Serum 25-hydroxyvitamin D mediates the association between heavy metal exposure and cardiovascular disease

In the world, cardiovascular disease (CVD) account for nearly one-third of all deaths, making them an important public health problem [1]. The top six causes of CVD death include hypertension, smoking, diabetes mellitus or elevated glucose level, elevated cholesterol levels, and obesity or being overweight [2]. However, there is increasing evidence that the incidence of CVD appears to also be linked to environmental pollutants including polyfluoroalkyl chemicals, acrylamide, and so on [3‐5]. As a result of their extensive use in industries, homes, agriculture, and medicine, heavy metals are widely distributed throughout the environment [6]. It is reported that most heavy metals are highly toxic [7]. Besides ingestion and inhalation, they can also be absorbed through the skin, causing heavy health effects when in contact with humans [8, 9]. Arsenic and other (often co-occurring) toxic metals have also been suggested as independent cardiovascular disease risk factors [10, 11]. Vitamin D plays a crucial role in calcium and phosphorus metabolism in bones and minerals as a fat-soluble vitamin [12]. Besides its well-known role in calcium homeostasis, Vitamin D deficiency also contributes to CVD [13]. A new study revealed that the complicated relationship between vitamin D, folate, and heavy metals may be able to lessen the impact on blood pressure [14]. It is not known in the United States (U.S.) general population whether serum 25-hydroxyvitamin D (25(OH)D) levels are related to heavy metal exposure. The research also shows that the metabolism of heavy metals is affected by the Vitamin D status of the chicken body [15]. According to our hypothesis, 25(OH)D regulates heavy metal metabolism, thus reducing the harmful effects of heavy metal exposure. Therefore, in this study, we investigated the link between heavy metal exposure and 25(OH)D using the National Health and Nutrition Examination Survey (NHANES) database. Additionally, the mediation effect of vitamin D on heavy metal exposure in humans with CVD was further explored for the first time.

In this study, we examined the mediation of cardiovascular toxicity by 25(OH)D in the general population of the U.S. for the first time. First of all, we found that there was a positive linear correlation between Cadmium, Lead and the prevalence of CVD, a linear negative correlation between Mercury, Manganese and the prevalence of CVD, and a similar L-shaped and U-shaped relationship between Selenium, 25(OH)D and the prevalence of CVD. In addition, we also found that serum 25(OH)D was independently related to Cadmium and Lead. Furthermore, we found a 6.7% association between Manganese levels and CVD prevalence mediated by 25(OH)D levels.

Due to the rapid industrialization of the world, the harmful effects of environmental pollution, which is closely related to industry, have been widely concerned. As an important part of industry-related environmental pollution, heavy metals, including lead, manganese and cadmium, are widespread in the surrounding environment. As a result, the cytotoxicity and tissue toxicity caused by heavy metals has become a major health problem in environmental science [9]. For example, Domingo-Relloso et al. found that urine Cu, Zn, Sb, Cd, Cr and V were independently related to the risk of cardiovascular events in a cohort study of 1,171 Spaniards without CVD, while the urine metals in the mixture were also commonly related to CVD [20]. Another systematic review and meta-analysis involving 348,259 participants also showed that lead, arsenic, copper and cadmium were independently related to the increased risk of CVD, coronary heart disease and stroke, but mercury was not significantly related to these diseases [21]. In addition, Choi et al. also proved in Korea National Health and Nutrition Survey that the blood Cd, Hg and Pb levels of the general population in Korea were strongly correlated with the 10-year CVD risk score, and this correlation was stronger among men [22]. In addition to CVD, Guo et al. found that lead, cadmium and arsenic were closely related to all-cause, CVD-related and cancer-related mortality in a systematic review and meta-analysis of 42 cohort studies, but found no significant correlation between other heavy metals and CVD [23]. However, the above studies have not evaluated the effects of manganese exposure on CVD. In the previous published research, blood manganese levels were negatively correlated with CVD risk based on the published NHANES data [5]. Nevertheless, the mechanism of the association between heavy metals and the risk of CVD is very complicated. Increasing our understanding of the relationship between occupational exposure to heavy metals and CVD risk will require further evaluation of the effects of heavy metal exposure on CVD risks and possible mechanisms. In view of this, Zhu et al. conducted a cross-sectional study of 3081 adults and explored the possible mediating effects of heavy metals on CVD and found that elevated urinary iron, zinc and antimony concentrations were associated with an increased 10-year risk of CVD and that their associations were mediated by mean platelet volume by 17.55%, 6.15% and 7.38%, respectively [24]. Similarly, we found that the association between heavy metals and CVD could be mediated by other factors, that is, 25(OH)D mediated 6.7% of the association between Manganese exposure and CVD risk, but no such interaction between other heavy metals and 25(OH)D was found. These data reveal the relationship between heavy metal exposure and 25(OH)D levels. The relationship between cardiovascular toxicity of heavy metals and CVD is very complicated. Observational studies are insufficient to report the association between heavy metal exposure and CVD. Similar to our study, Yin et al. also found the mediating effect of 25(OH)D by using the same open database, that is, they found that 25(OH)D mediated the negative correlation between acrylamide and obesity in a study containing 10,377 participants from NHANES [25]. As we all know, vitamin D is a fat-soluble vitamin, which can not only exist naturally in food, but also can be used as a dietary supplement to provide nutritional support to people with vitamin D deficiency. Previous studies have shown that lower vitamin D levels are associated with higher prevalence of obesity, cancer, CVD and mortality [13, 26‐28]. Our study found that 25(OH)D levels were not only associated with CVD, but also closely related to blood manganese levels. Therefore, in the mediating effect analysis, we further found that 25(OH)D as an intermediary variable was involved in the association between manganese exposure and CVD. This is the first time that we have assessed the regulatory effect of 25(OH)D on heavy metal-induced toxicity in the general population, and the findings of our study will contribute to the pathophysiological understanding of heavy metal toxicity in humans. In addition, our study also provided information for potential interventions in clinical observation studies.

