations of mercury with depressive risk and symptoms [20
]. In Iraq, total blood mercury level was reported to be higher in depressed patients with symptoms of depressive behavior, lack of interest, and deficient concentration [20
]. Moreover, study participants from the Minimata area of Japan, who had been highly exposed to methylmercury, showed a higher prevalence of depressive and psychiatric symptoms than did participants from other areas [21
]. By contrast, among older adults in the general American population, lower risk of depression was associated with higher levels of blood mercury [2
]. Overall, the findings from epidemiologic studies on possible links between mercury and depression risk are inconsistent and mixed.
The aim of the present study was to examine the association between mercury and depression risk and to determine whether it differs by fish intake level and gender using the Korean National Health and Nutrition Examination Survey (KNHANES) 2008–2013.
The distributions of the general characteristics of the study subjects by quintile of blood mercury are shown in Table 1
. Blood mercury level was significantly related to age (p
< 0.0001), BMI (p
< 0.0001), marital status (p
< 0.0001), smoking (p
= 0.02), drinking (p
< 0.0001), household income (p
< 0.0001), physical activity (p
= 0.03), and intake of fish, white fish, fatty fish, and other seafood (p
< 0.0001). Subjects in the highest quintile of blood mercury relative to those in the lowest quintile included adults who were older, female, more likely to be obese, more likely to be married, heavier drinkers, and who had higher household income. With respect to fish intake, the frequency of fish consumption increased as blood mercury levels increased. Individuals in the highest quintiles of blood mercury consumed white fish, fatty fish, and other seafood more frequently than did those in the lowest quintile.
The multivariate logistic regression results of the relationship between depression and blood mercury are presented in Table 2
. For the total subjects, the participants did not show any significant association between blood mercury and depression, despite the multivariate analysis (model 1) controlling for demographic and lifestyle variables. However, a statistically significant association between depression and blood mercury was noted after adding fatty fish intake (OR = 1.77; 95% CI = 1.12–2.78) (p
-trend = 0.02) and fish intake (OR = 1.76; 95% CI = 1.12–2.76) (p
-trend = 0.03) to the multivariate adjustment of demographic and lifestyle variables. When the multivariate logistic regression analysis was performed by gender, the association between depression and blood mercury differed. Females showed a significant association between depression and blood mercury in model 2 (OR = 2.07; 95% CI = 1.22–3.51) (p
-trend = 0.03) and in model 3 (OR = 2.05; 95% CI = 1.20–3.48) (p
-trend = 0.03). By contrast, among males, blood mercury was not significantly related to depression in any of the models examined.
provides the odds ratios and 95% confidence intervals for the association between depression and blood mercury as stratified by gender and fish intake. Total fish intake was divided into tertiles by gender. In females, the association between depression and blood mercury differed by a tertile of fish intake. In the lowest tertile of fish intake among females, the association between depression and blood mercury was strengthened in the multivariate-adjusted model (OR = 4.00; 95% CI = 1.51–10.6) (p
-trend = 0.01). However, the odds ratios and 95% confidence intervals were not significantly increased as the quintiles of blood mercury increased among females with greater fish intake. However, in males, depression was not associated with blood mercury in either the age-adjusted or multivariate-adjusted model by tertile of fish intake.
In this study, we analyzed the relationship between blood mercury levels by fish consumption and depressive symptoms using KNHANES 2008–2013. Higher mercury level was associated with increased risk of depression in Korean adults; however, the association varied by fish intake and gender. After multivariate adjustment, females showed a positive association between blood mercury and depressive symptoms. A significant predominant association was observed between blood mercury and depression among female participants with low fish intake.
