Special Issue "Cadmium Sources and Toxicity"

A special issue of Toxics (ISSN 2305-6304). This special issue belongs to the section "Toxicology and Public Health".

Deadline for manuscript submissions: closed (1 July 2018)

Special Issue Editor

Guest Editor
Prof. Soisungwan Satarug

Centre for Kidney Disease Research, University of Queensland Faculty of Medicine and Translational Research Institute, Brisbane, Australia
Website | E-Mail
Interests: epidemiology of cadmium toxicity; genetic and nutritional influence of cadmium toxicity outcomes; cadmium toxicity in at-risk subpopulations; novel methods of measuring cadmium in tissues; reverse dosimetry

Special Issue Information

Dear Colleagues,

Cadmium is an environmental toxicant with high toxicity potential due to its non-biodegradability, coupled with high rates of soil-to-plant transference. It is estimated that 40–60% of dietary cadmium intake in the average consumer comes from dietary staples, such as rice, potatoes, and wheat, while shellfish, crustaceans, molluscs, offal and spinach form the remaining dietary sources. The divalent metal transporter, DMT1, the primary iron transporting protein in the intestine, is a major cadmium carrier, while ferroportin1 (FPN1) may mediate the transport of cadmium into the circulation. DMT1 expression is heightened in people with low body iron stores and iron deficiency; conditions common in women of reproductive age and children, rendering them at greatest risk of cadmium toxicity due to enhanced cadmium uptake. Chronic dietary cadmium exposure has been associated with increased risks of numerous diseases, including chronic kidney disease, hypertension, heart disease, osteoporosis, type 2 diabetes, liver inflammation, hearing loss, depression, macular degeneration, obstructive lung disease, infection with HBV and H. pylori, breast cancer, lung cancer and death from cancer and Alzheimer’s disease. These data signal that current population exposure levels have exceeded toxicity thresholds in many tissues, but the therapeutically effective metal chelating agents for reducing toxic Cd body burden are currently lacking.

This Special Issue will focus on highlighting timely research studies addressing sources and toxicity of cadmium. Topics are expected to include novel methods of measuring cadmium in tissues, validation of novel biomarkers of cadmium exposure, molecular basis for cadmium toxicity, interaction with zinc, copper, calcium, selenium and iron, strategies for minimizing cadmium in the global diet, strategies for reducing absorption of dietary cadmium, mitigation of cadmium toxicity, and the use of physiologically-based pharmacokinetic (PBPK) modeling in health risk assessment. Studies may include, but are not limited to toxicity in subpopulations at risk, such as young children who have greater food consumption rates per unit body mass and women of the reproductive age. Authors are invited and welcome to submit original research papers, reviews, and short communications.

Prof. Dr. Soisungwan Satarug
Guest Editor

Manuscript Submission Information

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Keywords

  • Cadmium toxicity threshold
  • Cancer and chronic disease risks
  • Cadmium exposure biomarkers
  • Endogenous and exogenous antioxidants
  • Metal chelators
  • Metal dysregulation
  • Metal transporters
  • Phosphate fertilizer
  • Pregnancy outcomes
  • Safe intake level of dietary cadmium
  • Soil contamination
  • Synchroton and tissue metal analysis

Published Papers (9 papers)

