Toxicity Tolerance in the Carcinogenesis of Environmental Cadmium.

Cadmium (Cd) is an environmental toxicant of worldwide public health significance. Diet is the main non-workplace Cd exposure source other than passive and active smoking. The intestinal absorption of Cd involves transporters for essential metals, notably iron and zinc. These transporters determine the Cd body burden because only a minuscule amount of Cd can be excreted each day. The International Agency for Research on Cancer listed Cd as a human lung carcinogen, but the current evidence suggests that the effects of Cd on cancer risk extend beyond the lung. A two-year bioassay demonstrated that Cd caused neoplasms in multiple tissues of mice. Also, several non-tumorigenic human cells transformed to malignant cells when they were exposed to a sublethal dose of Cd for a prolonged time. Cd does not directly damage DNA, but it influences gene expression through interactions with essential metals and various proteins. The present review highlights the epidemiological studies that connect an enhanced risk of various neoplastic diseases to chronic exposure to environmental Cd. Special emphasis is given to the impact of body iron stores on the absorption of Cd, and its implications for breast cancer prevention in highly susceptible groups of women. Resistance to cell death and other cancer phenotypes acquired during Cd-induced cancer cell transformation, under in vitro conditions, are briefly discussed. The potential role for the ZnT1 efflux transporter in the cellular acquisition of tolerance to Cd cytotoxicity is highlighted.

Estimation of health risks associated with dietary cadmium exposure.

In much of the world, currently employed upper limits of tolerable intake and acceptable excretion of cadmium (Cd) (ECd/Ecr) are 0.83 µg/kg body weight/day and 5.24 µg/g creatinine, respectively. These figures were derived from a risk assessment model that interpreted ß2-microglobulin (ß2MG) excretion > 300 µg/g creatinine as a "critical" endpoint. However, current evidence suggests that Cd accumulation reduces glomerular filtration rate at values of ECd/Ecr much lower than 5.24 µg/g creatinine. Low ECd/Ecr has also been associated with increased risks of kidney disease, type 2 diabetes, osteoporosis, cancer, and other disorders. These associations have cast considerable doubt on conventional guidelines. The goals of this paper are to evaluate whether these guidelines are low enough to minimize associated health risks reliably, and indeed whether permissible intake of a cumulative toxin like Cd is a valid concept. We highlight sources and levels of Cd in the human diet and review absorption, distribution, kidney accumulation, and excretion of the metal. We present evidence for the following propositions: excreted Cd emanates from injured tubular epithelial cells of the kidney; Cd excretion is a manifestation of current tissue injury; reduction of present and future exposure to environmental Cd cannot mitigate injury in progress; and Cd excretion is optimally expressed as a function of creatinine clearance rather than creatinine excretion. We comprehensively review the adverse health effects of Cd and urine and blood Cd levels at which adverse effects have been observed. The cumulative nature of Cd toxicity and the susceptibility of multiple organs to toxicity at low body burdens raise serious doubt that guidelines concerning permissible intake of Cd can be meaningful.

Cadmium-Induced Proteinuria: Mechanistic Insights from Dose-Effect Analyses.

Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular ultrafiltrate are reabsorbed. Here, we analyzed archived data on the estimated glomerular filtration rate (eGFR) and excretion rates of Cd (ECd), total protein (EProt), albumin (Ealb), ß2-microglobulin (Eß2M), and α1-microglobulin (Eα1M), which were recorded for residents of a Cd contamination area and a low-exposure control area of Thailand. Excretion of Cd and all proteins were normalized to creatinine clearance (Ccr) as ECd/Ccr and EProt/Ccr to correct for differences among subjects in the number of surviving nephrons. Low eGFR was defined as eGFR ≤ 60 mL/min/1.73 m2, while proteinuria was indicted by EPro/Ccr ≥ 20 mg/L of filtrate. EProt/Ccr varied directly with ECd/Ccr (ß = 0.263, p < 0.001) and age (ß = 0.252, p < 0.001). In contrast, eGFR values were inversely associated with ECd/Ccr (ß = -0.266, p < 0.001) and age (ß = -0.558, p < 0.001). At ECd/Ccr > 8.28 ng/L of filtrate, the prevalence odds ratios for proteinuria and low eGFR were increased 4.6- and 5.1-fold, respectively (p < 0.001 for both parameters). Thus, the eGFR and tubular protein retrieval were both simultaneously diminished by Cd exposure. Of interest, ECd/Ccr was more closely correlated with EProt/Ccr (r = 0.507), Eß2M (r = 0.430), and Eα1M/Ccr (r = 0.364) than with EAlb/Ccr (r = 0.152). These data suggest that Cd may differentially reduce the ability of tubular epithelial cells to reclaim proteins, resulting in preferential reabsorption of albumin.

Chronic Kidney Disease Induced by Cadmium and Diabetes: A Quantitative Case-Control Study.

Kidney disease associated with chronic cadmium (Cd) exposure is primarily due to proximal tubule cell damage. This results in a sustained decline in glomerular filtration rate (GFR) and tubular proteinuria. Similarly, diabetic kidney disease (DKD) is marked by albuminuria and a declining GFR and both may eventually lead to kidney failure. The progression to kidney disease in diabetics exposed to Cd has rarely been reported. Herein, we assessed Cd exposure and the severity of tubular proteinuria and albuminuria in 88 diabetics and 88 controls, matched by age, gender and locality. The overall mean blood and Cd excretion normalized to creatinine clearance (Ccr) as ECd/Ccr were 0.59 µg/L and 0.0084 µg/L filtrate (0.96 µg/g creatinine), respectively. Tubular dysfunction, assessed by ß2-microglobulin excretion rate normalized to Ccr(Eß2M/Ccr) was associated with both diabetes and Cd exposure. Doubling of Cd body burden, hypertension and a reduced estimated GFR (eGFR) increased the risks for a severe tubular dysfunction by 1.3-fold, 2.6-fold, and 84-fold, respectively. Albuminuria did not show a significant association with ECd/Ccr, but hypertension and eGFR did. Hypertension and a reduced eGFR were associated with a 3-fold and 4-fold increases in risk of albuminuria. These findings suggest that even low levels of Cd exposure exacerbate progression of kidney disease in diabetics.

The Effect of Cadmium on GFR Is Clarified by Normalization of Excretion Rates to Creatinine Clearance.

Erroneous conclusions may result from normalization of urine cadmium and N-acetyl-ß-D-glucosaminidase concentrations ([Cd]u and [NAG]u) to the urine creatinine concentration ([cr]u). In theory, the sources of these errors are nullified by normalization of excretion rates (ECd and ENAG) to creatinine clearance (Ccr). We hypothesized that this alternate approach would clarify the contribution of Cd-induced tubular injury to nephron loss. We studied 931 Thai subjects with a wide range of environmental Cd exposure. For x = Cd or NAG, Ex/Ecr and Ex/Ccr were calculated as [x]u/[cr]u and [x]u[cr]p/[cr]u, respectively. Glomerular filtration rate (GFR) was estimated according to the Chronic Kidney Disease (CKD) Epidemiology Collaboration (eGFR), and CKD was defined as eGFR < 60 mL/min/1.73m2. In multivariable logistic regression analyses, prevalence odds ratios (PORs) for CKD were higher for log(ECd/Ccr) and log(ENAG/Ccr) than for log(ECd/Ecr) and log(ENAG/Ecr). Doubling of ECd/Ccr and ENAG/Ccr increased POR by 132% and 168%; doubling of ECd/Ecr and ENAG/Ecr increased POR by 64% and 54%. As log(ECd/Ccr) rose, associations of eGFR with log(ECd/Ccr) and log(ENAG/Ccr) became stronger, while associations of eGFR with log(ECd/Ecr) and log(ENAG/Ecr) became insignificant. In univariate regressions of eGFR on each of these logarithmic variables, R2 was consistently higher with normalization to Ccr. Our tabular and graphic analyses uniformly indicate that normalization to Ccr clarified relationships of ECd and ENAG to eGFR.

