Association of blood cadmium and metabolic syndrome: a cross-sectional analysis of National Health and Nutrition Examination Survey 2017–2020

Previous findings have reported the role of different types of heavy metals in cardiometabolic diseases. In the present research, we aim to evaluate the association between blood cadmium levels and Metabolic Syndrome (MetS) based on the large-sample NHANES data. Public availably data from NHANES 2017–2020 cycle was obtained. Participants were divided into MetS and non-MetS groups according to waist circumference (WC), triglyceride (TG), high-density lipoprotein (HDL), blood pressure (BP) and fasting plasma glucose (FPG) levels based on the National Cholesterol Education Program (NCEP) criteria. Student’s t test, Mann–Whitney U test, and Chi-square test were performed for univariate analysis. Multivariate logistic analysis was performed to explore the relationship between blood cadmium and MetS and research findings were presented in forest plot. We also investigated the association of blood cadmium and MetS in subgroups stratified by age, gender and race. Population with MetS had significantly higher levels of blood [0.30 (0.18–0.54) vs. 0.24 (0.15–0.46) ug/L, p < 0.001] and urinary cadmium levels [0.29 (0.17–0.52) vs. 0.20 (0.09–0.42) ug/L, p < 0.001] compared with those without MetS. Higher blood cadmium concentrations were also observed in participants with elevated WC (0.28 vs. 023 ug/L, p < 0.001], TG (0.28 vs. 0.26 ug/L, p = 0.029), BP (0.33 vs. 0.23 ug/L, p < 0.001) and FPG (0.29 vs. 0.24 ug/L, p < 0.001) compared with those with normal metabolic parameters. Multivariate logistic regression showed that one-unit increasement of blood cadmium was associated with 1.25 times higher prevalence ratios for MetS after adjusting potential confounders (95% CI: 1.06–1.48, p = 0.0083). The associations between serum cadmium concentrations and MetS components were then evaluated, and the results showed higher blood cadmium levels were associated with higher risk for elevated TG, low HDL and elevated BP when treated as continuous variable. When treated as categorical variable, only BP was found positively associated with blood cadmium. Stratified multiple logistic regression analysis indicated that the positive association between blood cadmium and MetS remained significant in subjects less than 60 years old and female subgroup. In conclusion, the cross-sectional survey suggested the positive association between blood cadmium levels and risk for MetS, prospective research need to be conducted for further evaluation of the causal relationship between blood cadmium and MetS.


