Cadmium exposure and its association with serum uric acid and hyperuricemia

Few studies have investigated the association between serum uric acid (UA) and cadmium exposure. Our previous study revealed a significantly higher blood cadmium (CdB) level in the Chinese population compared to populations in other countries. To determine whether CdB in Chinese adults is associated with serum UA and hyperuricemia, 2996 participants from the cross-sectional SPECT-China study were recruited. CdB was measured by atomic absorption spectrometry. Hyperuricemia was defined as a serum UA concentration ≥416.4 μmol/L for men and ≥356.9 μmol/L for women. Regression analyses were used to analyze the association of CdB with serum UA and hyperuricemia. We found that the median CdB level was higher in men with hyperuricemia (2.40 μg/L) than in men without hyperuricemia (1.98 μg/L, P < 0.05). A positive relationship between serum UA and CdB was found in Chinese men after adjusting for the estimated glomerular filtration rate (eGFR), current smoking status, diabetes, dyslipidemia, hypertension and body mass index and in participants with eGFR > 60 mL/min per 1.73 m2. Further, the odds ratio of hyperuricemia increased with increasing CdB quartiles (P for trend < 0.05) in men. In conclusion, CdB was positively related to the serum UA level and to hyperuricemia in Chinese men but not in Chinese women.

still had a CdB level higher than 5.0 µg/L. No study has ever explored this association in the Chinese population at the current CdB level, which differs from the level in the US. Hence, using data from a population-based investigation called the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China) in 2014, we aimed to explore the relationships between the CdB and serum UA levels and hyperuricemia in the general Chinese population.

Results
Characteristics of participants by hyperuricemia status. The characteristics of the study population, categorized by sex and hyperuricemia status, are provided in Table 1. Participants with hyperuricemia were more likely to have comorbid conditions such as obesity, hypertension, dyslipidemia and reduced renal function in both genders (P < 0.05). The median CdB level was 2.40 (0.68-4.61) μg/L higher in men with hyperuricemia than in men without hyperuricemia (P < 0.05), but the CdB levels in women showed no significant difference between individuals with and without hyperuricemia. Additionally, the median blood lead (PbB) levels were comparable between different serum UA levels.
Association of serum UA level with CdB by linear regression. Linear regression modeling of the data showed that a higher CdB level was associated with a higher serum UA concentration (B = 2.963, p < 0.05) in  (Table 2). This positive correlation remained even after the data were adjusted for estimated glomerular filtration rate (eGFR), current smoking status, diabetes, dyslipidemia, hypertension and body mass index (BMI) (B = 2.718, p < 0.05). After we excluded participants with renal impairment (eGFR ≤ 60 mL/ min per 1.73 m 2 ) and smokers, the serum UA level remained positively associated with CdB (B = 2.595, p < 0.05 and B = 2.771, p < 0.05, separately). However, no relation between the CdB and serum UA levels was observed in women in either the crude or the fully adjusted model. Furthermore, PbB was analyzed as an independent variable, and we found no correlation between PbB and serum UA levels in either gender.

Association of CdB quartiles with hyperuricemia by logistic regression analyses.
In multivariate-adjusted logistic regression analyses ( .80) were observed in participants with relatively normal renal function (eGFR > 60 mL/min per 1.73 m 2 , P for trend < 0.01). After we excluded smoking participants, a marginal significance for CdB as a risk factor for hyperuricemia remained (P for trend = 0.08). In women, the CdB levels were still not related to hyperuricemia (P for trend > 0.05).