The inverse association of glomerular function and urinary ß2-MG excretion and its implications for cadmium health risk assessment.

Urinary ß2-microgroblin (ß2-MG) excretion levels above 300 µg/g creatinine are used to indicate defective tubular reabsorption. Arguably, increased urinary ß2-MG excretion could also reflect glomerular filtration rate decline. Thus, we investigated an association between urinary ß2-MG and estimated glomerular filtration rate (eGFR). We studied 527 subjects, aged 30-87 years (mean 51.2), who lived in a rural area of Thailand polluted with cadmium (Cd). Of this cohort, 10.3% had urinary Cd levels <2 µg/g creatinine and 53.5% had urinary Cd levels ≥5 µg/g creatinine. Half (53.1%) of the participants had urinary ß2-MG levels ≥ 300 µg/g creatinine, and 11.6% had low GFR, defined as eGFR <60 mL/min/1.73 m2. Lower eGFR values were associated with older age (ß = -0.568, P < 0.001), higher urinary ß2-MG (ß = -0.170, P < 0.001), higher urinary Cd (ß = -0.103, P = 0.005) and diabetes (ß = 0.074, P = 0.032). An inverse association between eGFR and urinary ß2-MG was evident in subjects with low GFR (ß = -0.332, P = 0.033), but not in those with GFR >90 mL/min/1.73 m2 (ß = -0.008, P = 0.896). These findings suggested Cd-induced nephron loss and reduced tubular reabsorption in low eGFR subjects. Urinary ß2-MG levels <300 µg/g creatinine were associated with 4.66 (95% CI: 1.92, 11.32) fold increase in the POR for low GFR, compared with urinary ß2-MG levels <100 µg/g creatinine. Findings in the present study cast doubt on a cut-off value for urinary ß2-MG, while lending support to the notion that elevated urinary ß2-MG excretion could indicate a fall of GFR.

Kidney Cadmium Toxicity, Diabetes and High Blood Pressure: The Perfect Storm.

Cadmium (Cd) is an environmental toxicant of widespread exposure and pervasive toxicity. Absorption, systemic transport and uptake of Cd are mediated by metal transporters that the body uses for acquisition of physiologically-essential elements, notably of iron, zinc and calcium. Currently, human exposure to Cd is known to damage the kidneys, especially the proximal tubular cells that actively reabsorb Cd along with zinc, glucose and amino acids in the glomerular filtrate. Severe kidney damage, glycosuria and proteinuria are known outcomes after high dietary Cd intake (> 200 µg/day). Dietary Cd intake of 10-30 µg/day has been linked with reduced tubular reabsorption, chronic kidney disease, hypertension, coronary arterial and peripheral arterial diseases, macular degeneration, obesity-independent diabetes, and cancer. The links between diabetes, hypertension and end stage kidney disease (ESKD) are indisputable. ESKD requires dialysis or kidney transplant, an immense health care cost. This review adds to these connections by presenting the synergism of kidney Cd toxicity on blood pressure control and glucose homeostasis. Blood pressure control is mediated at least in part by cytochrome P450 (CYP) enzymes such as CYP4A11 and CYP4F2 that produce 20-hydroxyeicosatetraenoic acid (20-HETE), involved in salt balance in the kidney, and all are known to be altered during Cd exposure. The potential effects of Cd exposure on glucose reabsorption, inflammation, oxidative stress, and heme oxygenase activity are highlighted. The information presented offers strategies for mitigation of toxic effects of Cd through minimization of the food-chain transfer of Cd, and modulation of mechanistic pathways altered by Cd exposure.

