Metal-induced neurotoxicity in a RAGE-expressing C. elegans model.

Environmental and occupational metal exposure poses serious global concerns. Metal exposure have severally been associated with neurotoxicity and brain damage. Furthermore, receptor for advanced glycation end products (RAGE) is also implicated in neurological disorders, particularly those with altered glucose metabolism. Here, we examine potential compounding effect of metal exposure and RAGE expression on dopamine (DA) and serotonin (SER) neurons in C. elegans. In addition, we evaluate the effect of RAGE expression on DA and SER neurons in hyperglycemic conditions. Newly generated RAGE-expressing C. elegans tagged with green fluorescent proteins (GFP) in DAergic and SERergic neurons were treated with cadmium (Cd) or manganese (Mn). Additionally, the RAGE-expressing worms were also exposed to high glucose conditions. Results showed metals induced neurodegeneration both in the presence and absence of RAGE expression, but the manner of degeneration differed between Cd and Mn treated nematodes. Furthermore, RAGE-expressing worms showed significant neurodegeneration in both DAergic and SERergic neurons. Our results indicate co-occurrence of metal exposure and RAGE expression can induce neurodegeneration. Additionally, we show that RAGE expression can exacerbate hyperglycemic induced neurodegeneration.

Heavy Metal Toxicity in Chronic Renal Failure and Cardiovascular Disease: Possible Role for Chelation Therapy.

Exposure to heavy metals is common. This exposure is related to environmental contamination of air, water and soil, occupational exposure, accumulation in food, tobacco, and other factors. Cadmium and lead are notable for their widespread contamination, long-lasting effects in the body, and renal as well as cardiovascular toxicity. Acute toxicity due to high-level exposure, as well as chronic low-level exposure are now well-established pathogenic entities. Both chronic renal failure and ischemic heart disease patients have been treated separately in recent studies with ethylenediaminetetraacetic acid (EDTA) chelation therapy. In patients with chronic kidney disease (serum creatinine: 1.5-4.0 mg/dL) and increased body lead burden, weekly low-dose chelation with calcium EDTA slowed the rate of decline in renal function in patients with diabetes and in non-diabetic patients. In patients with a history of myocardial infarction, the Trial to Assess Chelation Therapy study showed that EDTA chelation decreased the likelihood of cardiovascular events, particularly in patients with diabetes. However, heavy metal levels were not measured in this study. It is clear that more research is needed in this area. There is also a need to more frequently consider and test for the possibility of cadmium and lead toxicity in patients with increased risk, such as those with hypertension, diabetes mellitus, and chronic renal disease.

High dose of standardised extract of Costus afer leaves potentiates cadmium reproductive toxicity in Wistar rats.

Protective effects of standardised extract of Costus afer leaves (CAME), an extract with good antioxidants on cadmium-induced reproductive toxicity in male rats, were investigated in this study. Forty-two adult male Wistar rats were randomly divided into six groups and were treated every day regularly for 4 weeks. G1 (control) rats received 1 ml of vehicle treatment. G2 rats were intoxicated with 2.5 mg kg-1  day-1 s.c cadmium chloride for 1 week. G3 and G4 rats were intoxicated with cadmium as in G2 rats and were treated orally with 100 and 200 mg/kg bwt/day of CAME, respectively, for 4 weeks. Group G5 and G6 rats were orally treated with 100 and 200 mg kg-1  day-1 bwt of CAME, respectively, for 4 weeks. Significant changes (p < 0.05) in andrological parameters (sperm count, sperm morphology, serum testosterone and nitric oxide concentration) and testicular antioxidant parameters (reduced glutathione, lipid peroxidation and activities of catalase, glutathione S-transferase and glutathione peroxidase) caused by Cd toxicity were improved in cadmium-intoxicated rats treated with 100 mg/kg body weight of CAME. Administration of 200 mg/kg body weight of CAME to cadmium-intoxicated rats potentiated reproductive toxic effects of cadmium. In conclusion, lower dose of CAME is preferred over high dose in treatment of cadmium-induced reproductive toxicity in rats.

Zn Supplement-Antagonized Cadmium-Induced Cytotoxicity in Macrophages In Vitro: Involvement of Cadmium Bioaccumulation and Metallothioneins Regulation.

