Copper, one of the essential nutrients for the human body, acts as an electron relay in multiple pathways due to its redox properties. Both deficiencies and excesses of copper lead to cellular fragility. Therefore, it can manifest pro- and anti-cancer properties in tumors. Therefore, it is crucial to clarify the copper activity within the cell. We have thoughtfully summarized the metabolic activities of copper from a macro and micro perspective. Cuproptosis, as well as other forms of cell death, is directly or indirectly interfered with by Cu2+, causing cancer cell death. Meanwhile, we did pan-cancer analysis of cuproptosis-related genes to further clarify the roles of these genes. In addition, copper has been found to be involved in multiple pathways within the metastasis of cancer cells. Given the complexity of copper's role, we are compelled to ask: is copper a friend or a foe? Up to now, copper has been used in various clinical applications, including protocols for measurement of copper concentration and bioimaging of radioactive 64Cu. But therapeutically it is still a continuation of the old medicine, and new possibilities need to be explored, such as the use of nanomaterials. Some studies have also shown that copper has considerable interventional power in metabolic cancers, which provides the great applications potential of copper therapy in specific cancer types. This paper reviews the dual roles played by cuproptosis in cancer from the new perspectives of oxidative stress, cell death, and tumor metastasis, and points out the value of its application in specific cancer types, summarizes the value of its testing and imaging from the perspective of clinical application as well as the current feasible options for the new use of the old drugs, and emphasizes the prospects for the application of nano-copper.

Copper is a transition metal and an essential element for the organism, as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs, including the central nervous system. Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B, Menkes disease and Wilson's disease, respectively, and also in multifactorial neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology, reports about unbalances in copper levels and/or distribution under disease, describes relevant animal models for human disorders where copper metabolism genes are dysregulated, and discusses relevant therapeutic approaches modulating copper availability. Overall, alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.

Copper plays a vital role in human physiological functions. However, limited epidemiologic evidence exists for an association between dietary copper intake and chronic obstructive pulmonary disease (COPD).

This study aimed to assess the association between dietary copper intake and COPD in American adults.

This cross-sectional study used data from the US National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018.

Following the inclusion criteria, data from a total of 39 644 adults aged 20 and older were included in this study, out of which 3159 individuals had been diagnosed with COPD by a health care provider.

Dietary data were obtained through 24-hour dietary recall, and COPD diagnosis information was derived from a standardized medical condition questionnaire.

Multivariable logistic regression analysis was conducted to explore the association between dietary copper intake and COPD. To assess the dose-response relationship, a 3-piecewise restricted cubic spline analysis was employed. Potential thresholds were identified with a 2-piecewise logistic regression model. Subgroup analysis was performed to assess heterogeneity and explore potential interactions.

Compared with individuals in the lowest tertile of dietary copper intake (T1, <0.89 mg/day), those in the highest tertile (T3, >1.35 mg/day) had an adjusted odds ratio (OR) of 0.79 for COPD (95% confidence interval [CI], 0.68-0.92, P = .002). The relationship between dietary copper intake and COPD followed a nonlinear L-shaped curve (P < .001). Threshold analysis found a statistically significant inverse association between dietary copper intake and the odds of COPD for intakes < 1.5 mg/day but no significant association for intakes ≥ 1.5 mg/day. Subgroup analysis indicated an interaction effect with age.

An L-shaped inverse association was observed between dietary copper intake and COPD in US adults, at a threshold of approximately 1.5 mg/day, with an observed age interaction.

The usage of copper (II) oxide nanoparticles (CuO NPs) has significantly expanded across industries and biomedical fields. However, the potential toxic effects on non-target organisms and humans lack comprehensive understanding due to limited research on molecular mechanisms. With this study, by combining the 96 h in vivo exposure of crucian carp fish, Carassius carassius, to sub-lethal CuO NPs doses (0.5 and 1 mg/dL) with image-based quantification, and docking and molecular dynamics approaches, we aimed to understand the mechanism of CuO NPs-induced cyto-genotoxicity in the fish erythrocytes. The results revealed that both doses of copper NPs used were toxic to erythrocytes causing oxidative stress response and serious red blood cell morphological abnormalities, and genotoxicity. Docking and 10-ns molecular dynamics confirmed favorable interactions (ΔG = -2.07 kcal mol-1) and structural stability of Band3-CuO NP complex, mainly through formation of H-bonds, implying the potential of CuO NPs to induce mitotic nuclear abnormalities in C. carassius erythrocytes via Band3 inhibition. Moreover, conventional and multiple ligand simultaneous docking with DNA revealed that single, double and triple CuO NPs bind preferentially to AT-rich regions consistently in the minor grooves of DNA. Of note, the DNA-binding strength subtantially increased (ΔG = -2.13 kcal mol-1, ΔG = -4.08 kcal mol-1, and ΔG = -6.03 kcal mol-1, respectively) with an increasing number of docked CuO NPs, suggesting that direct structural perturbation on DNA could also count for the molecular basis of in-vivo induced DNA damage in C. carassius erythrocytes. This study introduces the novel term "erythrotope" to describe comprehensive red blood cell morphological abnormalities. It proves to be a reliable and cost-effective biomarker for evaluating allostatic erythrocyte load in response to metallic nanoparticle exposure, serving as a distinctive fingerprint to assess fish erythrocyte health and physiological fitness.