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Research

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Open AccessArticle The NOAEL Metformin Dose Is Ineffective against Metabolic Disruption Induced by Chronic Cadmium Exposure in Wistar Rats
Received: 16 August 2018 / Revised: 6 September 2018 / Accepted: 7 September 2018 / Published: 10 September 2018
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Abstract
Previous studies have proposed that cadmium (Cd) is a metabolic disruptor, which is associated with insulin resistance, metabolic syndrome, and diabetes. This metal is not considered by international agencies for the study of metabolic diseases. In this study, we investigate the effect of
[...] Read more.
Previous studies have proposed that cadmium (Cd) is a metabolic disruptor, which is associated with insulin resistance, metabolic syndrome, and diabetes. This metal is not considered by international agencies for the study of metabolic diseases. In this study, we investigate the effect of metformin on Cd-exposed Wistar rats at a lowest-observed-adverse-effect level (LOAEL) dose (32.5 ppm) in drinking water. Metabolic complications in the rats exposed to Cd were dysglycemia, insulin resistance, dyslipidemia, dyslipoproteinemia, and imbalance in triglyceride and glycogen storage in the liver, muscle, heart, kidney, and adipose tissue. Meanwhile, rats treated orally with a No-observable-adverse-effect level (NOAEL) dose of metformin (200 mg/kg/day) showed mild improvement on serum lipids, but not on glucose tolerance; in tissues, glycogen storage was improved, but lipid storage was ineffective. In conclusion, metformin as a first-line pharmacological therapy must take into consideration the origin and duration of metabolic disruption, because in this work the NOAEL dose of metformin (200 mg/kg/day) showed a limited efficiency in the metabolic disruption caused by chronic Cd exposure. Full article
(This article belongs to the Special Issue Cadmium Sources and Toxicity)
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Open AccessFeature PaperArticle Intrauterine Exposure to Cadmium Reduces HIF-1 DNA-Binding Ability in Rat Fetal Kidneys
Received: 11 June 2018 / Revised: 7 August 2018 / Accepted: 29 August 2018 / Published: 3 September 2018
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Abstract
During embryonic development, some hypoxia occurs due to incipient vascularization. Under hypoxic conditions, gene expression is mainly controlled by hypoxia-inducible factor 1 (HIF-1). The activity of this transcription factor can be altered by the exposure to a variety of compounds; among them is
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During embryonic development, some hypoxia occurs due to incipient vascularization. Under hypoxic conditions, gene expression is mainly controlled by hypoxia-inducible factor 1 (HIF-1). The activity of this transcription factor can be altered by the exposure to a variety of compounds; among them is cadmium (Cd), a nephrotoxic heavy metal capable of crossing the placenta and reaching fetal kidneys. The goal of the study was to determine Cd effects on HIF-1 on embryonic kidneys. Pregnant Wistar rats were exposed to a mist of isotonic saline solution or CdCl2 (DDel = 1.48 mg Cd/kg/day), from gestational day (GD) 8 to 20. Embryonic kidneys were obtained on GD 21 for RNA and protein extraction. Results show that Cd exposure had no effect on HIF-1α and prolyl hydroxylase 2 protein levels, but it reduced HIF-1 DNA-binding ability, which was confirmed by a decrease in vascular endothelial growth factor (VEGF) mRNA levels. In contrast, the protein levels of VEGF were not changed, which suggests the activation of additional regulatory mechanisms of VEGF protein expression to ensure proper kidney development. In conclusion, Cd exposure decreases HIF-1-binding activity, posing a risk on renal fetal development. Full article
(This article belongs to the Special Issue Cadmium Sources and Toxicity)
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Open AccessArticle Cadmium Exposure Disrupts Periodontal Bone in Experimental Animals: Implications for Periodontal Disease in Humans
Received: 26 April 2018 / Revised: 11 June 2018 / Accepted: 11 June 2018 / Published: 13 June 2018
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Abstract
Cadmium (Cd) is an environmental contaminant that damages the kidney, the liver, and bones. Some epidemiological studies showed associations between Cd exposure and periodontal disease. The purpose of this study was to examine the relationship between Cd exposure and periodontal disease in experimental
[...] Read more.
Cadmium (Cd) is an environmental contaminant that damages the kidney, the liver, and bones. Some epidemiological studies showed associations between Cd exposure and periodontal disease. The purpose of this study was to examine the relationship between Cd exposure and periodontal disease in experimental animals. Male Sprague/Dawley rats were given daily subcutaneous injections of Cd (0.6 mg/kg/day) for up to 12 weeks. The animals were euthanized, and their mandibles and maxillae were evaluated for levels of periodontal bone by measuring the distance from the cementoenamel junction (CEJ) to the alveolar bone crest (ABC) of the molar roots. After 12 weeks of Cd exposure in animals, there was a significantly greater distance between the CEJ and ABC in the palatal aspect of the maxillary molars and the lingual aspect of the mandibular molars when compared with controls (p < 0.0001). This study shows that Cd has significant, time-dependent effects on periodontal bone in an animal model of Cd exposure. These findings support the possibility of Cd being a contributing factor to the development of periodontal disease in humans. Full article
(This article belongs to the Special Issue Cadmium Sources and Toxicity)
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Open AccessFeature PaperArticle Urinary Cadmium Threshold to Prevent Kidney Disease Development
Received: 9 March 2018 / Revised: 12 April 2018 / Accepted: 23 April 2018 / Published: 1 May 2018
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Abstract
The frequently observed association between kidney toxicity and long-term cadmium (Cd) exposure has long been dismissed and deemed not to be of clinical relevance. However, Cd exposure has now been associated with increased risk of developing chronic kidney disease (CKD). We investigated the
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The frequently observed association between kidney toxicity and long-term cadmium (Cd) exposure has long been dismissed and deemed not to be of clinical relevance. However, Cd exposure has now been associated with increased risk of developing chronic kidney disease (CKD). We investigated the link that may exist between kidney Cd toxicity markers and clinical kidney function measure such as estimated glomerular filtration rates (eGFR). We analyzed data from 193 men to 202 women, aged 16−87 years [mean age 48.8 years], who lived in a low- and high-Cd exposure areas in Thailand. The mean (range) urinary Cd level was 5.93 (0.05–57) μg/g creatinine. The mean (range) for estimated GFR was 86.9 (19.6−137.8) mL/min/1.73 m2. Kidney pathology reflected by urinary β2-microglobulin (β2-MG) levels ≥ 300 μg/g creatinine showed an association with 5.32-fold increase in prevalence odds of CKD (p = 0.001), while urinary Cd levels showed an association with a 2.98-fold greater odds of CKD prevalence (p = 0.037). In non-smoking women, Cd in the highest urinary Cd quartile was associated with 18.3 mL/min/1.73 m2 lower eGFR value, compared to the lowest quartile (p < 0.001). Evidence for Cd-induced kidney pathology could thus be linked to GFR reduction, and CKD development in Cd-exposed people. These findings may help prioritize efforts to reassess Cd exposure and its impact on population health, given the rising prevalence of CKD globally. Full article