Cadmium (Cd) is a toxic metal leading to multiple forms of organ damage. Zinc (Zn) was reported as a potential antagonist against Cd toxicity. The present study investigates the antagonistic effect of Zn (20 µM) on Cd (20 or 50 µM) cytotoxicity in macrophages in vitro. The results shows that Cd exposure caused dose-dependent morphologic and ultrastructural alterations in RAW 264.7 macrophages. Zn supplement significantly inhibited Cd cytotoxicity in RAW 264.7 or HD-11 macrophages by mitigating cell apoptosis, excessive ROS output, and mitochondrial membrane depolarization. Notably, Zn supplement for 12 h remarkably prevented intracellular Cd2+ accumulation in 20 µM (95.99 ± 9.93 vs 29.64 ± 5.08 ng/106 cells; P = 0.0008) or 50 µM Cd (179.78 ± 28.66 vs 141.62 ± 22.15 ng/106 cells; P = 0.003) exposed RAW 264.7 cells. Further investigation found that Cd promoted metallothioneins (MTs) and metal regulatory transcription factor 1 (MTF-1) expression in RAW 264.7 macrophages. Twenty µM Zn supplement dramatically enhanced MTs and MTF-1 levels in Cd-exposed RAW 264.7 macrophages. Intracellular Zn2+ chelation or MTF-1 gene silencing inhibited MTs synthesis in Cd-exposed RAW 264.7 macrophages, which was accompanied by the declined expression of MTF-1, indicating that regulation of Zn on MTs was partially achieved by MTF-1 mobilization. In conclusion, this study demonstrates the antagonism of Zn against Cd cytotoxicity in macrophages and reveals its antagonistic mechanism by preventing Cd2+ bioaccumulation and promoting MTs expression.

The potential modulatory role of herbal additives against Cd toxicity in human, animal, and poultry: a review.

Cadmium (Cd) is a heavy and toxic metal and easily absorbed by animals and plants; subsequently, it is an environmental risk factor with several toxic effects in humans and animals. The main pathway of human or animal exposure to Cd is through its ingestion by water or food and by particles or fume inhalation during industrial processes. With continuous exposure to small levels of cadmium, it is being deposited in different tissues day after day, causing toxic effects on the liver, kidney, and testes. Long-term exposure to this toxic metal resulted in inflammatory infiltration, necrosis of hepatocytes, degenerative changes in testis tissues, reduction in spermatocytes, degeneration in renal tubules, and hypertrophy of renal epithelium. Therefore, we need an effective treatment to overcome cadmium poisoning. Thus, in the current review, we try to provide compiled reports and summarize information about the toxicological effects of Cd in human, animals, and poultry. This review also provides updated information about the protective actions of herbs and herbal extracts and their role as an effective strategy in reducing or preventing serious health problems and tissue damage in response to Cd toxicity.

Estimation of weekly intake of cadmium and lead by consumption of commercial ready-to-feed infant foods.

The purpose of this survey was to estimate the safety of ready-to-eat infant foods in terms of Pb and Cd content. The studied samples were ready-to-eat infant products: dinners (n = 74), soups (n = 27) and desserts (n = 82) containing components of animal origin: meat and/or milk. Cd and Pb content was determined using a GF-AAS method. The analysed products contained 1.82-3.54 µg Pb and 1.32-1.50 µg Cd per kg. The content of Pb per kg of the product can be represented as dinners > soups > desserts, whereas the content of Cd was dinners > desserts > soups. The analysed ready-to-eat products could be regarded as safe, because they supply 12-month-old infants with Pb in an amount accounting for nearly 22% BMDL01 and Cd accounting for ca. 8.6% of the total weekly intake.

Identification of ARNT-regulated BIRC3 as the target factor in cadmium renal toxicity.

Cadmium (Cd) is an environmental contaminant that exhibits renal toxicity. The target transcription factors involved in Cd renal toxicity are still unknown. In this study, we demonstrated that Cd decreased the activity of the ARNT transcription factor, and knockdown of ARNT significantly decreased the viability of human proximal tubular HK-2 cells. Microarray analysis in ARNT knockdown cells revealed a decrease in the expression of a number of genes, including a known apoptosis inhibitor, BIRC3, whose gene and protein expression level was also decreased by Cd treatment. Although the BIRC family consists of 8 members, Cd suppressed only BIRC3 gene expression. BIRC3 is known to suppress apoptosis through the inhibition effect on caspase-3. Knockdown of BIRC3 by siRNA as well as Cd treatment increased the level of active caspase-3. Moreover, knockdown of BIRC3 not only triggered cell toxicity and apoptosis but also strengthened Cd toxicity in HK-2 cells. Meanwhile, the activation of caspase-3 by suppression of BIRC3 gene expression was mostly specific to Cd and to proximal tubular cells. These results suggest that Cd induces apoptosis through the inhibition of ARNT-regulated BIRC3 in human proximal tubular cells.