Several studies have reported that mercury, which is generated by human activity and natural environmental change, causes several adverse health effects in humans [29
]. Methyl mercury is absorbed in the gut and dispersed to the whole body by mixing with red blood cells, and is excreted from the body via urine and feces. Both organic and inorganic forms of mercury, which can be transported through the blood–brain barrier and from the placenta to the fetus, induce neurotoxic symptoms [18
]. Higher exposure to the inorganic form of mercury, especially methylmercury, causes neuropsychiatric symptoms by eliciting oxidative stress in the central nervous system [29
]. Apart from this, mercury also induces symptoms of gingivitis, stomatitis, dermatitis, ischemic stroke, and dementia in affected individuals [30
]. Additionally, it leads to gastrointestinal toxicity, nephrotoxicity, risk of atherosclerosis and cardiovascular diseases, and depression [18
Dietary intake, environmental factors, and conditions are believed to increase the blood mercury levels in human beings. Mercury level in the blood of the general population are derived mainly from the dietary intake of the organic form of methylmercury [35
]. They vary based on the frequency and type of fish consumed [36
]. A cross-sectional study reported that higher intake of large predatory fish species was associated with a significantly higher level of blood mercury level among Japanese children [37
]. Fish intake exerts several beneficial health effects; however, higher consumption leads to some contradictory outcomes, as fish is considered to be an important confounder that increases blood mercury levels. Among coastal populations residing in Florida, high rates of seafood consumption resulted in elevated levels of blood mercury [38
]. Among the Japanese and Korean populations, mercury concentrations were found to be higher in coastal areas than in inland areas, owing to their higher intake of fish and shell-fish-related foods [39
]. Similarly, in the United States, increased frequency of fish consumption by New York and San Francisco residents was associated with increased blood mercury concentration [41
]. Studies on the Korean population also have reported that consumption of higher proportions of fish, shellfish, mackerel, oyster, sushi, and sea mustard (more than once a week) increased blood mercury levels [15
]. A general-population study in the Czech Republic showed results consistent with our study, in that women had higher blood mercury concentrations than did men [43
]. From all of the studies noted above, it is clear that dietary patterns and certain environmental conditions influence the mercury level in blood. Thus, further studies are needed to analyze the various other factors that contribute to an increased blood mercury level.
Our study showed that blood mercury was not associated with depression in model 1 (demographic and lifestyle factors), which showed mixed results with respect to the effect of fish and mercury on depression. After adjustment for potential confounders (model 2 (fatty fish) and model 3 (model 2+ total fish)), the blood mercury level was significantly associated with increased risk of depression in Korean women. These results suggest that high fish intake may neutralize the effect of mercury on an increased risk of depression, due to high contents of omega-3 fatty acids having protective effects against psychiatric problems such as depression [11
]. In our analysis of the association of depression, we found a significantly increased risk of depression for high mercury exposure with low fish intake, but no associations among subjects in higher fish intake group (tertiles 2 and 3, Table 3
). As for gender stratification, we found a significant association of depression with high mercury exposure only among women, but not men. However, the mechanisms of the gender difference remain unclear. Recently, depression has been widely recognized as multifactorial, having environmental, cultural, psychological, and socio-economical factors. We can consider several possible factors for women’s susceptibility to diseases: biological factors such as higher body fat, smaller liver, and other hormonal factors, among others [44
]. This may suggest a role of estrogen in the immune response to many physical and psychological illnesses. However, plausible mechanisms by which estrogen modulates the host defense system remain to be elucidated. Another possible explanation for the gender difference in the present study is the relatively smaller sample size of men (n
= 86) compared with women (n
= 256). According to the National Health and Nutrition Examination Survey (NHANES) data from 1999–2002, blood mercury levels in females are higher in Asians than in Europeans [45
]. According to a cross-sectional study on the Korean general population, the mean concentration of total mercury was 2.92 μg/L, and was significantly higher in males (3.11 μg/L) than in females (2.77 μg/L) [46
]. Blood mercury in Korean subjects was 3.7–5 times higher than in Germans (0.58 μg/L), Americans (0.70 μg/L), and Canadians (0.79 μg/L) [47
]. Thus, further investigation is needed to clarify the gender differences in the distribution of and susceptibility to mercury intoxication and depression.