Induction of MITF expression in human cholangiocarcinoma cells and hepatocellular carcinoma cells by cyclopamine, an inhibitor of the Hedgehog signaling.

Microphthalmia-associated transcription factor (MITF) is a key regulator of differentiation of melanocytes and retinal pigment epithelial cells, but it also has functions in non-pigment cells. MITF consists of multiple isoforms, including widely expressed MITF-A and MITF-H. In the present study, we explored the potential role played by the Hedgehog signaling on MITF expression in two common types of primary liver cancer, using human cholangiocarcinoma cell lines, the KKU-100 and HuCCT1, along with the HepG2 human hepatocellular carcinoma cell line. Importantly, cholangiocarcinoma is characterized by the activated Hedgehog signaling. Here we show that MITF-A mRNA is predominantly expressed in all three human liver cancer cell lines examined. Moreover, cyclopamine, an inhibitor of the Hedgehog signalling, increased the expression levels of MITF proteins in HuCCT1 and HepG2 cells, but not in KKU-100 cells, suggesting that MITF expression may be down-regulated in some liver cancer cases.

Is Chronic Kidney Disease Due to Cadmium Exposure Inevitable and Can It Be Reversed?

Cadmium (Cd) is a metal with no nutritional value or physiological role. However, it is found in the body of most people because it is a contaminant of nearly all food types and is readily absorbed. The body burden of Cd is determined principally by its intestinal absorption rate as there is no mechanism for its elimination. Most acquired Cd accumulates within the kidney tubular cells, where its levels increase through to the age of 50 years but decline thereafter due to its release into the urine as the injured tubular cells die. This is associated with progressive kidney disease, which is signified by a sustained decline in the estimated glomerular filtration rate (eGFR) and albuminuria. Generally, reductions in eGFR after Cd exposure are irreversible, and are likely to decline further towards kidney failure if exposure persists. There is no evidence that the elimination of current environmental exposure can reverse these effects and no theoretical reason to believe that such a reversal is possible. This review aims to provide an update on urinary and blood Cd levels that were found to be associated with GFR loss and albuminuria in the general populations. A special emphasis is placed on the mechanisms underlying albumin excretion in Cd-exposed persons, and for an accurate measure of the doses-response relationships between Cd exposure and eGFR, its excretion rate must be normalised to creatinine clearance. The difficult challenge of establishing realistic Cd exposure guidelines such that human health is protected, is discussed.

The pathogenesis of albuminuria in cadmium nephropathy.

Background: Urinary cadmium excretion (ECd) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since ß2-microglobulinuria (Eß2M) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (Ealb) to Eß2M in Cd-exposed subjects would provide evidence of similar mishandling of both proteins. Methods: To depict excretion rates per functional nephron, ECd, Ealb, and Eß2M were normalized to creatinine clearance (Ccr), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate Ealb/Ccr, Eß2M/Ccr, and eGFR to several independent variables. Simple linear regressions of eGFR, Ealb/Ccr, and Eß2M/Ccr on ECd/Ccr were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in Ealb/Ccr and Eß2M/Ccr and decrements in eGFR were quantified through four quartiles of ECd/Ccr. Results: As age or ECd/Ccr rose, Ealb/Ccr and Eß2M/Ccr also rose, and eGFR fell. In linear regressions, slopes relating Ealb/Ccr and Eß2M/Ccr to ECd/Ccr were similar. After adjustment of dependent variables for age, coefficients of determination (R2) for all regressions rose by a multiple, and slopes approached unity. Ealb/Ccr and Eß2M/Ccr were similarly associated with each other. Mean Ealb/Ccr and Eß2M/Ccr rose and mean eGFR fell in stepwise fashion through quartiles of ECd/Ccr. Whereas Eß2M/Ccr did not vary with blood pressure, Ealb/Ccr rose in association with hypertension in two of the four quartiles. Conclusions: Our data indicate that Cd in renal tissue affected tubular reabsorption of albumin and ß2M similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.