Itai-itai disease: Lessons from the investigations of environmental epidemiology conducted in the 1970's, with special reference to the studies of the Toyama Institute of Health.

The outbreak of itai-itai disease, which is the most severe stage of chronic cadmium poisoning, has occurred in the cadmium-polluted Jinzu River basin in Toyama. In this area, the river was contaminated by slags from a mine upstream; consequently, the soil in rice paddies became polluted with heavy metals including cadmium through irrigation water streams from around 1910 to the 1960s. The inhabitants of the Jinzu River basin used the river water for drinking and cooking until around 1960. In this paper, we review the geographical features of the Jinzu River basin and the endemic area of itai-itai disease, and reevaluated the studies conducted in 1970's by the Toyama Institute of Health, because these studies have revealed a clear relationship between renal dysfunction or occurrence of itai-itai disease and exposure to cadmium through irrigation water streams.

[Metals and their compounds as contaminants in food : Arsenic, cadmium, lead and aluminum]. / Metalle und ihre Verbindungen als Kontaminanten in Lebensmitteln : Arsen, Cadmium, Blei und Aluminium.

Metals and their compounds are ubiquitously distributed in the environment, thus reaching plant and animal derived food. While actual exposure levels in Europe do not give rise to concern for acute toxicity, chronic toxicity of some metals and metalloids cannot be completely ruled out. Thus, in the case of inorganic arsenic, an elevated risk of carcinogenicity in different organs cannot be excluded even under actual dietary exposure conditions. In the case of cadmium, nephrotoxicity may be a particular problem for certain subgroups, such as children. Regarding lead, exposure levels have dropped considerably during the last two decades; nevertheless, developmental neurotoxicity may still be a problem during prenatal development and early childhood. Also in the case of aluminum current dietary exposure levels are close to the tolerable weekly intake (TWI) value derived by the European Food Safety Authority (EFSA). Taken together, for all four examples, further reductions in exposure levels are required.

Threshold limit values of the cadmium concentration in rice in the development of itai-itai disease using benchmark dose analysis.

The aim of this study was to estimate the benchmark dose (BMD) as the threshold limit level of the cadmium (Cd) concentration in rice for itai-itai disease and/or suspected disease; it was based on the data that previously evaluated the association for such diseases with the Cd concentration in rice by using a logistic regression model. From 1971 to 1976, a total of 2446 rice samples were analyzed across the 88 hamlets in the Jinzu river basin. The mean Cd concentration in rice in each hamlet was used as the index of external Cd exposure of the entire population of the hamlet. We employed the incidence of itai-itai disease and/or suspected disease obtained from the available 55 hamlets. As the threshold, the lower limit of the BMD (BMDL) of the Cd concentration in rice for itai-itai disease and/or suspected disease was estimated using a logistic model, setting the benchmark response at 1% or 2%. The estimated BMDLs of the Cd concentration in rice for itai-itai disease and/or suspected disease were 0.62-0.76 and 0.27-0.56 mg kg-1 in men and women, respectively. The lowest BMDL was 0.27 mg kg-1 in women. In the present study, the threshold limit level of the Cd concentration in rice for itai-itai disease, which is the most severe form of chronic Cd poisoning, was estimated for the first time. This result provides important information about the worldwide standard for the Cd concentration in rice. Copyright © 2017 John Wiley & Sons, Ltd.

Risk of ingesting As, Cd, and Pb in animal products in north Rio de Janeiro state, Brazil.

This study evaluated the levels of As, Cd, and Pb in muscle and liver the cattle and chicken. The risk was estimated for the adult population of a midsized city in southeast Brazil, concerning the tolerable ingestion and cancer risk. Samples of muscle and liver (cattle and chicken) were collected (n = 250). Samples of mineral supplements for cattle (n = 4) and chicken feed samples (n = 4) were evaluated as one of many potential source of contamination. Muscle, liver, mineral supplement, and feed samples were dissolved in acid medium and analyzed by ICP-OES. Daily muscle and liver intake was estimated using a questionnaire (N = 427). Daily intake of trace elements by the population based on the consumption of cattle muscle, cattle liver, chicken muscle, and chicken liver was low, corresponding to 2.76%, 0.33%, 2.12%, and 0.22% of the Tolerable Intake defined by the WHO for As; 0.54%, 0.29% 0.55%, 0.01%, for Cd; and 0.80%, 0.07%, 0.62%, 0.02%, for Pb. The mean of total ingestion of As, Cd and Pb was 5.43%, 1.18% and 1.51%, respectively of Tolerable Intake defined by WHO. Cancer risk was lower than 5 × 10-5 year-1. The results indicate that the muscle and liver consumption is a source of As, Cd, and Pb. Consumers that ingest cattle and chicken muscle need attention in terms the risk of cancer related to intake of As and Cd. Feed and mineral supplementation remain as one of many sources of exposure of As, Cd, and Pb.

