Cardiovascular disease (CVD) is the leading cause of disability and death worldwide, and the numbers of CVD cases and deaths continue to rise (1). In Korea, although the prevalence has been declining in recent years, CVD is still the second main cause of mortality (2). In addition to traditional risk factors for CVD, such as hypertension, diabetes, obesity, and high salt consumption, there are growing concerns about environmental toxicants, such as toxic metals and persistent organic pollutants, as a potential risk factor for CVD (3, 4). In particular, potentially toxic metals are widely distributed in the ambient air, drinking water, and foods; thus, the adverse health effects of toxic metal exposure are of great concern to many population groups globally (5).

Among metals, mercury (Hg) is a toxic metal, with known harmful effects on human health following exposure (6). The general population may be exposed to Hg through environmental or occupational exposure sources; additionally, consumption of fish/seafood is the most common route of exposure to methylmercury (MeHg), a highly toxic form of Hg (7). Hg exposure is recognized as an important public health issue, as Hg is reported primarily as a metal that causes neurodevelopmental toxicity in neonates and children (8, 9). However, there is a growing body of epidemiological and experimental evidence indicating that Hg exposure may increase the risk of adverse cardiovascular outcomes (10–12).

Although the mechanisms supporting the association between Hg exposure and CVD prevalence have not been elucidated in detail, there are some reports that Hg exposure impairs the activity of selenoproteins and promotes lipid peroxidation, as well as chronic inflammation (13). As chronic inflammation is the critical mechanism in the pathogenesis of CVD (14) and serum high-sensitivity C-reactive protein (hs-CRP) is an indicator of inflammation (15–18), hs-CRP is considered to be a biomarker of CVD risk (19).

The identification of environmental risk factors influencing the incidence of CVD in the general population is important for the reduction of disability and premature death from CVD. However, few studies have examined the association between blood concentration of Hg and the hs-CRP level, as a sensitive marker of CVD risk, in the general Korean population. Therefore, the present study was conducted to evaluate this association in Korean adults using data from the Korea National Health and Nutrition Examination Survey (KNHANES).

The study sample consist of 3,773 adults aged ≥20 years; their sociodemographic characteristics are presented in Table 1. The average age of the study participants was 48.3 years, and the mean BMI was 23.9 kg/m².

The geometric mean blood Hg level is presented according to the participants’ demographic characteristics in Table 2. Of the 3,773 participants, the geometric mean blood Hg level was 3.28 μg/L; the Hg concentration in men was significantly higher than that in women (p < 0.001). The geometric mean blood Hg level increased with BMI, education level, and income (p < 0.05). In addition, age, cigarette smoking, and alcohol drinking were significantly associated with blood Hg (p < 0.001).

The serum hs-CRP level was significantly associated with an increased quartile of blood Hg concentration (p for trend = 0.019; Figure 2). The serum hs-CRP concentration was 1.18 (95% CI, 1.08–1.27) mg/L among participants having the highest quartile Hg compared to 1.03 (95% CI, 0.94–1.11) mg/L among those having the lowest quartile Hg.

Table 3 shows the prevalences and ORs for the associations of having a risky hs-CRP level (moderate-to-high level) with respect to quartiles of Hg concentration. The prevalence of a having a hs-CRP level > 1.0 mg/L was higher among participants in the higher quartile Hg concentration: 26.1% among participants with the lowest quartile Hg (<2.14 μg/L), and 32.0% among those with the highest quartile Hg (> 4.89 μg/L) (p = 0.003). The crude and adjusted ORs (Models 1 and 2) for a risky hs-CRP level was positively correlated with an increasing quartile Hg level (p < 0.01). The crude OR of a risky hs-CRP level in the highest quartile Hg group (blood Hg level > 4.89 μg/L) relative to the reference group (blood Hg level < 2.14 μg/L) was 1.56 (95% CI, 1.23–1.99), and the fully adjusted OR for a risky hs-CRP level was 1.34 (95% CI, 1.02–1.77) (Model 2).

Hg is considered to be one of the most widespread toxic environmental pollutants, and exposure to Hg can occur from both natural and artificial sources (22). Humans are exposed to Hg through several sources including environmental pollutants, contaminated seafood, metallic Hg-containing dental amalgam, and ethyl-Hg-containing vaccines (23, 24). Hg has possible toxic effects on the nervous, digestive, and immune systems, as well as renal function (25, 26). However, accumulating evidence suggests that exposure to Hg is contribute to the risk of CVD and related outcomes, including hypertension and ischemic heart disease (IHD) (11, 12, 27). A meta-analysis of 14 studies reported that chronic exposure to Hg was associated with an increased risk of fatal/nonfatal IHD and all-cause mortality (28). However, in a cohort study of adults in the United States (US), blood Hg level was not significantly related to the risk of all-cause or CVD-related mortality (29). Another population-based cohort study conducted in Greenland also reported no association between blood Hg and the risk of developing CVD (30). Therefore, a potential biomarker associated with CVD could be used to better understand the causal relationship between Hg exposure and CVD prevalence.