Discussion
We explored the association between CdB and UA in Chinese adults. Our study revealed that CdB was positively associated with serum UA levels and hyperuricemia in Chinese men but not in women. This association was independent of PbB, eGFR, current smoking status, diabetes, dyslipidemia, hypertension and BMI. Furthermore, in male participants with relatively normal renal function (eGFR > 60 mL/min per 1.73 m 2 ), a positive relationship between CdB and hyperuricemia remained. Cadmium exposure has been linked to numerous human health problems 11 . Cadmium has been found to target the kidneys and induce proximal tubular reabsorptive dysfunction 7 . Prolonged exposure to high cadmium levels has given rise to osteomalacia as well as osteoporosis 7 . In particular, various studies have demonstrated the possible role of cadmium as an endocrine disruptor 11,14,15 . Cadmium can accumulate in the thyroid gland. Colloid cystic goiter, diffuse parafollicular cells, nodular hyperplasia and hypertrophy are often found in chronic cadmium toxicity 14 . Both animal studies and epidemiology studies have revealed that cadmium alters various blood sex hormone levels, such as luteinizing hormone, progesterone and testosterone 11,23 . Moreover, cadmium can exert an estrogenic effect both in vivo and in vitro 24 . Cadmium has been found to accumulate in the pancreas and exhibit detrimental effects on β cell function 25 . Both NHANES and our previous study showed that CdB level was associated with prediabetes 12,17 .
The CdB levels of our participants were higher than in those in developed countries 18,[26][27][28] , which may be attributed to the economic boom and industrialization 29 . Industrial uses have led to the widespread dispersion of Cd at trace levels into the air, water, and soil and thus into foods 18 . Atmospheric Cd emissions from non-ferrous metal smelting and coal combustion in China increased by approximately 4.6 fold from 1990 to 2010 29,30 . Another explanation is dietary habits. As in other Asian countries such as Bangladeshi and Korea 26, 31 , our staple foods are rice and vegetables, which are more likely to be contaminated by cadmium pollution 7 . Furthermore, participants living in areas with low economic status had higher CdB than participants in high-economic-status areas 17 . Industrial factories prefer to build sites in low-economic-status areas because of the low prices of land and labor. Poor infrastructure construction and environmental supervision systems combined with a lack of water-quality monitoring together led to water cadmium contamination 17 .
Little is known about the association of cadmium exposure with UA. The NHANES data for 2005-2008 revealed no relationship between cadmium and gout in the USA 2 . However, the CdB levels in Americans were much lower than those in Chinese adults 17 . Previous animal studies have established models of renal toxicity with decreased eGFR upon cadmium administration, which resulted in elevated serum UA levels 32,33 . Nevertheless, in our research, CdB was positively correlated with hyperuricemia after adjustment for eGFR and in participants with an eGFR > 60 mL/min per 1.73 m 2 , suggesting other mechanisms beyond a decreased eGFR.
UA is primarily produced in the liver by xanthine oxidoreductase 34 and then undergoes glomerular filtration, tubular reabsorption and excretion by the kidneys 35 . The excretion of UA consists of a basolateral uptake step mediated by an organic anion transporter 36 , followed by an efflux step mediated by multidrug resistance protein 4 and the urate transporter 37 . Cadmium-related renal damage begins with proximal renal tubular injury 38 before glomerular injury. Tubular organic anion uptake transporters may be a target for cadmium 19,33 because sub-chronic cadmium intoxication results in a loss of basolateral invaginations and the down-regulation of organic anion transporters and organic cation transporters, which may lead to decreased urate secretion from the tubular cells. Cadmium toxicity may lead to impaired p-aminohippurate excretion due to a loss of organic anion carriers in the proximal tubular basolateral membranes 20 . Therefore, we hypothesized that the early renal damage by cadmium exposure might lead to a defect in urate excretion and give rise to hyperuricemia.
Oxidative stress is among the important mechanisms of cadmium toxicity, and the liver is a critical target organ 39 . There is an increased conversion of xanthine oxidoreductase from xanthene dehydrogenase to xanthine oxidase in the cadmium-treated liver 40 . The transition from purine to UA, mediated by xanthine oxidase, leads to the production of reactive oxygen species, which may be accompanied by increased UA production. Furthermore, previous studies have suggested that serum UA is an antioxidant 41 . Hence, elevated serum UA may be a protective mechanism against oxidative stress from cadmium exposure.
The gender-specific association between CdB and UA level is inconclusive. Sex hormones may be involved. CdB was found in a previous study to negatively correlate with total testosterone and sex hormone binding globulin in Chinese men 23 . Conversely, the data from NHANES 2011-2012 show significantly positive associations between CdB and serum testosterone in men 42 . Moreover, estrogen-induced increases in the fractional excretion of UA were associated with lower levels of UA in male-to-female transsexuals 43 . A previous study showed that women and men differed in their pathogenic factors and treatment monitoring because female patients had greater co-morbidities and received the appropriate treatment more often 44 . Knowledge on this gender-specific association is thus rather limited.
Cadmium and lead (Pb) are two toxic metals that are widely distributed in the environment. They share similar population exposure routes 45,46 . Concurrent exposure to both metals is very common 46,47 . Epidemiological evidence has shown that CdB is positively related to PbB 17,48 and that the two metals have interactive effects in certain diseases 45,49 . Lead toxicity (>80 μg/dL) is associated with hyperuricemia and gout 47,50,51 . Moreover, there is still a link between relatively lower PbB and hyperuricemia 2,52 . Thus, we regarded PbB as an important confounding factor. Moreover, we evaluated the relationship between PbB and UA levels in our participants, but there was no significant relationship in either men or women.  This study is the first exploration of the relationship between CdB and hyperuricemia in different genders in the Chinese population. Homogeneity and strict quality control were guaranteed because the same trained staff was used. Furthermore, we considered PbB to be a confounding factor when exploring the association between CdB and UA levels.
There are some limitations of this study. First, using a cystatin C-based formula to adjust for the GFR estimates is required in healthy populations with normal renal function, which was not available to us, but the CKD-EPI equation applied in our study was confirmed to be more accurate than the Modification of Diet in Renal Disease Study equation, particularly for censoring numerical estimates greater than 60 mL/min per 1.73 m 2 53 . Second, we used the blood cadmium levels rather than urinary cadmium. Urinary cadmium reflects lifetime cadmium exposure, but for relatively low cadmium exposure levels, blood cadmium levels may be more appropriate 38 . It would have been ideal if we could detect both. Third, this study did not include information on food intake. A high serum UA level is usually associated with an intake of large amounts of food that is high in purines 2 . It is reasonable that the CdB levels are parallel with the serum UA levels in participants with large daily food intakes. Furthermore, we could not determine the causal relationship between CdB and hyperuricemia in this cross-sectional study.
In conclusion, CdB was positively associated with serum UA levels and hyperuricemia in Chinese men but not in women. This study indicated that cadmium exposure may confer a risk for hyperuricemia, which was not attributed solely to cadmium toxicity-induced renal dysfunction. However, in cases of relatively normal renal function, the CdB level was still positively related to serum UA. Further study is needed to demonstrate causality and elucidate the underlying mechanisms. In addition, efforts to reduce cadmium exposure in adults are warranted.