Modulation of Adverse Health Effects of Environmental Cadmium Exposure by Zinc and Its Transporters.

Zinc (Zn) is the second most abundant metal in the human body and is essential for the function of 10% of all proteins. As metals cannot be synthesized or degraded, they must be assimilated from the diet by specialized transport proteins, which unfortunately also provide an entry route for the toxic metal pollutant cadmium (Cd). The intestinal absorption of Zn depends on the composition of food that is consumed, firstly the amount of Zn itself and then the quantity of other food constituents such as phytate, protein, and calcium (Ca). In cells, Zn is involved in the regulation of intermediary metabolism, gene expression, cell growth, differentiation, apoptosis, and antioxidant defense mechanisms. The cellular influx, efflux, subcellular compartmentalization, and trafficking of Zn are coordinated by transporter proteins, solute-linked carriers 30A and 39A (SLC30A and SLC39A), known as the ZnT and Zrt/Irt-like protein (ZIP). Because of its chemical similarity with Zn and Ca, Cd disrupts the physiological functions of both. The concurrent induction of a Zn efflux transporter ZnT1 (SLC30A1) and metallothionein by Cd disrupts the homeostasis and reduces the bioavailability of Zn. The present review highlights the increased mortality and the severity of various diseases among Cd-exposed persons and the roles of Zn and other transport proteins in the manifestation of Cd cytotoxicity. Special emphasis is given to Zn intake levels that may lower the risk of vision loss and bone fracture associated with Cd exposure. The difficult challenge of determining a permissible intake level of Cd is discussed in relation to the recommended dietary Zn intake levels.

Plant-Based Diet and Glycemic Control in Type 2 Diabetes: Evidence from a Thai Health-Promoting Hospital.

The prevalence of type 2 diabetes (T2DM) is associated with diet. While consumption of plant-based foods may reduce blood sugar levels, the impact of consuming plant-based foods on fasting blood sugar levels has not been well defined. This cross-sectional study was conducted at the Health-Promoting Hospital in Pak Phun Municipality, Thailand. It included 61 patients with T2DM and 74 controls matched for age and gender. Dietary intake levels among T2DM and controls were assessed by a validated food-frequency questionnaire from which plant-based-food scores were calculated. This study found significant differences between specific plant foods and fasting blood sugar levels in patients with T2DM. Adherence to a plant-based diet appeared to influence fasting blood sugar levels. Patients who consumed higher amounts of certain vegetables and fruits showed lower fasting blood sugar levels. Diabetic patients consumed more legumes than controls, but the consumption of cereals and nuts/seeds in the two groups were similar. Consumption of nuts and seeds was also associated with a 76.3% reduction in the risk of a T2DM diagnosis. These findings suggest the potential efficacy of glycemic control in T2DM patients. More work is required to explore strategies for preventing and treating metabolic disorders through dietary modification.

Is Environmental Cadmium Exposure Causally Related to Diabetes and Obesity?

Cadmium (Cd) is a pervasive toxic metal, present in most food types, cigarette smoke, and air. Most cells in the body will assimilate Cd, as its charge and ionic radius are similar to the essential metals, iron, zinc, and calcium (Fe, Zn, and Ca). Cd preferentially accumulates in the proximal tubular epithelium of the kidney, and is excreted in urine when these cells die. Thus, excretion of Cd reflects renal accumulation (body burden) and the current toxicity of Cd. The kidney is the only organ other than liver that produces and releases glucose into the circulation. Also, the kidney is responsible for filtration and the re-absorption of glucose. Cd is the least recognized diabetogenic substance although research performed in the 1980s demonstrated the diabetogenic effects of chronic oral Cd administration in neonatal rats. Approximately 10% of the global population are now living with diabetes and over 80% of these are overweight or obese. This association has fueled an intense search for any exogenous chemicals and lifestyle factors that could induce excessive weight gain. However, whilst epidemiological studies have clearly linked diabetes to Cd exposure, this appears to be independent of adiposity. This review highlights Cd exposure sources and levels associated with diabetes type 2 and the mechanisms by which Cd disrupts glucose metabolism. Special emphasis is on roles of the liver and kidney, and cellular stress responses and defenses, involving heme oxygenase-1 and -2 (HO-1 and HO-2). From heme degradation, both HO-1 and HO-2 release Fe, carbon monoxide, and a precursor substrate for producing a potent antioxidant, bilirubin. HO-2 appears to have also anti-diabetic and anti-obese actions. In old age, HO-2 deficient mice display a symptomatic spectrum of human diabetes, including hyperglycemia, insulin resistance, increased fat deposition, and hypertension.