Introduction
Metabolic syndrome (MetS) comprises of a cluster of metabolic conditions, including central obesity, hypertension, distorted glucose metabolism and atherogenic dyslipidemia [Rizvi et al. 2021]. MetS has emerged as a public health issue due to its rapidly increasing prevalence and association with diabetes, cardiovascular diseases and all-cause mortality [Sundström et al. 2006]. The prevalence rate of MetS is estimated to affect nearly one quarter of population worldwide [Saklayen 2018]. A nationally representative survey conducted in China from 2015 to 2017 reported that the Responsible Editor: Lotfi Aleya * Weilong Xing xingweilong@nies.org standard prevalence rate of MetS had reached 31.3% (men 30.0%, women 32.3%) in residents aged over 20 ]. Therefore, further understanding of risk of MetS is of great clinical significance. It has been widely acknowledged that environmental contaminants could contribute to the development of MetS [Lind et al. 2017]. Recently, interest has grown toward the association of environmental heavy metal exposure and MetS with uncontrolled industrialization and increased awareness of environmental health. Furthermore, healthy blood uncontaminated by environmental pollutants was also pivotal in medical health system [Kallaj et al. 2021]. Recent studies have provided evidence that exposure to heavy metals could contribute to metabolic disorders [Zhou et al. 2022]. For instance, higher prevalence of MetS was associated with higher blood lead levels [Rhee et al. 2013]. Park et al. reported a positive association between serum high-density lipoprotein (HDL) level and blood mercury concentration in Korean men with MetS [Park et al. 2016]. Adjusted multivariable regression model showed that only plasma titanium level was related to the risk for Mets through increasing waist circumference (WC) and triglyceride (TG) in 2019 participants who underwent occupational exposure to heavy metals [Huang et al. 2021].
Among these heavy metals, cadmium plays no physiological role [Tian et al. 2021]. Cadmium has been designated as class I carcinogen ] and identified as top ten chemicals of major public health concern due to its high toxicity [Planchart et al. 2018]. Additionally, its biological half-life is up to 10-35 years [Kubier et al. 2019]. Nowadays, cadmium contamination has become a ubiquitous environmental issue posing threat to human health [Satarug 2018] due to large amount of anthropogenic release from industrial process including mining, smelting, wastewater irrigation, industrial and vehicles emissions, et al. [Khan et al. 2017].
Several cross-sectional studies have evaluated the association between blood cadmium and MetS components. It was reported that blood cadmium levels were positively associated with Type 2 Diabetes Mellitus and fasting plasma glucose (FPG) levels in the general population from Norway [Hansen et al. 2017] and China [Nie et al. 2016], respectively. Epidemiological research provided conflicting results on the association between cadmium exposure and the risk for MetS. For example, a meta-analysis revealed that cadmium exposure was significantly associated with MetS in Asian studies [Lu et al. 2022], while Nour et al. found a negative association between serum cadmium and the prevalence of diabetes and obesity in Lebanon population [Ayoub et al. 2021]. Another two researches from KNHANES data suggested a positive association between blood cadmium and MetS in males but not females Kim 2013, Lee andKim 2016]. Considering the ubiquitous distribution of cadmium in the environmental media, the limited and inconsistent findings on the association of cadmium exposure and MetS, it is necessary to further address the impact of exposure of cadmium on the risk for MetS on the basis of representative large-sample epidemiological research. Therefore, in the present study, we aim to investigate the association of blood cadmium with MetS and its components based on the large-sample research data from NHANES 2017-2020.

Data source and study population
NHANES program refers to a cross-sectional survey conducted among noninstitutionalised participants to collect a detailed data on health and nutritional status in the USA. In the current study, 15,560 data were initially included from NHANES 2017-2020 cycle. 11,467 subjects were excluded for missing data of WC, blood pressure (BP), HDL, TG and FPG. Another 9 subjects were excluded due to lack of blood cadmium data. Thus, a total of 4084 participants were eventually included in the analysis (Fig. 1) after removal of the outlier data. All of the participants provided written informed consent, and the program was approved by the National Center for Health Statistics Ethics Review Board.

Measurement of blood and urinary metals
Blood samples were collected and stored under appropriate frozen (-30 °C) conditions until they are shipped to the National Center for Environmental Health for testing. Whole blood concentrations of cadmium, lead, manganese, mercury, and selenium were measured using triple quadrupole inductively coupled plasma mass spectrometer (ICP-QQQ-MS). Detailed measurement methods and quality control process could be found on NHANES 2017-2020 Data Documentation of Lead, Cadmium, Total Mercury, Selenium, and Manganese.
Urine samples were processed, stored, and shipped to the Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA for analysis. arsenic, chromium, barium, cadmium, cesium, cobalt, manganese, molybdenum, lead, antimony, thallium, tin, tungsten, and other elemental content of urine specimens were measured using inductively coupled plasma universal cell technology mass spectrometry (ICP-UCT-MS) after a simple dilution sample preparation step. Detailed measurement methods and quality control process could be found on NHANES 2017-2020 Data Documentation of Metals-Urine.

Covariates
Standard questionnaires by trained interviewers using Computer-Assisted Personal Interview (CAPI) system were asked to obtain demographic characteristics, life style and clinical factors from participants. Demographic and anthropometric variables including age, gender, race, body mass index (BMI), questionnaire data consisting of smoking, drinking, physical activity and cancer, and blood parameters comprising alanine transaminase (ALT), aspartate transaminase (AST), serum creatinine (Scr), C reactive protein (CRP) and blood metals levels were selected covariates in the current study based on previous reports on the risk factors of MetS. Race was classified as Mexican American, Other Hispanic, Non-Hispanic White, Non-Hispanic Black and other race. Current smoker was defined from the dataset with question "Have you smoked at least 100 cigarettes in your entire life?" and "Do you now smoke cigarettes?". Self-reported drinking behavior during the past 30 days was used for alcohol consumption assessment. Physical activity was categorized as mild, moderate and vigorous work.