Methods
Study population. Our data (n = 6899) were from the SPECT-China study 54,55 . The sampling method was described in detail in our previous study 23 . A total of 2996 subjects were enrolled in our final study after excluding participants with missing values for UA (n = 3429) and CdB (n = 474). Before the data collection, written informed consent was provided by all participants. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. The study protocol was approved by the Ethics Committee of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine.
Measurements. The questionnaires about demographic characteristics, medical history and lifestyle risk factors and anthropometric data were constructed by the same trained staff as previously described 54,55 . Body weight, height and the calculation of BMI were calculated consistently with the previous study 23 . Waist circumference and blood pressure were measured by strict adherence to the standard procedure 21 . Current smoking was defined as having smoked at least 100 cigarettes in one's lifetime and currently smoking cigarettes 17 .
Cadmium and lead levels in blood samples were tested using graphite furnace atomic absorption spectrometry 17 . Standard curves were established, and quality control materials were tested before the samples were measured. Two quality control personnel participated in the process control. Outliers were detected by duplicate runs. The detection limits for blood cadmium and lead were 0.01 µg/L and 0.1 µg/L, respectively. The inter-assay coefficient of variation for cadmium was 10%.

Definition of variables.
Hyperuricemia was defined as a serum UA concentration ≥416.4 μmol/L and ≥356.9 μmol/L for men and women, respectively 2 . The definitions of overweight, obese, diabetic and hypertensive in this study have been previously described 21 . Dyslipidemia was defined as described previously 56 .
Statistical analyses. The IBM SPSS Statistics software, version 22 (IBM Corporation, Armonk, NY, USA), was used for data analysis. Analyses were performed separately for men and women due to major gender differences in serum UA concentrations. A P value < 0.05 for a two-tailed test indicated a significant difference. The specific statistical methods for continuous variables and categorical variables were described in detail in a previous study 17 .
The association of CdB (an independent variable) with serum UA levels (a dependent variable) was assessed by linear regression analysis. The results were expressed as unstandardized coefficients (B) and standard errors. The full model included PbB, eGFR (which incorporates age and serum creatinine level), current smoking status, diabetes, dyslipidemia, hypertension and BMI.
Scientific RepoRts | 7: 550 | DOI:10.1038/s41598-017-00661-3 To consider the association of CdB with hyperuricemia, logistic regression analyses were used. CdB was divided into quartiles, with the first quartile representing the lowest levels and the fourth quartile the highest. The full model included eGFR (which incorporates age and serum creatinine levels), current smoking status, PbB, diabetes, dyslipidemia, hypertension and BMI. PbB, eGFR, and BMI were entered as continuous measures. Data were expressed as odds ratios (ORs) (95% confidence interval (CI).

Subgroup analyses.
Because hyperuricemia is known to be associated with kidney dysfunction and the kidneys are the most important target organs for cadmium exposure, we performed subgroup analyses that excluded participants with an eGFR of 60 mL/min per 1.73 m 2 or less 2 . Moreover, smokers are at high risk of cadmium exposure 17 , and previous studies have indicated an association between smoking and increased purine catabolism 57 . Thus, we performed another subgroup analysis excluding current smokers. The regressions were performed by the same strategy as in the above analyses.