(This article belongs to the Special Issue Cadmium Sources and Toxicity)
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Open AccessFeature PaperArticle Cancer Mortality in Residents of the Cadmium-Polluted Jinzu River Basin in Toyama, Japan
Received: 28 February 2018 / Revised: 2 April 2018 / Accepted: 4 April 2018 / Published: 6 April 2018
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Abstract
After 26 years, we followed up 7348 participants in a 1979–1984 health screening survey in the Jinzu River basin, the heaviest cadmium-polluted area in Japan. We assessed the associations of cadmium exposure levels and mortality from cancer and renal damage, indicated by records
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After 26 years, we followed up 7348 participants in a 1979–1984 health screening survey in the Jinzu River basin, the heaviest cadmium-polluted area in Japan. We assessed the associations of cadmium exposure levels and mortality from cancer and renal damage, indicated by records of proteinuria and glucosuria in the original survey. Mortality risks (hazard ratios) were analyzed using the Cox proportional hazards model, stratified by sex, after adjusting for age, smoking status, and hypertension, as indicated in the original survey records. In men, the adjusted hazard ratio for mortality from lung cancer was significantly lower in individuals residing in an area of historically high cadmium exposure and in subjects with a historical record of proteinuria, glucosuria, and glucoproteinuria. The risk of mortality from prostate cancer was borderline higher in cadmium-exposed men. In women, historical cadmium exposure was not associated with an increased risk of mortality from malignant neoplasms, but the adjusted hazard ratios for death from total malignant neoplasms or from renal and uterine cancers were significantly higher in exposed subjects with a historical record of proteinuria, glucosuria, and glucoproteinuria. These findings suggest that women residing in cadmium-polluted areas who exhibit markers of renal damage may be at risk of dying of cancer. Full article
(This article belongs to the Special Issue Cadmium Sources and Toxicity)
Open AccessFeature PaperArticle Mitochondrial Morphology and Function of the Pancreatic β-Cells INS-1 Model upon Chronic Exposure to Sub-Lethal Cadmium Doses
Received: 19 February 2018 / Revised: 12 March 2018 / Accepted: 20 March 2018 / Published: 22 March 2018
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Abstract
The impact of chronic cadmium exposure and slow accumulation on the occurrence and development of diabetes is controversial for human populations. Islets of Langerhans play a prominent role in the etiology of the disease, including by their ability to secrete insulin. Conversion of
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The impact of chronic cadmium exposure and slow accumulation on the occurrence and development of diabetes is controversial for human populations. Islets of Langerhans play a prominent role in the etiology of the disease, including by their ability to secrete insulin. Conversion of glucose increase into insulin secretion involves mitochondria. A rat model of pancreatic β-cells was exposed to largely sub-lethal levels of cadmium cations applied for the longest possible time. Cadmium entered cells at concentrations far below those inducing cell death and accumulated by factors reaching several hundred folds the basal level. The mitochondria reorganized in response to the challenge by favoring fission as measured by increased circularity at cadmium levels already ten-fold below the median lethal dose. However, the energy charge and respiratory flux devoted to adenosine triphosphate synthesis were only affected at the onset of cellular death. The present data indicate that mitochondria participate in the adaptation of β-cells to even a moderate cadmium burden without losing functionality, but their impairment in the long run may contribute to cellular dysfunction, when viability and β-cells mass are affected as observed in diabetes. Full article
(This article belongs to the Special Issue Cadmium Sources and Toxicity)
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Open AccessFeature PaperArticle Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex
Received: 28 February 2018 / Revised: 8 March 2018 / Accepted: 9 March 2018 / Published: 15 March 2018
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Abstract
Cadmium (Cd) is a nephrotoxic environmental pollutant that causes a generalized dysfunction of the proximal tubule characterized by polyuria and proteinuria. Even though the effects of Cd on the kidney have been well-characterized, the molecular mechanisms underlying these effects have not been fully
[...] Read more.
Cadmium (Cd) is a nephrotoxic environmental pollutant that causes a generalized dysfunction of the proximal tubule characterized by polyuria and proteinuria. Even though the effects of Cd on the kidney have been well-characterized, the molecular mechanisms underlying these effects have not been fully elucidated. MicroRNAs (miRNAs) are small non-coding RNAs that regulate cellular and physiologic function by modulating gene expression at the post-transcriptional level. The goal of the present study was to determine if Cd affects renal cortex miRNA expression in a well-established animal model of Cd-induced kidney injury. Male Sprague-Dawley rats were treated with subcutaneous injections of either isotonic saline or CdCl2 (0.6 mg/kg) 5 days a week for 12 weeks. The 12-week Cd-treatment protocol resulted in kidney injury as determined by the development of polyuria and proteinuria, and a significant increase in the urinary biomarkers Kim-1, β2 microglobulin and cystatin C. Total RNA was isolated from the renal cortex of the saline control and Cd treated animals, and differentially expressed miRNAs were identified using µParafloTM microRNA microarray analysis. The microarray results demonstrated that the expression of 44 miRNAs were significantly increased and 54 miRNAs were significantly decreased in the Cd treatment group versus the saline control (t-test, p ≤ 0.05, N = 6 per group). miR-21-5p, miR-34a-5p, miR-146b-5p, miR-149-3p, miR-224-5p, miR-451-5p, miR-1949, miR-3084a-3p, and miR-3084c-3p demonstrated more abundant expression and a significant two-fold or greater increased expression in the Cd-treatment group versus the saline control group. miR-193b-3p, miR-455-3p, and miR-342-3p demonstrated more abundant expression and a significant two-fold or greater decreased expression in the Cd-treatment group versus the saline control group. Real-time PCR validation demonstrated (1) a significant (t-test, p ≤ 0.05, N = 6 per group) increase in expression in the Cd-treated group for miR-21-5p (2.7-fold), miR-34a-5p (10.8-fold), miR-146b-5p (2-fold), miR-224-5p (10.2-fold), miR-3084a-3p (2.4-fold), and miR-3084c-3p (3.3-fold) and (2) a significant (t-test, p ≤ 0.05, N = 6 per group) 52% decrease in miR-455-3p expression in the Cd-treatment group. These findings demonstrate that Cd significantly alters the miRNA expression profile in the renal cortex and raises the possibility that dysregulated miRNA expression may play a role in the pathophysiology of Cd-induced kidney injury. In addition, these findings raise the possibility that Cd-dysregulated miRNAs might be used as urinary biomarkers of Cd exposure or Cd-induced kidney injury. Full article
(This article belongs to the Special Issue Cadmium Sources and Toxicity)
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Review