The baseline demographic and lifestyle characteristics of our subjects showed significant relationships with a blood mercury level (Table 1
). The highest quintile of blood mercury level was associated with older age, obesity, being married, heavy drinking, and higher economic status. Several studies have reported positive associations between blood mercury and obesity among Korean adults [50
]. Similarly, higher socio-economic status was associated with higher mercury levels due to the participants’ ability to buy expensive predatory fish such as sharks, tuna, and billfish that contain higher levels of mercury [54
]. In our study, increased consumption of white fish, fatty fish such as mackerel, tuna, croaker, and pollack, shellfish and sea food showed high mercury levels among Koreans. Correspondingly, high mercury concentrations have been reported in deep-sea fish such as sharks, tuna, swordfish, smooth hammerheads, crocodile sharks, and shellfish [55
No previous studies have been reported on the relationship of mercury with fish intake and risk of depression in humans. According to the Korea Food and Drug Administration (KFDA), the total mercury concentration in fish/shellfish and deep-sea fish should be below 0.5 ppm and 1 ppm, respectively [55
]. The Stony Brook Medical Center in New York reported that consumption of high-mercury deep-sea fish such as shark, marlin, swordfish, mackerel, tuna, and tile fish was associated with development of fatigue and depressive symptoms [56
]. The results of our stratified analysis showed that the association between blood mercury and depression was predominant at the lowest tertile of fish consumption in females. According to KNHANES 2013–2015, consumption of fish greater than four times per week was associated with lower odds of depression among Korean women [57
]. Similarly, the Japan Public Health Center-based Prospective Study (JPHC) showed that moderate fish intake can reduce the risk of major depressive disorder [8
]. In a Danish National Birth Cohort Study (DNBC), increased risk of postpartum depression was reported for low consumption of fish and n3 polyunsaturated fatty acids (PUFAs) during pregnancy [58
]. Recent consideration of the protective effect of fish with high levels of omega-3 fatty acids on depression suggests an important potential role of neuro-inflammation in depression, which might explain why diets low in omega-3 PUFAs are associated with incidence of depressive symptoms [59
]. Among the general population of Finland, moreover, incidence of depressive symptoms was significantly higher among infrequent consumers of fish, especially women [60
]. Thus, fish consumption has a dual role, in that it positively reduces depressive mood and negatively increases levels of blood mercury.
This study has some limitations. Given its cross-sectional design, we could not infer causality. In addition, as it was observational, interventional studies are needed to obtain stronger evidence regarding the potential benefits of fish consumption for mental health and reduction of depressive symptoms in different ethnic groups. Second, the fact that we did not perform a clinical interview for psychiatric diagnosis could have resulted in misclassification of mental health problems. Third, there is a possibility of missing data on blood of mercury concentration in the survey analysis, which may have resulted from selection bias. Furthermore, survey errors on the food frequency questionnaire (FFQ) might have occurred due to the study participants’ seasonal or daily dietary patterns. Moreover, we estimated fish intake from an interviewer-administered questionnaire, which would not fully reflect exact consumption of fish. We could not estimate n-3 and n-6 PUFA intake from a dietary questionnaire, although epidemiologic studies have suggested the hypothetical association between omega-3 fatty acids and decreased risk of depression. Despite these limitations, the major strength of the present study is that it provides the first report focusing on the relationship between blood mercury and fish intake and its effect on risk of depression among Koreans. Moreover, this study included a large number of participants, which allowed for greater generalizability and consistency in the use of nationally representative data. Additionally, our study results were adjusted for several demographic factors, lifestyles, dietary factors, and different fish types as potential confounders. This study also faithfully followed and ensured all KHNANES procedures respecting blood mercury level and depression evaluation over a long investigative duration, which helped to ensure the integrity of the mercury-concentration data.
The results of the present study indicated an association between blood mercury level and depression among Koreans adults. Higher level of blood mercury was associated with depression among female participants. Additionally, a significant predominant association was observed between blood mercury and depression among female participants with low fish intake. Future research should address the issue of how geographic variability among fish species and consumption of fish from various water bodies effect differences in blood mercury concentration.