Statistical analysis
R software 4.2.0 and SPSS 22.0 (SPSS Inc. Chicago, USA) were used for all statistical analyses. Mean ± standard deviation or median (P25-P75) were used to describe normally and non-normally distributed continuous variables, respectively. Categorical data was presented as frequencies and percentages. Student's t test or Mann-Whitney U test, and Chi-square test were performed to compare continuous and categorical data in different groups. Blood cadmium levels were treated as continuous and categorical variables (classified as quartiles, Q1-Q4). Logistic regression analysis was utilized for investigation of the independent risk factors of MetS, and the results were presented in forest plot. Both crude and adjusted model including the confounders of age, sex, BMI, race, physical activity, smoking, drinking, cancer, ALT, AST, Scr, CRP, blood lead, blood mercury and blood selemium were developed to explore the relationship between blood cadmium and risk for MetS. Then, the association between blood cadmium and risk of MetS was evaluated in population stratified by age, gender and race. Hosmer-Lemeshow goodness of fit test was used to evaluate the model fitness of the study. A two-side p value < 0.05 was recognized as statistically significant.

Baseline characteristic of study population
Among 4084 participants, 2038 (49.9%) were male and 2046 (50.1%) were female, with the average age of 45.26 ± 20.31. MetS was present in 1040 study participants, while 3044 subjects did not meet the diagnostic criteria for MetS. Baseline characteristics were compared between MetS and non-MetS group. Subjects with MetS were older, and they had higher anthropometric parameters including: SBP, DBP, heart rate (HR), BMI, WC and hip circumference. Additionally, they had higher smoking and drinking rate, higher prevalence in hypertension, diabetes, hyperlipidemia, CHD, heart failure, stroke and cancer. ALT, AST, ALP and Scr were all significantly higher in individuals with MetS. Participants with MetS were more prevalent in elevated blood metabolic and inflammatory indicators, such as TG, TC, LDL, FPG, insulin and CRP. However, lower HDL were observed in participants with MetS compared with those without MetS. Of note, MetS patients presented significantly higher blood lead 183.37 ± 25.72 ug/L, p < 0.001), whereas no significance was found in blood manganese concentration between MetS and non-MetS group (9.89 ± 3.61 vs. 9.88 ± 3.58 ug/L, p = 0.548). Furthermore, the distribution of blood heavy metals in population with and without MetS were presented in Fig. 2. In addition, higher urinary lead, cadmium, arsenic and tin levels were also observed in population with MetS. The details of other characteristics were showed in Table 1.

Blood cadmium concentration in MetS and its components group
As mentioned before, higher blood cadmium levels were found in individuals with MetS. Then, we compared blood cadmium concentrations in subjects with different WC, TG, HDL, BP and FPG levels. As shown in Fig

Univariate analysis for MetS
The relationship between different variables and MetS was evaluated using univariate analysis. As shown in Table 2, age, BMI, smoking, drinking, ALT, AST, Scr, CRP were all risk factors for the MetS, whereas participants of Non-Hispanic Black and other race had lower risk developing MetS compared with those Mexican American. In terms of blood metals, higher blood lead (OR = 1.08, 95% CI: 1.02-1.14, p = 0.0053), cadmium (OR = 1.29, 95% CI: 1.14-1.47, p < 0.0001) and selemium levels (OR = 1.01, 95% CI: 1.00-1.01, p < 0.0001) were all associated with increased risk for MetS. Furthermore, population with increased urinary cadmium and arsenic levels were more likely to have MetS.