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Open AccessFeature PaperReview Dietary Cadmium Intake and Its Effects on Kidneys
Received: 28 February 2018 / Revised: 8 March 2018 / Accepted: 9 March 2018 / Published: 10 March 2018
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Abstract
Cadmium (Cd) is a food-chain contaminant that has high rates of soil-to-plant transference. This phenomenon makes dietary Cd intake unavoidable. Although long-term Cd intake impacts many organ systems, the kidney has long been considered to be a critical target of its toxicity. This
[...] Read more.
Cadmium (Cd) is a food-chain contaminant that has high rates of soil-to-plant transference. This phenomenon makes dietary Cd intake unavoidable. Although long-term Cd intake impacts many organ systems, the kidney has long been considered to be a critical target of its toxicity. This review addresses how measurements of Cd intake levels and its effects on kidneys have traditionally been made. These measurements underpin the derivation of our current toxicity threshold limit and tolerable intake levels for Cd. The metal transporters that mediate absorption of Cd in the gastrointestinal tract are summarized together with glomerular filtration of Cd and its sequestration by the kidneys. The contribution of age differences, gender, and smoking status to Cd accumulation in lungs, liver, and kidneys are highlighted. The basis for use of urinary Cd excretion to reflect body burden is discussed together with the use of urinary N-acetyl-β-d-glucosaminidase (NAG) and β2-microglobulin (β2-MG) levels to quantify its toxicity. The associations of Cd with the development of chronic kidney disease and hypertension, reduced weight gain, and zinc reabsorption are highlighted. In addition, the review addresses how urinary Cd threshold levels have been derived from human population data and their utility as a warning sign of impending kidney malfunction. Full article
(This article belongs to the Special Issue Cadmium Sources and Toxicity)
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Other

