To the best of our knowledge, this is the first study to evaluate the associations of exposure to multiple metals with SUA levels and the risk of having hyperuricemia. Herein, we found that vanadium and arsenic exposure were associated with increased SUA levels and hyperuricemia risk, especially in males. Selenium content might be associated with decreased SUA levels and hyperuricemia risk in males. Furthermore, co-exposure to vanadium and arsenic was associated with greatly increased SUA levels and hyperuricemia risk, while high selenium status perhaps could partly counteract their effects.
Vanadium is the 21st most abundant element in the earth’s crust and is ubiquitously distributed in the soil, water, and atmosphere. Natural processes and accelerated anthropogenic activities such as combusting fossil fuels, mining, and widespread industrial utilization aggravate the contamination situation of vanadium . In our study, all participants had detectable vanadium concentrations in urine, revealing the extensive vanadium exposure in their daily life. Kidneys are the primary organs where vanadium is accumulated . Experimental studies demonstrated that high vanadium exposure caused granular and vacuolar degeneration in renal tubular and glomerulus epithelial cells, which could lead to urate underexcretion [41, 42]. Furthermore, vanadium compounds inhibited superoxide dismutase and glutathione peroxidase (GSH-Px) activity of scavenging hydroxyl radicals, thus further worsening renal function and restricting urate excretion . Moreover, vanadium not only induced the secretion of pro-inflammatory cytokines (interleukin-6 and interleukin-8) but itself could be a pro-inflammatory agent to upregulate the expression of cyclooxygenase-2, or stimulate mitogen-activated protein kinase cascades and the nuclear factor-κB signal, resulting in renal oxidative damage and urate excretion reduction [43–45]. Meanwhile, high oxidative stress status in the body will mobilize the antioxidant system to produce more UA for redox balance . In the context of vanadium exposure, increased UA production and decreased urate excretion might lead to high SUA levels.
Evidence about arsenic exposure with UA in epidemiological studies and experimental research still was disagreement, which might be partly due to the disparate purine metabolism in humans (loss of urate oxidase activity) and other mammals [8, 18, 47, 48]. Arsenic could bind to the molybdenum center in XO, thus retarding the catabolism of xanthine to UA via inhibiting the activity of XO, leading to a reduction in SUA levels . Moreover, arsenic exposure, trivalent arsenicals in particular, depleted UA by generating reactive oxygen species (ROS) . The two aspects of arsenic reduced the production and increased the consumption of UA. Nevertheless, arsenic-triggered lipid peroxidation in kidneys caused tubular injury, glomerulus sclerosis, and glomerulus collapse, leading to reduced urate excretion . Furthermore, similar to lead, arsenic-damaged proximal convoluted tubule may strengthen the reabsorption of urate. In summary, arsenic exposure not only reduced the UA production, depleted the anti-oxidative UA, but blocked the excretion and strengthed the reabsorption of urate. Whether arsenic exposure was associated with hyperuricemia might depend on its total effects.
Selenium has anti-oxidative and anti-inflammatory effects . We found that urinary selenium concentrations were not only inversely associated with SUA and hyperuricemia but could partly counteract the hazardous effects of vanadium and arsenic. GSH-Px widely exists in the body and plays a pivotal role in ROS metabolism. The synthesis of GSH-Px in kidneys requires selenium as an essential cofactor . High selenium status promoted the capacity of GSH-Px to neutralize lead, vanadium, and arsenic-induced ROS. Accordingly, less UA would be produced to maintain redox balance. In addition, selenium could reduce internal arsenic contents via the excretion of arsenic-selenium compounds . Moreover, selenium could improve renal function, accelerate the excretion of toxic metals and UA mainly by its anti-oxidative ability [53, 54]. Therefore, selenium supplements might contribute to reducing SUA levels and hyperuricemia risk.