The association of blood cadmium and risk for MetS and its components
Both crude and adjusted models were constructed to assess the association between blood cadmium and the risk for MetS. In crude model, no covariates were adjusted, and blood cadmium was treated as continuous and categorical variables, respectively. The overall fit for the curde and adjusted models were evaluated using the Hosmer-Lemeshow goodness-of-fit test, and p = 0.059 and 0.307, respectively. As shown in Table 3, blood cadmium level was significantly positively related to the prevalence of MetS. Specifically, an increasement of one unit in blood cadmium was associated with 1.29 times higher risk for MetS (95% CI: 1.14-1.47, p < 0.0001). The relationship between blood cadmium and risk for MetS components was also evaluated. Higher blood cadmium was found correlated to higher risk for elevated TG, low HDL and elevated BP, while no statistical significances were found between blood cadmium and elevated WC or elevated FPG. Then, participants were equally divided into 4 groups according to the blood cadmium concentration: Q1 (blood cadmium ≤ 0.155), Q2 (0.155 < blood cadmium ≤ 0.260), Q3 (0.260 < blood cadmium ≤ 0.481), and Q4 (blood cadmium > 0.481). When treating blood cadmium as a categorical variable, highest blood cadmium concentration (Q4) had remarkably increased risk for MetS compared with those with Q1 of blood cadmium levels (OR = 1.63, 95% CI: 1.33-2.00, p < 0.0001). In the model adjusted for age, sex, BMI, race, physical activity, smoking, drinking, cancer, ALT, AST, Scr, CRP, blood lead, mercury and selenium, per 1 μg/L blood cadmium increasement was associated with 1.25 times higher risk for MetS (95% CI: 1.06-1.48, p = 0.0083). When SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; BMI, body mass index; WC, waist circumference; ALT, alanine transaminase; AST, aspartate transaminase; ALP, alkaline phosphatase; Scr, serum creatinine; TG, triglyceride; HDL, high-density lipoprotein; FPG, fasting plasma glucose; TC, total cholesterol; LDL, low-density lipoprotein; CRP, C reactive protein

Association of blood cadmium and risk for MetS in different subgroups
Stratified multiple logistic regression analysis was performed in different age, gender and race groups to explore potential heterogeneities. Table 4 showed the associations between blood cadmium levels and the risk for MetS in different age, gender and race groups. The associations between MetS and blood levels of cadmium remained significant in subjects less than 60 years old (OR = 1.33, 95% CI: 1.08-1.64; p = 0.0078) and females (OR = 1.35, 95% CI: 1.08-1.70, p = 0.0089). While no significant associations were present between blood cadmium and the risk for MetS in population elder than 60, males and any race.