Cadmium-Induced Tubular Dysfunction in Type 2 Diabetes: A Population-Based Cross-Sectional Study.

The global prevalence of diabetes, and its major complication, diabetic nephropathy, have reached epidemic proportions. The toxic metal cadmium (Cd) also induces nephropathy, indicated by a sustained reduction in the estimated glomerular filtration rate (eGFR) and the excretion of ß2-microglobulin (ß2M) above 300 µg/day, which reflects kidney tubular dysfunction. However, little is known about the nephrotoxicity of Cd in the diabetic population. Here, we compared Cd exposure, eGFR, and tubular dysfunction in both diabetics (n = 81) and non-diabetics (n = 593) who were residents in low- and high-Cd exposure areas of Thailand. We normalized the Cd and ß2M excretion rates (ECd and Eß2M) to creatinine clearance (Ccr) as ECd/Ccr and Eß2M/Ccr. Tubular dysfunction and a reduced eGFR were, respectively, 8.7-fold (p < 0.001) and 3-fold (p = 0.012) more prevalent in the diabetic than the non-diabetic groups. The doubling of ECd/Ccr increased the prevalence odds ratios for a reduced eGFR and tubular dysfunction by 50% (p < 0.001) and 15% (p = 0.002), respectively. In a regression model analysis of diabetics from the low-exposure locality, Eß2M/Ccr was associated with ECd/Ccr (ß = 0.375, p = 0.001) and obesity (ß = 0.273, p = 0.015). In the non-diabetic group, Eß2M/Ccr was associated with age (ß = 0.458, p < 0.001) and ECd/Ccr (ß = 0.269, p < 0.001). However, after adjustment for age, and body mass index (BMI), Eß2M/Ccr was higher in the diabetics than non-diabetics of similar ECd/Ccr ranges. Thus, tubular dysfunction was more severe in diabetics than non-diabetics of similar age, BMI, and Cd body burden.

Gender Differences in the Severity of Cadmium Nephropathy.

The excretion of ß2-microglobulin (ß2M) above 300 µg/g creatinine, termed tubulopathy, was regarded as the critical effect of chronic exposure to the metal pollutant cadmium (Cd). However, current evidence suggests that Cd may induce nephron atrophy, resulting in a reduction in the estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2. Herein, these pathologies were investigated in relation to Cd exposure, smoking, diabetes, and hypertension. The data were collected from 448 residents of Cd-polluted and non-polluted regions of Thailand. The body burden of Cd, indicated by the mean Cd excretion (ECd), normalized to creatinine clearance (Ccr) as (ECd/Ccr) × 100 in women and men did not differ (3.21 vs. 3.12 µg/L filtrate). After adjustment of the confounding factors, the prevalence odds ratio (POR) for tubulopathy and a reduced eGFR were increased by 1.9-fold and 3.2-fold for every 10-fold rise in the Cd body burden. In women only, a dose-effect relationship was seen between ß2M excretion (Eß2M/Ccr) and ECd/Ccr (F = 3.431, η2 0.021). In men, Eß2M/Ccr was associated with diabetes (ß = 0.279). In both genders, the eGFR was inversely associated with Eß2M/Ccr. The respective covariate-adjusted mean eGFR values were 16.5 and 12.3 mL/min/1.73 m2 lower in women and men who had severe tubulopathy ((Eß2M/Ccr) × 100 ≥ 1000 µg/L filtrate). These findings indicate that women were particularly susceptible to the nephrotoxicity of Cd, and that the increment of Eß2M/Ccr could be attributable mostly to Cd-induced impairment in the tubular reabsorption of the protein together with Cd-induced nephron loss, which is evident from an inverse relationship between Eß2M/Ccr and the eGFR.