Low-grade inflammation is a known contributor to the pathogenesis of several chronic diseases, including CVD, and the use of hs-CRP as a sensitive marker for low-grade inflammation has been investigated extensively (31–33). Several cohort studies have reported that an elevated hs-CRP level is independently associated with an increased incidence of major cerebrovascular and cardiovascular outcomes (34, 35). Similarly, many recent studies have shown that the hs-CRP level is positively correlated with CV risk in various clinical settings (36–39).

In this study, an increase in the blood Hg concentration was significantly associated with an increase in the hs-CRP concentration. Acute exposure to Hg from dental amalgam was reported to have no significant effect on the level of C-reactive protein (CRP) (40), but the association between blood Hg and the level of CRP has been reported in some epidemiological studies (41, 42). In a study of premenopausal women (mean age, 27.4 years) in the US, although it was not statistically significant, a positive association was observed between Hg concentration and hs-CRP level with an adjusted beta coefficient of 0.02 (41). In addition, in the NHANES 2005–2006 study conducted with US participants aged 16–49 (mean age, 34 years), the beta coefficient between Hg and CRP levels was positive in a fully adjusted multiple linear regression model in women, but not in men (42). These two previous studies of US participants showed a positive correlation between Hg and CRP levels only in women and did not reach statistical significance. In our study of Korean adults, a high level of Hg exposure significantly increased the hs-CRP concentration and the frequency of having a risky (> 1.0 mg/L) hs-CRP level. Specifically, participants with the highest quartile of blood Hg were more likely than those with the lowest quartile to have an hs-CRP level > 1.0 mg/L (adjusted OR = 1.34; 95% CI, 1.02–1.77); the cutoff value is associated with the CVD risk. The mean age of our study population was 48.3 years; the difference between the OR values found in our study and those reported in the US studies may be due, at least in part, to the difference in the average age of the study subjects. Given that the geometric mean of blood Hg concentration was much higher in Korean participants than in US participants (3.28 μg/L vs. 1.05 μg/L), the blood Hg level may also have affected the statistical significance of the results. Additionally, differences in race and ethnicity between Korean and US participants likely influenced the findings.

Few epidemiological studies have examined the associations between body burden of Hg and hs-CRP level. To the best of our knowledge, this study is the first to elucidate the relationship between Hg exposure and hs-CRP level, as a highly sensitive cardiovascular biomarker, using population-based survey data on Korean adults aged ≥20 years. However, there are several limitations to this study. First, given the complexity of potential factors affecting serum hs-CRP concentrations, additional factors, including oxidative stress and inflammatory comorbidities, which were not fully considered in the model of this study, could have significant effects on serum hs-CRP (43). Therefore, future studies should consider factors such as antioxidant food or supplement consumption; the use of anti-inflammatory drugs; and the prevalence of inflammatory diseases such as cancer, inflammatory bowel disease, chronic kidney disease, and type 2 diabetes. Second, several sociodemographic factors, including alcohol drinking and cigarette smoking, were derived from self-reporting and therefore may have introduced misclassification or recall bias. Third, although we adjusted for potential confounders in the analysis, several confounding factors, such as vitamins and trace elements that are associated with inflammatory markers and may interact with Hg, were not adjusted for in the study. Despite these limitations, our study findings are important in view of a nationwide study that found an association between body burden of Hg and the potential for chronic low-grade inflammation that can lead to CVDs. Due to the limitation of the cross-sectional design of our study, prospective cohort studies are warranted to elucidate a causal relationship between Hg exposure and cardiovascular markers such as hs-CRP.

In the present study using nationally representative survey data on Korean adults aged ≥20 years, an increase in blood Hg concentration increased the low-grade inflammatory response, as reflected in the hs-CRP level. The results of this study show that Hg exposure may increase chronic inflammation, which in turn may lead to an increased risk of inflammatory diseases such as CVD, type 2 diabetes, and cancer.

Publicly available datasets were analyzed in this study. This data can be found at: https://knhanes.kdca.go.kr/knhanes/eng/index.do.

The studies involving human participants were reviewed and approved by Korean Ministry of Health and Welfare. The patients/participants provided their written informed consent to participate in this study.

KK: conceptualization, methodology, investigation, and writing–review and editing. HP: investigation, data curation, and writing–original draft. All authors have read and agreed to the published version of the manuscript.

This research was supported by the Keimyung University Research Grant of 2019.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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