Metallothionein, Metallothionein Antibody And Cadmium Induced Renal Dysfunction

Metallothionein (MT) is a family of stress proteins containing a high content of cysteine and divalent metals. MT genes are expressed ubiquitously in many tissues on basal levels. MT expression could be induced by many factors, especially by metals such as cadmium, zinc, and copper. The physiological function of MT remains under study. MTs have been suggested to play a role in the homeostasis of essential trace elements such as zinc and copper, in the detoxification of certain toxic metals, and as scavengers of free radicals. The role of MT in the absorption, transportation, and excretion of metals has been demonstrated in some studies related to several toxic metals, especially cadmium.Cadmium, an environmental pollutant, causes a number of adverse health effects, particularly toward the kidneys. When taken up in the body, cadmium circulates initially in plasma primarily bound to albumin; cadmium then enters the liver where it is bound to metallothionein and is later released into the blood stream. Metallothionein-bound cadmium is readily filtered through the renal glomerulus and reabsorbed by proximal tubule cells. Cadmium bound to metallothionein is degraded in tubular lysosomes to release free cadmium, which then induces the synthesis of metallothionein in renal cell. Renal damage is believed to occur once free cadmium or an excessive concentration of non-MT-bound cadmium increased within the cell. Till now, quite a lot of studies had been undertaken to explore the relationship between metallothionein and cadmium toxicity, however, some aspects had never been elucidated.Cadmium is a well-known nephrotoxic agent with extremely long biological half-time of 15-30 years in humans. To prevent nephrotoxicity induced by cadmium, it is necessary to identify specific and sensitive biomarkers of cadmium exposure andrenal damage, and to define critical exposure levels related to minimal nephrotoxicity in humans. In this study, urinary cadmium (UCd), blood cadmium (BCd) and total uptake of cadmium (TTCd) were used as cadmium exposure indicators, urinary β₂-microglobulin (UB2M), N-acetyl-β-D-glucosaminidase (UNAG) and albumin (UALB) were applied as the effect biomarkers of tubular and glomerular dysfunction. The relationship between urinary metallothionein (UMT) and cadmium exposure biomarkers as well as effect biomarkers was examined. Significant correlations were found between the UMT and TTCd, BCd, and UCd. At the same time, UB2M, UALB and UNAG showed positive correlation with UMT as well. According to this finding, cadmium-exposed individuals with renal dysfunction excreted more metallothionein than those without. Dose-response relationships between UCd and urinary biomarkers of renal dysfunction were studied. The critical concentration of UCd was quantitatively estimated by the benchmark dose (BMD) method. The lower confidence limit of the BMD-10 (BMDL) of UCd (3.1 μg/g Cr) related to increased excretion of urinary metallothionein was slightly higher than that for UNAG (2.7 μg/g Cr), but lower than those of UB2M (3.4 μg/g Cr) and UALB (4.2 μg/g Cr). The results demonstrate that UMT may be used as a sensitive biomarker of renal tubular dysfunction in cadmium-exposed populations.Few studies have been conducted in the relationship between metallothionein gene polymorphisms and cadmium induced renal dysfunction. In this study, MTlA-rs 11640851 gene polymorphism was assayed by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) techniques, and the interaction between MTlA-rs 11640851 gene polymorphism and cadmium on renal dysfunction was studied in a Chinese population environmentally exposed to cadmium. There was no significant difference between cases with renal dysfunction and those without in distribution frequencies of MTlA-rs 11640851 genotypes. However, the risk of renal tubular dysfunction increase 8.4 (95%CI: 1.67-42.16) folds in those subjects with A/C + C/C genotypes compared with those with A/A genotype when their UCd level was below 5 μg/g Cr. It was indicated that MT-rs 11640851 gene has a genetic modification on cadmium induced renal dysfunction, which exhibited that the risk of renal damage with A/C + C/C genotypes was significantly higher that of A/A genotype at low exposure level.It has been reported that anti-metallothionein (a metallothionein antibody) is present in the circulation of healthy subjects and in patients suffering from atopic dermatitis. The aim of this study was to investigate whether cadmium-induced renal dysfunction is related to the presence of the plasma metallothionein antibody (MT-Ab) in workers exposed to cadmium occupationally. Plasma metallothionein antibody was determined by enzyme linked immunosorbent assay (ELISA) techniques, and both exposure assessment and risk assessment were conducted in Cd exposed workers in China. We demonstrate that there is a significantly increased prevalence of renal dysfunction with respect to the level of urinary cadmium in a dose-dependant manner. We found no significant correlations between the levels of MT-Ab and the external or internal doses of cadmium (P > 0.05), but the levels of MT-Ab did correlate positively with two biomarkers of renal dysfunction—urinary β₂-microglobulin (UB2M; r = 0.218, P < 0.05) and N-acetyl-β-D-glucosaminidase (UNAG; r = 0.302, P < 0.001)—in the cadmium-exposed workers. Workers with high levels of MT-Ab display cadmium-induced tubular nephrotoxicity more frequently than those with low levels of MT-Ab, odds ratio (OR) 4.2; 95%-confidence intervals 1.2-14.5 (P < 0.05). This study suggests that subjects with higher MT-Ab levels more readily develop cadmium-induced renal dysfunction. Thus, the levels of plasma MT-Ab can be used as a biomarker of susceptibility to renal dysfunction in occupational cadmium exposure.It has been reported that diabetes could increase the risk of cadmium induced kidney damage. In this present study, we focus on the relationships between MT-Ab, urinary cadmium (UCd) and kidney function, in a Chinese diabetic population. The results show that tubular indicator UB2M increased significantly with both the elevation of MT-Ab and urinary cadmium; however, glomerular indicator UALB didn't display such a pattern. Those patients with tubular but not glomerular damage have highest UB2M, MT-Ab, and UCd levels compared with those subjects with normal renal function and those with glomerular but not tubular dysfunction. Both in male and female subjects, UB2M statistically correlate with UCd (r = 0.25 and 0.24, P < 0.05) and MT-Ab (r = 0.21 and 0.21, P < 0.05), while UCd did not show any significant correlation with MT-Ab (P > 0.05). After adjusting for potential confounding covariates, logistic regression showed the odds ratios (OR) of tubular dysfunction increased with elevation of MT-Ab levels from low-level to high-level (OR = 5.56,95% CI: 2.25-13.73); with increase of urinary cadmium from < lμg/g Cr to ≥ 1μg/g (OR = 3.34, 95% CI: 1.17-9.53); and the OR of current smoking was 3.51 (95% CI: 1.14-10.80) compared to never smoking. As for glomerular dysfunction, patients with fasting blood capillary glucose ≥ 6.1mmol/L had a 2.75-fold OR (95% CI: 1.12-6.74) compared with that < 6.1 mmol/L. It has been demonstrated that MT-Ab could potentiate tubular dysfunction among diabetic subjects, and those patients with high levels MT-Ab were more prone to develop tubular damage.