Evidence Linking Cadmium Exposure and ß2-Microglobulin to Increased Risk of Hypertension in Diabetes Type 2.

The most common causes of chronic kidney disease, diabetes, and hypertension are significant public health issues worldwide. Exposure to the heavy metal pollutant, cadmium (Cd), which is particularly damaging to the kidney, has been associated with both risk factors. Increased levels of urinary ß2-microglobulin (ß2M) have been used to signify Cd-induced kidney damage and circulating levels have been linked to blood pressure control. In this study we investigated the pressor effects of Cd and ß2M in 88 diabetics and 88 non-diabetic controls, matched by age, gender and locality. The overall mean serum ß2M was 5.98 mg/L, while mean blood Cd and Cd excretion normalized to creatinine clearance (Ccr) as ECd/Ccr were 0.59 µg/L and 0.0084 µg/L of filtrate (0.95 µg/g creatinine), respectively. The prevalence odds ratio for hypertension rose by 79% per every ten-fold increase in blood Cd concentration. In all subjects, systolic blood pressure (SBP) showed positive associations with age (ß = 0.247), serum ß2M (ß = 0.230), and ECd/Ccr (ß = 0.167). In subgroup analysis, SBP showed a strong positive association with ECd/Ccr (ß = 0.303) only in the diabetic group. The covariate-adjusted mean SBP in the diabetics of the highest ECd/Ccr tertile was 13.8 mmHg higher, compared to the lowest tertile (p = 0.027). An increase in SBP associated with Cd exposure was insignificant in non-diabetics. Thus, for the first time, we have demonstrated an independent effect of Cd and ß2M on blood pressure, thereby implicating both Cd exposure and ß2M in the development of hypertension, especially in diabetics.

Health Risk in a Geographic Area of Thailand with Endemic Cadmium Contamination: Focus on Albuminuria.

An increased level of cadmium (Cd) in food crops, especially rice is concerning because rice is a staple food for over half of the world's population. In some regions, rice contributes to more than 50% of the total Cd intake. Low environmental exposure to Cd has been linked to an increase in albumin excretion to 30 mg/g creatinine, termed albuminuria, and a progressive reduction in the estimated glomerular filtration rate (eGFR) to below 60 mL/min/1.73 m2, termed reduced eGFR. However, research into albuminuria in high exposure conditions is limited. Here, we applied benchmark dose (BMD) analysis to the relevant data recorded for the residents of a Cd contamination area and a low-exposure control area. We normalized the excretion rates of Cd (ECd) and albumin (Ealb) to creatinine clearance (Ccr) as ECd/Ccr and Ealb/Ccr to correct for differences among subjects in the number of surviving nephrons. For the first time, we defined the excretion levels of Cd associated with clinically relevant adverse kidney health outcomes. Ealb/Ccr varied directly with ECd/Ccr (ß = 0.239, p < 0.001), and age (ß = 0.203, p < 0.001), while normotension was associated with lower Ealb/Ccr (ß = −0.106, p = 0.009). ECd/Ccr values between 16.5 and 35.5 ng/L of the filtrate were associated with a 10% prevalence of albuminuria, while the ECd/Ccr value of 59 ng/L of the filtrate was associated with a 10% prevalence of reduced eGFR. Thus, increased albumin excretion and eGFR reduction appeared to occur at low body burdens, and they should form toxicity endpoints suitable for the calculation of health risk due to the Cd contamination of food chains.