Although we have found for the first time that 25(OH)D mediated a link between Manganese exposure and CVD, the mechanism is still unknown. At present, there may be several potential mechanisms that play a direct or indirect role. For example, there is evidence that after exposure to heavy metals, oxidative stress promotes the transduction of harmful signals and leads to CVD [9], while Christakos et al. have shown that a certain level of vitamin D can resist oxidative stress and reduce the risk of CVD [29]. Therefore, we hypothesized that 25(OH)D can reduce the oxidative stress induced by heavy metal exposure and reduce the prevalence of CVD. In addition, it is reported that heavy metal exposure can enhance the inflammatory response, which plays a vital role in the pathogenesis of CVD [30, 31]. However, Guillot et al. reviewed vitamin D and inflammation and found that the immunomodulatory effect of vitamin D is not only suitable for rheumatoid arthritis and inflammatory bowel disease, but also for infection and CVD [32]. Therefore, we believed that 25(OH)D can regulate the inflammatory activity caused by heavy metals and thus reduce the risk of CVD. Previously, most studies mainly focused on the relationship between vitamin D, heavy metal exposure and CVD, rather than their interaction, while the level of serum 25(OH)D can mediate the association between heavy metal exposure and CVD in our study. Mediating factors can help to sort out the biological pathways that link harmful factors with cardiovascular events, which is essential for which is essential for detecting and preventing cardiovascular events at an early stage.

Although our study has achieved encouraging results, there were still several limitations. First, as a cross-sectional study, we only conducted a single assessment of heavy metal exposure and did not continuously monitor long-term exposure to heavy metals and their longitudinal effects on CVD. Second, instead of real medical records, the self-reported approach was used to assess the incidence of CVD among participants. This may have led to a bias in the results. Third, this study was a cross-sectional study. Therefore, the causal relationship between heavy metal exposure and CVD cannot be determined. Additionally, although the intermediary effect analysis well described the effects of heavy metals on CVD, it was still unable to determine the causal correlation. Forth, there might be other potential influencing factors that have not been adjusted, such as environment, diet and genetic susceptibility. Fifth, most of the heavy metals are excreted from the kidneys, so the levels of heavy metals in the urine may better reflect their long-term exposure, while we only assessed the blood levels of heavy metals. Finally, our study only covered the general population in the United States, so the results may not be extended to other countries and populations. Therefore, further studies are necessary to determine whether heavy metal exposure and 25(OH)D interact.

According to our study, there was a substantial inverse correlation between Manganese exposure and 25(OH)D. In addition, 25(OH)D mediated a negative connection between manganese and incident CVD shows that 25(OH)D supplementation may enhance the protective effect of manganese intake on CVD. An in-depth study of Manganese’s relationship to serum 25(OH)D is required.