Discussion
The current representative research established an association between blood cadmium and MetS. Participants with MetS had remarkably increased blood lead, cadmium, mercury and selenium levels compared with those without MetS. Multiple logistic regression analysis revealed that blood cadmium was independently associated with the Fig. 3 The distribution of blood cadmium in MetS and its components prevalence of MetS and its components, including elevated TG, low HDL and elevated BP after adjusting confounding factors. The positive association between blood cadmium and MetS remained significant in subgroup aged less than 60 and females. Increasing reports have revealed that MetS is closely related to higher cardiovascular risk and mortality, and MetS has become a global public health concern due to its lifethreatening property and high prevalence nowadays [Nilsson et al. 2019]. It has been reported that MetS is a multiple factor-related metabolic disorder and the risk for MetS can be enhanced by environmental pollutant exposure to a large extent [Hou et al. 2020]. Recently, the effect of heavy metals exposure on cardiometabolic health has received extensive attention from researchers, and compelling evidence has confirmed its association and MetS [Xu et al. 2020]. Among these heavy metals, cadmium is a kind of widespread environmental contaminant with a release of 2.2 × 10 4 t globally due to steadily increasing industrial activities, and cadmium has been recognized as a metabolic disruptor [Barn et al. 2019]. Occupational exposure to cadmium is very common in mining, welding and battery recycling workers, which posed adverse impact on health [Baloch et al. 2020]. Cadmium has no biological role in human, additionally, cadmium has an extreme long biological life-time of approximately nearly 20-30 years and rather low excretion rate, leading to huge cardiometabolic threat to residents [Branca et al. 2018]. Recently, higher levels of cadmium levels were reported in subjects with MetS. Liu et al. reported that urinary cadmium was significantly higher in diabetic coke oven workers compared with normoglycemia workers [Liu et al. 2016].
Previous reports have investigated the effect of cadmium exposure on MetS risk in different population. However, the existing results of these researches remained contradictory. For instance, rats exposed to cadmium for 3 months displayed significant MetS phenotype characterized by dyslipidemia, hyperglycemia, and visceral adiposity [Sarmiento-Ortega et al. 2021]. Chronic exposure to cadmium indicated by higher urinary cadmium increased the odds for MetS among current smokers [Noor et al. 2018]. On the contrary, blood concentration of cadmium showed a negative association with MetS in Korean population [Moon 2014]. Another research suggested cadmium contributed negatively to the environmental risk for the development of MetS among 15 heavy metals in a prospective cohort [Wang et al. 2022]. The present research indicated an independent positive correlation between blood cadmium and the prevalence of MetS.
The research findings on the relationship between cadmium exposure and MetS individual components also remained inconsistent. For example, the Korea National Health and Nutrition Examination Survey showed that blood cadmium levels was associated with waist circumference [Park and Oh 2021]. In aggrement with these studies showing significant positive association between blood cadmium, BP levels, and the prevalence of hypertension [Garner andLevallois 2017, Wang andWei 2018], the current research  -Plaza et al. 2008]. The differences in research population, research design, methodology, and confounding factors might give an explanation on the conflicting results. Compelling evidence has indicated that cadmium exposure increased the risk for hyperlipidemia. Elevated serum cadmium level was found significantly associated with 3 times higher risk for dyslipidemia in academic institution staff in Beirut [Ayoub et al. 2021]. A Korean study also revealed higher blood cadmium concentration increased high TG/HDL ratio risk [Kim 2012]. A dose-dependent relationship between blood cadmium and the prevalence of elevated TG and low HDL was identified in a Chinese worker occupational exposure to cadmium [Zhou et al. 2016]. Consistently with previous reports, the present research suggested that blood cadmium was significantly positively associated with 1.21 and 1.29 times higher risk for elevated TG and low HDL, respectively. The underlying molecular mechanism of increased cadmium exposure to dyslipidemia remained largely unexplored. Experimental research revealed that alteration in macroautophagy regulating lipid storage and reduced expression of LDL receptor might be involved in cadmium-induced dyslipidemia , Rosales-Cruz et al. 2018. Moreover, considering that cadmium could exhaust protein and glutathione-bound sulfhydryl groups, upregulation of lipid peroxidation might also participate in the underlying mechanism [Dong et al. 2021].
With respect to the findings of hyperglycemia, in a longitudinal prospective cohort including 3521 Chinese adults, chronic cadmium exposure indicated by urinary cadmium levels was found associated with increased FPG, which elucidated the diabetogenic effect of cadmium [Xiao et al. 2021]. Cadmium has been categorized as hyperglycemia metal through upregulation of gluconeogenesis and pancreatic islet dysfunction [Hong et al. 2021]. In detail, the exposure of cadmium affected the expression of essential enzymes and proteins in insulin signaling transduction. Cadmium may also disturb the production of insulin through inflammation, oxidative stress damage, and mitochondrial dysfunction [Buha et al. 2020]. While no statistical significance was found in the present research between blood cadmium and FPG after adjustment of confounding factors, which could be due to the differences in research population, different definition criteria used for elevated FPG, etc. Consistent with our research, Yan et al. reported a negative association between blood cadmium concentration, blood glucose level, insulin level and incidence of diabetes [Borné et al. 2014].