Estimation of the Cadmium Nephrotoxicity Threshold from Loss of Glomerular Filtration Rate and Albuminuria.

Cadmium (Cd) is a pervasive, toxic environmental pollutant that preferentially accumulates in the tubular epithelium of the kidney. Current evidence suggests that the cumulative burden of Cd here leads to the progressive loss of the glomerular filtration rate (GFR). In this study, we have quantified changes in estimated GFR (eGFR) and albumin excretion (Ealb) according to the levels of blood Cd ([Cd]b) and excretion of Cd (ECd) after adjustment for confounders. ECd and Ealb were normalized to creatinine clearance (Ccr) as ECd/Ccr and Ealb/Ccr. Among 482 residents of Cd-polluted and non-polluted regions of Thailand, 8.1% had low eGFR and 16.9% had albuminuria (Ealb/Ccr) × 100 ≥ 20 mg/L filtrate. In the low Cd burden group, (ECd/Ccr) × 100 < 1.44 µg/L filtrate, eGFR did not correlate with ECd/Ccr (ß = 0.007) while an inverse association with ECd/Ccr was found in the medium (ß = -0.230) and high burden groups (ß = -0.349). Prevalence odds ratios (POR) for low eGFR were increased in the medium (POR 8.26) and high Cd burden groups (POR 3.64). Also, eGFR explained a significant proportion of Ealb/Ccr variation among those with middle (η2 0.093) and high [Cd]b tertiles (η2 0.132) but did not with low tertiles (η2 0.001). With an adjustment of eGFR, age and BMI, the POR values for albuminuria were increased in the middle (POR 2.36) and high [Cd]b tertiles (POR 2.74) and those with diabetes (POR 6.02) and hypertension (2.05). These data indicate that (ECd/Ccr) × 100 of 1.44 µg/L filtrate (0.01-0.02 µg/g creatinine) may serve as a Cd threshold level based on which protective exposure guidelines should be formulated.

Emerging roles of cadmium and heme oxygenase in type-2 diabetes and cancer susceptibility.

Many decades after an outbreak of severe cadmium poisoning, known as Itai-itai disease, cadmium continues to pose a significant threat to human health worldwide. This review provides an update on the effects of this environmental toxicant cadmium, observed in numerous populations despite modest exposure levels. In addition, it describes the current knowledge on the link between heme catabolism and glycolysis. It examines novel functions of heme oxygenase-2 (HO-2) that protect against type 2-diabetes and obesity, which have emerged from diabetic/obese phenotypes of the HO-2 knockout mouse model. Increased cancer susceptibility in type-2 diabetes has been noted in several large cohorts. This is a cause for concern, given the high prevalence of type-2 diabetes worldwide. A lifetime exposure to cadmium is associated with pre-diabetes, diabetes, and overall cancer mortality with sex-related differences in specific types of cancer. Liver and kidney are target organs for the toxic effects of cadmium. These two organs are central to the maintenance of blood glucose levels. Further, inhibition of gluconeogenesis is a known effect of heme, while cadmium has the propensity to alter heme catabolism. This raises the possibility that cadmium may mimic certain HO-2 deficiency conditions, resulting in diabetic symptoms. Intriguingly, evidence has emerged from a recent study to suggest the potential interaction and co-regulation of HO-2 with the key regulator of glycolysis: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4). HO-2 could thus be critical to a metabolic switch to cancer-prone cells because the enzyme PFKFB and glycolysis are metabolic requirements for cell proliferation and resistance to apoptosis.

Editorial to Special Issue Toxic Metals, Chronic Diseases and Related Cancers.

In this Special Issue, entitled "Toxic Metals, Chronic Diseases and Related Cancers", there are 19 published manuscripts, including reports of environmental exposure monitoring [...].