Expression of metallothionein isoforms in peripheral blood leukocytes from Thai population residing in cadmium-contaminated areas

Metallothionein (MT) is a group of proteins with high cadmium (Cd) affinity and with a potential role in Cd transportation and detoxification. The aim of the present study was to investigate the relationship between MT (MT-1A, MT-2A, and MT-3 isoforms) gene expression level in peripheral blood leukocytes and Cd-associated renal injury in non-occupational exposed Thai population. The study was conducted in adult subjects residing in Cd-contaminated areas of Mae Sot District, Thailand. The basal levels of MT-1A, MT-2A, and MT-3 mRNA expression were determined in leukocytes by quantitative RT-PCR. MT-1A and MT-2A expressions, particularly MT-1A, were found to be significantly increased with elevated levels of blood and urinary Cd levels. In subjects with high urinary Cd levels, negative correlations between MT-1A and microalbumin, and between MT-2A and β-MG, were observed. These results suggest that MT gene expression may reflect susceptibility of the exposed population to Cd-induced renal dysfunction. MT-1A mRNA expression in leukocytes might be developed as a potential biomarker of Cd exposure and Cd-induced renal dysfunction

Is renal tubular cadmium toxicity clinically relevant?

Exposure to cadmium (Cd) has been associated with the development of hypertension, especially in women, but the mechanism of such an association is not understood. We hypothesize that Cd exposure alters renal production of 20-hydroxyeicosatetraenoic acid (20-HETE), which plays an indispensable role in renal salt balance and blood pressure control.We examined long-term Cd exposure in relation to urinary 20-HETE excretion levels, tubular dysfunction and blood pressure measures, using data from a population-based, cross-sectional study that included 115 normotensive and 110 hypertensive women, 33-55 years of age, who lived in Cd contamination areas in Thailand.The mean [standard deviation (SD)] blood Cd level of the study subjects was 3.57 (3.3) µg/L, while the mean (SD) urinary Cd and urinary 20-HETE levels were 0.58 (0.47) µg/g creatinine and 1651 (4793) pg/mL, respectively. Elevated 20-HETE levels were associated with a 90% increase in prevalence odds of hypertension (P = 0.029), four times greater odds of having higher urinary Cd levels (P = 0.030) and a 53% increase in odds of having higher levels of tubular dysfunction (P = 0.049), evident from an increase in urinary excretion of β2-microglobulin. In normotensive subjects, an increase in urinary 20-HETE levels from tertile 1 to tertile 3 was associated with a systolic blood pressure increase of 6 mmHg (95% confidence interval 0.3-12, P = 0.040).This is the first report that links urinary 20-HETE levels to blood pressure increases in Cd-exposed women, thereby providing a plausible mechanism for associated development of hypertension

The stress response of human proximal tubule cells to cadmium involves up-regulation of haemoxygenase 1 and metallothionein but not cytochrome P450 enzymes

Enzymes of the cytochrome P450 (CYP) super-family are implicated in cadmium (Cd) -induced nephrotoxicity, however, direct evidence is lacking. This study investigated the endogenous expression of various CYP proteins together with the stress-response proteins, heme oxygenase-1 (HO-1) and metallothionein (MT) in human kidney sections and in cadmium-exposed primary cultures of human proximal tubular epithelial cells (PTC). By immunohistochemistry, the CYP members 2B6, 4A11 and 4F2 were prominently expressed in the cortical proximal tubular cells and to a lesser extent in distal tubular cells. Low levels of CYPs 2E1 and 3A4 were also detected. In PTC, in the absence of Cd, CYP2E1, CYP3A4, CYP4F2 and MT were expressed, but HO-1, CYP2B6 and CYP4A11 were not detected. A range of cadmium concentrations (0-100 μM) were utilized to induce stress conditions. MT protein was further induced by as little as 0.5 μM cadmium, reaching a 6-fold induction at 20 μM, whereas for HO-1, a 5 μM cadmium concentration was required for initial induction and at 20 μM cadmium reached a 15-fold induction. The expression of CYP2E1, CYP3A4, and CYP4F2 were not altered by any cadmium concentrations tested at 48 h. Cadmium caused a reduction in cell viability at concentrations above 10 μM. In conclusion although cultured PTC, do express CYP proteins, (CYP2E1, CYP3A4, and CYP4F2), Cd-induced cell stress as indicted by induction of HO-1 and MT does not alter expression of these CYP proteins at 48 h

Chronic exposure to cadmium is associated with a marked reduction in glomerular filtration rate

Background. Urinary 20-hydroxyeicosatetraenoic acid (20-HETE) has been associated with hypertension in women with elevated urinary cadmium (Cd) excretion rates. The present study investigates the urinary Cd and 20-HETE levels in relation to the estimated glomerular filtration rate (eGFR) and albumin excretion in men and women.Methods. A population-based, cross-sectional study, which included 225 women and 84 men aged 33-55 years, was conducted in a rural area known to be polluted with Cd.Results. In all subjects, lower eGFR values were associated with higher urinary Cd excretion (P = 0.030), and tubulopathy markers N-acetyl-beta-D-glucosaminidase (P< 0.001) and beta 2-microglobulin (beta 2-MG) (P< 0.001). On average, the hypertensive subjects with the highest quartile of urinary Cd had eGFR values of 12 and 17 mL/min/1.73 m(2) lower than that in the hypertensive (P = 0.009) and normotensive subjects (P< 0.001) with the lowest quartile of urinary Cd, respectively. In men, urinary albumin was inversely associated with 20-HETE (beta = -0.384, P< 0.001), while showing a moderately positive association with systolic blood pressure (SBP) (beta = 0.302, P = 0.037). In women, urinary albumin was not associated with 20-HETE (P = 0.776), but was associated with tubulopathy, reflected by elevated urinary excretion of beta 2-MG (beta = 0.231, P = 0.002).Conclusions. Tubulopathy is a determinant of albumin excretion in women, while 20-HETE and SBP are determinants of urinary albumin excretion in men. Associations of chronic exposure to Cd with marked eGFR decline and renal tubular injury seen in both Cd-exposed men and women add to mounting research data that links Cd to the risk of developing chronic kidney disease