Copper functions as a structural component in many proteins involved in energy and iron metabolism, production of neurotransmitters, formation of connective tissue and endogenous antioxidant defence. Several biochemical indices have been suggested and used to assess copper status, but none of these has been found suitable for the detection of marginal copper deficiency or marginal copper toxicity. Copper imbalances have been linked to the pathogenesis of several chronic inflammatory diseases. During the last decade, a number of meta-analyses and systematic reviews have been published shedding light on the association between copper imbalances and some of these pathologies. Most of these meta-analyses are based on case-control studies. All show that blood copper concentrations are higher in cases than in controls, but there is inconclusive evidence to change the recommendations.

Endocrine disrupting chemicals (EDCs) have been extensively explored due to their harmful effects on individual health and the environment by interfering with hormone activity and disrupting the endocrine system. However, their relationship with essential trace elements remains uncertain. This research aimed to investigate the possible correlation between essential trace elements and toxic metals, including cadmium (Cd), and lead (Pb) in children aged 1-5 years with various infectious diseases, including gastrointestinal disorders, typhoid fever, and pneumonia. The study was conducted on biological testing and specimen (scalp hair and whole blood) of diseased and non-diseased children of the same residential area and referent/control age-matched children from developed cities consuming domestically treated water. The media of biological samples were oxidized by an acid mixture before being analyzed by atomic absorption spectrophotometry. The accuracy and validity of the methodology were verified through accredited reference material from scalp hair and whole blood sample. The study results revealed that diseased children had lower mean values of essential trace elements (iron, copper, and zinc) in both scalp hair and blood, except for copper, which was found to be higher in blood samples of diseased children. This implies that the deficiency of essential residue and trace elements in children from rural areas who consume groundwater is linked to various infectious diseases. The study highlights the need for more human biomonitoring of EDCs to better comprehend their non-classical toxic properties and their concealed costs on human health. The findings suggest that exposure to EDCs could be associated with unfavorable health outcomes and emphasizes the need for future regulatory policies to minimize exposure and safeguard the health of current and forthcoming generations of children. Furthermore, the study highlights the implication of essential trace elements in maintaining good health and their potential correlation with toxic metals in the environment.

Copper is an essential micronutrient and also a regulated product used in organic and in conventional farming pest management. Both deficiency and excessive exposure to copper can have adverse health effects. In this Scientific Opinion, the EFSA 2021 harmonised approach for establishing health-based guidance values (HBGVs) for substances that are regulated products and also nutrients was used to resolve the divergent existing HBGVs for copper. The tightly regulated homeostasis prevents toxicity manifestation in the short term, but the development of chronic copper toxicity is dependent on copper homeostasis and its tissue retention. Evidence from Wilson disease suggests that hepatic retention is indicative of potential future and possibly sudden onset of copper toxicity under conditions of continuous intake. Hence, emphasis was placed on copper retention as an early marker of potential adverse effects. The relationships between (a) chronic copper exposure and its retention in the body, particularly the liver, and (b) hepatic copper concentrations and evidence of toxicity were examined. The Scientific Committee (SC) concludes that no retention of copper is expected to occur with intake of 5 mg/day and established an Acceptable Daily Intake (ADI) of 0.07 mg/kg bw. A refined dietary exposure assessment was performed, assessing contribution from dietary and non-dietary sources. Background copper levels are a significant source of copper. The contribution of copper from its use as plant protection product (PPP), food and feed additives or fertilisers is negligible. The use of copper in fertilisers or PPPs contributes to copper accumulation in soil. Infant formula and follow-on formula are important contributors to dietary exposure of copper in infants and toddlers. Contribution from non-oral sources is negligible. Dietary exposure to total copper does not exceed the HBGV in adolescents, adults, elderly and the very elderly. Neither hepatic copper retention nor adverse effects are expected to occur from the estimated copper exposure in children due to higher nutrient requirements related to growth.

High plasma copper (Cu) and low zinc (Zn) levels have been associated with depression. However, most studies used low sample sizes and a cross-sectional design, and perinatal data are scarce. We investigated the possible association between pregnancy-specific psychological distress and the plasma CuZn ratio using a prospective design.