With regard to the underlying mechanisms of cadmium exposure on metabolic disorders. Previous researches have made some explorations. Accumulated reactive oxygen species (ROS) that resulted from excessive oxidative stress was one of the leading causes [Mezynska and Brzóska 2018]. Moreover, cadmium had high affinity to sulfhydryl groups, contributing to decreased cellular antioxidant potential [Yu Fig. 4 Forest plot of multivariate predictors for MetS Table 3 Association of blood cadmium and risk of MetS and its components in crude and adjusted models  [Olszowski et al. 2012], and epigenetic mechanisms including genotoxicity of cadmium [Pavlaki et al. 2016] were all the potential mechanisms. Insulin resistance exerted an essential role in cadmium-induced hyperglycemia. Hyperphosphorylation of tyrosine or threonine residue of insulin receptor [Samuel and Shulman 2016], provoked oxidative injury and inflammation [Skytte et al. 2020] could contribute to insulin resistance. Disrupted glycosis and gluconeogenesis through altered PI3K/Akt signaling pathway also involved in elevated plasma glucose level [Sarmiento-Ortega et al. 2021]. Experimental studies showed cadmium exposure reduced the size of adipocyte and promoted macrophage infiltration through upregulation of MCP-1 in white adipose tissue. Decreased expression of leptin, resistin and adiponectin, and dysregulated carbohydrate metabolism were observed in adipocyte exposed to cadmium [Tinkov et al. 2017]. Further experimental studies are needed to be conducted to explore the biological mechanisms of cadmium exposure and MetS.
In the stratified logistic regression analysis, we further explored the association between blood cadmium and risk for MetS in population stratified by age, gender and race. The findings showed that the positive association between blood cadmium and MetS remain significant in participants aged no more than 60 and females, which might help identify the susceptible individuals to cadmium exposure. Previous research showed conflicting results that subjects with higher cadmium had lower risk for MetS in all age groups and both genders [Zhou et al. 2022]. In a cross-sectional research conducted in Korea, blood cadmium levels were found associated with MetS only in men but not women [Lee and Kim 2013]. We speculated that the different research findings between the current and previous studies might arise from population with different countries and races. The exact mechanism of gender-and age-specificity remained unclear, more large-scale, multi-center prospective research are needed for further elucidating the association of cadmium exposure and MetS in population with different age and gender.
The current research has some advantages. First of all, it is a large-scale survey conducted in a representative general population with detailed data in America. Additionally, stratified multivariate logistic regression analysis was performed, females and subjects under 60 were identified susceptible to MetS under exposure to cadmium. However, there exist several limitations in the present study. Firstly, we could not give the causal interference between cadmium exposure and MetS temporarily on the basis of the cross-sectional study. Secondly, blood cadmium levels rather than urinary cadmium levels were investigated in the current research due to relatively large missing data of urinary metals. Blood cadmium was recognized as the most reliable biomarker for recent rather than long-term cadmium exposure [Akerstrom et al. 2013]. Large-scale, prospective and longitudinal studies are warranted to elucidate the impact of cadmium exposure on MetS in the future.

Conclusion
In conclusion, our findings highlighted an association between blood cadmium and MetS in a large-sample representative population. Blood cadmium levels were significantly higher in individuals with MetS, and blood cadmium was identified as an independent risk factor for MetS after adjusting confounding factors.
In addition, the findings from stratified analysis revealed that the positive association between cadmium exposure and MetS remained significant in population aged ≤ 60 and females. Therefore, strengthened monitoring of serum cadmium levels and MetS-related parameters was recommended in subjects under 60 and females because they were more vulnerable to the deleterious effect of cadmium exposure on MetS.
Funding The study was supported by the grants from Central Scientific Research Projects for Public Welfare Research Institutes (ZX2022QT020) and the Doctoral Program of Entrepreneurship and Innovation in Jiangsu Province (JSSCBS20211323).

Data availability
Publicly available datasets were analyzed in this study. This data can be found at: https:// www. cdc. gov/ nchs/ nhanes/ index. htm.

Declarations
Ethical approval and consent to participate The program was approved by the National Center for Health Statistics Ethics Review Board. All of the participants provided written informed consent.

Competing interests
The authors declare no competing interests.