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Open AccessBrief Report Effects of Cadmium Exposure on Age of Menarche and Menopause
Received: 7 December 2017 / Revised: 26 December 2017 / Accepted: 26 December 2017 / Published: 27 December 2017
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Abstract
Cadmium exposure can cause several adverse health effects. Animal studies have also shown that cadmium exposure can affect menarche or menopause. However, data is limited in humans. We conducted a retrospective study to assess whether cadmium exposure was associated with different ages of
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Cadmium exposure can cause several adverse health effects. Animal studies have also shown that cadmium exposure can affect menarche or menopause. However, data is limited in humans. We conducted a retrospective study to assess whether cadmium exposure was associated with different ages of menarche and menopause in a Chinese population. A total of 429 women living in control (n = 137) and two cadmium-polluted areas (n = 292) were included in this study. A total of 223 and 206 subjects were included in the analysis for menarche and menopause, respectively. The median menarche age of population living in the heavily cadmium-polluted area was significantly younger than those in the control area (14.0 vs. 15.0, p < 0.01). Logistic regression showed that the odds ratio (OR) of early occurrence of menarche (<13 years) in the population living in the heavily polluted area and moderately polluted area was 3.7 (95% confidence interval (CI): 1.5–9.7) and 1.3 (95% CI: 0.7–2.6) compared with control, respectively. No significant difference was observed in the age of menopause in the population of these three areas. In conclusion, our data indicated that cadmium exposure may cause early menarche. Full article
(This article belongs to the Special Issue Cadmium Sources and Toxicity)
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