We found positive associations of urinary aluminum, barium, lead, and uranium concentrations with SUA levels and hyperuricemia risk. Oxidative stress and subsequent renal injury were the mutual toxic mechanisms of these heavy metals, and to some extent, resulting in the increase of SUA [55–57]. Besides, in our study, we noticed that essential metal manganese in urine was associated with increased SUA levels in males. Similarly, a small-sample occupational study indicated that manganese exposure led to low UA concentrations in urine, indicating high UA accumulation in serum . As regard to zinc, Zhang et al. found that dietary zinc intake was inversely associated with the risk of hyperuricemia in both sexes, but our results indicated that urinary zinc concentrations were associated with increased SUA levels in females . There might exist no conflict in the two results. The human body has no storage of zinc that could be immediately mobilized to fill up the depletion. The excessive zinc concentrations in urine might be the consequence of disrupted zinc homeostasis and perhaps represented zinc deficiency in the body . Zinc deficiency might lead to elevated SUA levels while zinc supplements could mitigate this situation. We found beneficial effects of cobalt on hyperuricemia in females with high eGFR. Cobalt, as the vital component of Vitamin B12 (cobalamin), might affect UA production by controlling the generation of tetrahydrofolic acid in the purine metabolism . However, more evidence is needed to support this theory. As for the opposite association of strontium with SUA in males and females, additional investigation is deserved to preclude chances and explain the mechanism.
Low eGFR, hypertension, and diuretics are the risk factors of hyperuricemia . Moreover, renal function and diuretics have impacts on urate and metals excretion . In the sensitivity analysis, we excluded individuals with low eGFR (< 90 mL/min/1.73 m2) and individuals with hypertension no matter using antihypertensive or not. However, these stringent exclusion criteria only slightly weakened the association of vanadium with hyperuricemia in males while other associations were still robust. These analyses revealed that damaged renal function could only explain part of the associations between metals exposure and the changes in SUA levels. There might be other more specific and effective mechanisms underlying these associations.
Sex difference existed in our results. Though vanadium, cobalt, arsenic, and selenium concentrations were higher in females, most associations were still more significant in males. The mean eGFR value in males (92.4 mL/min/1.73 m2) was significantly lower than that in females (98.5 mL/min/1.73 m2). Low eGFR in males was associated with low urinary metals excretion, thus accumulated metals in the body would cause extra damage . Meanwhile, low eGFR reduced urate excretion and increased the risk of having hyperuricemia. Besides, male participants in our study had a high prevalence of smoking, drinking, hypertension, and hyperlipidemia. All these adverse factors might enhance metals’ impacts on hyperuricemia. Furthermore, compared with males, females physiologically had more antioxidant gene expression and possessed more metabolic capability to mitigate heavy metals’ deleterious impacts on UA metabolism [61, 62]. Moreover, the risk profile of hyperuricemia was different. Females with hyperuricemia were more due to diuretics use while males were more owing to inherent genetic variants [63, 64]. These differences in males and females help explain the sex-specific effects of metals, but more hypothesis-driven researches focusing on this topic are needed.
We evaluated the associations of metals exposure with SUA levels and hyperuricemia risk in the present study. Other strengths of this study included large sample size, standardized and validated measurements of urinary metals, and multiple sensitivity analyses. However, the cross-sectional study design restricted the causality of the associations. Nevertheless, given the well-documented association of lead exposure with hyperuricemia risk and the similarity among metals, it was more reasonable to hypothesize that metals exposure changed SUA levels, not vice versa. Second, although we adjusted for most confounders in our analyses, the associations might still be slightly influenced by residual confounding. However, since our results remained robust in different sensitivity analyses, reasons preceded chances in the associations. Further studies should take genetic variants (e.g., SLC2A9, ABCG2), dietary factors (seafood, beer, and red meat), and detailed drug use into consideration . Third, our study was launched in a physical examination center, selection bias might restrict the extrapolation of our findings. Considering the exploratory intention of this study, such a study design helps to increase the participation rate and contribute to high-standard quality control in data collection. Fourth, inorganic arsenic is more toxic than organic arsenic; pentavalent vanadium tends to be more deleterious than trivalent vanadium [8, 39]. Future studies should take the species of these metals into account. Fifth, we only measured metals concentrations in one urine sample, potential non-differential exposure misclassification might dilute the risk estimates. Hence, in prospective studies, using repeated urine samples and other biological matrixes to character metals exposure levels are recommended to confirm our findings.