Benchmark dose of cadmium concentration in rice for renal effects in a cadmium-polluted area in Japan.

The aim of this study was to estimate the reference level of cadmium in rice as the benchmark doses (BMD) and their 95% lower confidence limits (BMDL) for various renal effects by applying an updated hybrid approach. The participants were 1120 men and 1274 women aged 50 years or older who lived in the environmentally exposed Kakehashi river basin for at least 30 years. As indicators of renal dysfunction, glucose, protein, aminonitrogen, metallothionein and ß(2) -microgrobulin in urine were measured. Cadmium concentration was determined for rice samples stored in warehouses of the farmers in all of the polluted hamlets. The BMD and BMDL that corresponded to an additional risk of 5% were calculated with background risk at a zero exposure set at 5%. The obtained BMDLs were 0.39 (aminonitrogen), 0.26 (metallothionein), 0.25 (ß(2) -microgrobulin) mg kg(-1) in men and 0.44 (glucose), 0.32 (protein), 0.33 (aminonitrogen), 0.28 (metallothionein) and 0.24 (ß(2) -microgrobulin) mg kg(-1) in women. The lowest BMDL was 0.25 and 0.24 mg kg(-1) (ß(2) -microgrobulin) in men and women respectively. These values were lower than the maximum level (0.4 mg kg(-1)) determined by the Codex Alimentarius Commission, indicating that these BMDLs may contribute to further discussion on the health risk assessment of cadmium exposure.

Histopathological analysis for osteomalacia and tubulopathy in itai-itai disease.

BACKGROUND & AIMS: Cadmium (Cd) is a widespread environmental contaminant that causes both renal tubulopathy and osteomalacia. Osteomalacia is thought to be a result of renal tubulopathy, but there are few studies about the histopathological relationship between the two pathoses. Therefore, in the present study, we examined specimens from cases of itai-itai disease (IID), the most severe form of chronic cadmium poisoning, to evaluate the relationship between them. METHODS: We analyzed kidney and bone specimens of 61 IID cases and the data regarding Cd concentration in kidney and bone. Tubulopathy was graded on the basis of a three-step scale (mild, moderate, and severe) using the following three items: the degree of proximal tubular defluxion, thickness of renal cortex, and weight of the kidney. Osteomalacia was evaluated using the relative osteoid volume (ROV). RESULTS: There were 15 cases of mild, 19 cases of moderate, and 27 cases of severe tubulopathy. The average ROV was 24.9 ± 2.0%. ROV tended to increase as tubulopathy advanced in severity, and ROV was significantly higher in cases with severe tubulopathy than those with mild or moderate tubulopathy. ROV had a negative correlation with Cd concentration in the kidney but no correlation with that in the bone. CONCLUSIONS: Our results suggest that the development of osteomalacia was related to the development of tubulopathy.

Chronic exposure to cadmium disrupts the adrenal gland activity of the newt Triturus carnifex (Amphibia, Urodela).

We intended to verify the safety of the freshwater values established for cadmium by the European Community and the Italian Ministry of Health in drinking water (5 µg/L) and sewage waters (20 µg/L). Therefore, we chronically exposed the newt Triturus carnifex to 5 µg/L and 20 µg/L doses of cadmium, respectively, during 3 and 9 months and verified the effects on the adrenal gland. We evaluated the serum concentrations of adrenocorticotropic hormone (ACTH), corticosterone, aldosterone, norepinephrine, and epinephrine. During the 3-month exposure, both doses of cadmium decreased ACTH and corticosterone serum levels and increased aldosterone and epinephrine serum levels. During the 9-month exposure, the 5 µg/L dose decreased ACTH and increased aldosterone and epinephrine serum levels; the 20 µg/L dose decreased norepinephrine and epinephrine serum levels, without affecting the other hormones. It was concluded that (1) chronic exposure to the safety values established for cadmium disrupted the adrenal gland activity and (2) the effects of cadmium were related both to the length of exposure and the dose administered. Moreover, our results suggest probable risks to human health, due to the use of water contaminated by cadmium.

Cadmium toxicity and treatment.

Cadmium is a heavy metal of considerable toxicity with destructive impact on most organ systems. It is widely distributed in humans, the chief sources of contamination being cigarette smoke, welding, and contaminated food and beverages. Toxic impacts are discussed and appear to be proportional to body burden of cadmium. Detoxification of cadmium with EDTA and other chelators is possible and has been shown to be therapeutically beneficial in humans and animals when done using established protocols.

Co-exposure to lead increases the renal response to low levels of cadmium in metallurgy workers.

PURPOSE: Research on the effect of co-exposure to Cd and Pb on the kidney is scarce. The objective of the present study was to assess the effect of co-exposure to these metals on biomarkers of early renal effect. METHODS: Cd in blood (Cd-B), Cd in urine (Cd-U), Pb in blood (Pb-B) and urinary renal biomarkers, i.e., microalbumin (µ-Alb), beta-2-microglobulin (ß2-MG), retinol binding protein (RBP), N-acetyl-ß-d-glucosaminidase (NAG), intestinal alkaline phosphatase (IAP) were measured in 122 metallurgic refinery workers examined in a cross-sectional survey. RESULTS AND CONCLUSIONS: The median Cd-B, Cd-U, Pb-B were: 0.8 µg/l (IQR = 0.5, 1.2), 0.5 µg/g creatinine (IQR = 0.3, 0.8) and 158.5 µg/l (IQR = 111.0, 219.3), respectively. The impact of Cd-B on the urinary excretion of NAG and IAP was only evident among workers with Pb-B concentrations ≥ 75th percentile. The association between Cd-U and the renal markers NAG and RBP was also evidenced when Pb-B ≥ 75th percentile. No statistically significant interaction terms were observed for the associations between Cd-B or Cd-U and the other renal markers under study (i.e., µ-Alb and ß2-MG). Our findings indicate that Pb increases the impact of Cd exposure on early renal biomarkers.

Tissue distribution of metals in white-fronted geese and spot-billed ducks from Korea.

This study presents concentrations of Fe, Zn, Mn, Cu, Pb and Cd in livers, kidneys, muscles and bones of white-fronted geese Anser albifrons (geese) and spot-billed ducks Anas poecilorhyncha (ducks). Iron in livers, kidneys and muscles, Zn in muscles, Mn and Cd in every tissue, Cu in livers, muscles and bones and Pb in bones differed between species, and there were significant differences among tissues in both species. Essential elements such as Fe, Zn, Mn and Cu concentrations were within the background levels. Lead concentrations in livers of 7 of 14 geese and 7 of 19 ducks and in bones of 4 of 19 ducks exceeded background concentrations for waterfowl (5 µg/g dw for the liver, 10 µg/g dw for the bone). Almost all samples of both species had the background Cd concentrations in the liver (33 of 33 geese and ducks) and kidney (14 geese and 18 ducks). Tissue concentrations of Cd were greater in geese than ducks. In contrast, tissue concentrations of Pb in bones were greater in ducks than in geese. These different trends for Cd and Pb reflect a short and/or long term difference in exposure and degree of accumulation of these metals.

[Itai-itai disease: cadmium-induced renal tubular osteomalacia].

Cadmium (Cd) is one of the most toxic elements to which humans could be exposed at work or in the environment. The outbreak of itai-itai disease, which is the most severe stage of chronic Cd poisoning, occurred in the Cd-polluted Jinzu River basin in Toyama. In this area, the river was contaminated by slag from a mine upstream; as a consequence, the soil in rice paddies was polluted with heavy metals including Cd through irrigation water from around 1910 to the 1960s. The government of Toyama prefecture carried out an extensive survey on Cd concentration in rice and soil of the paddy fields and declared that the upper layer of a total of 1500 ha of paddy fields should be replaced by nonpolluted soil. Then, an intervention program of soil replacement in the polluted paddy fields was continually carried out from 1980 to 2011. As a result, Cd concentration in rice markedly decreased. The kidney is the organ critically affected after long-term exposure to Cd. Proximal tubular dysfunction (RTD) has been found among the inhabitants of the Jinzu River basin. The very recent report by the Environmental Agency in Japan in 2009 has disclosed that b2-microglobulinuria with RTD is still found at a high prevalence among the inhabitants of the Jinzu River basin of both sexes. Twenty patients with itai-itai disease (1 male and 19 females), who attended our hospital and received medical examination during 2000 to 2008, had applied for recognition as itai-itai disease patients to the government of Toyama prefecture. In this paper, the recent epidemiological and clinical features of itai-itai disease are discussed on the basis of a review of the cases of these 19 female patients.