Pregnancy-specific distress symptoms were assessed at each trimester by means of the Tilburg Pregnancy Distress Scale, negative affect subscale, in 2036 pregnant women. Cu and Zn were assessed at 12 wk of gestation in plasma samples by inductively coupled plasma mass spectrometry. Growth mixture modeling determined trajectories of women's pregnancy-specific negative affect (P-NA) symptoms, which were entered in a multiple logistic regression analysis as dependent variable and the CuZn ratio as independent variable.

Two P-NA symptom classes were found: 1) persistently low (n = 1820) and 2) persistently high (n = 216). A higher CuZn ratio was independently associated with persistently high P-NA symptom scores (odds ratio = 1.52; 95% confidence interval, 1.13-2.04) after adjustment for confounders. A sensitivity analysis was performed excluding all women with high P-NA scores at 12 wk (>1 SD above the mean P-NA score). In the 1719 remaining women, a higher CuZn ratio significantly predicted the development of increasing P-NA symptom scores after adjustment for confounders (odds ratio = 1.40; 95% confidence interval, 1.04-1.95).

A higher CuZn plasma ratio is an independent determinant of developing pregnancy-specific distress symptoms throughout pregnancy, suggesting that micronutrients could be used as novel biomarkers for psychological distress research of perinatal mood disorders.

Copper is associated with mild cognitive impairment (MCI). However, there is a lack of relevant population studies with large sample sizes.

This study used baseline data from a cohort study to determine the distribution characteristics of MCI in the elderly and to estimate the association between whole blood copper concentrations and MCI.

MCI status was screened by the Mini-Mental State Examination (MMSE) scale and Activities of Daily Living (ADL) scale. The concentration of copper in whole blood was determined by Inductively Coupled Plasma Mass Spectrometer (ICP-MS).

A total of 1057 subjects with an average age of 71.82 ± 6.45 years were included in this study. There were 215 patients with MCI, and the prevalence of MCI was 20.34%. After adjusting for general demographic variables, logistic regression analysis showed that the risk of MCI in the elderly with high copper level was 1.354 times higher than that in the elderly with low copper level (OR 1.354, 95% CI 1.047-1.983, P = 0.034).

In this study, it was found that the prevalence of MCI was different in gender, age, education level and other aspects, and a higher copper level in the elderly was significantly related to the occurrence of MCI. The association was stronger in older adults and men.

Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), are key regulators of differentiation and development. In the cell, transcription factors regulate the production of miRNA in response to different external stimuli. Copper (Cu) is a heavy metal and an essential micronutrient with widespread industrial applications. It is involved in a number of vital biological processes encompassing respiration, blood cell line maturation, and immune responses. In recent years, the link between deregulation of miRNAs' functionality and the development of various pathologies as well as cardiovascular diseases (CVDs) has been extensively studied. Alzheimer's disease (AD) is the most common cause of dementia in the elderly with a complex disease etiology, and its link with Cu abnormalities is being increasingly studied. A direct interaction between COMMD1, a regulator of the Cu pathway, and hypoxia-inducible factor (HIF) HIF-1a does exist in ischemic injury, but little information has been collected on the role of Cu in hypoxia associated with AD thus far. The current review deals with this matter in an attempt to structurally discuss the link between miRNA expression and Cu dysregulation in AD and CVDs.

The establishment of legal limits for soil contamination with trace elements is a global issue that has not yet been resolved. However, the resolution of any global problem begins at the national level. In this vein, we present the case of Chile, the world's leading copper producer, where soil contamination by trace elements in mining areas has been severe. We evaluated the magnitude of the ecological and human health risks from exposure to arsenic (As), copper (Cu), zinc (Zn), and lead (Pb) in soils of the La Ligua and Petorca basins, two important mining areas in Chile. Contrary to what might be expected in soils affected by Cu mining activities, As was identified as the most hazardous element in the studied soils, both in terms of ecological and human health risks. On the other hand, Chile does not currently have specific legislation establishing legal limits on soil contamination with trace elements. Since Chile is geochemically similar to New Zealand, Mexico, and Italy, we used the limits of these three countries as benchmarks. We determined the background concentrations of As, Cu, Zn, and Pb in the soils of the two river basins under study and found that they tend to exceed the limits established by foreign laws. We also found that the differences in background elemental concentrations in the studied soils were primarily due to the varied lithology of soil-forming rocks. This means that absolute "one-limit-fits-all" values of element concentrations may not be adequate to regulate the level of soil contamination in areas affected by mining. As a fundamental first step, it is necessary to establish background soil concentrations of trace elements in each river basin in Chile. It is clear that Chile urgently needs to move from rubber-stamping foreign laws to the development of national legislation on soil metal contamination.

Micronutrient malnutrition is a global concern that affects more than two billion people worldwide. Pea (Pisum sativum) is a nutritious pulse crop with potential to assist in tackling hidden hunger. Here we report seed ionomic data of 96 diverse pea accessions collected via inductively coupled plasma mass spectrometry (ICP-MS). We found a 100 g serving of peas provides the following average percent daily value for U.S. recommendations: 8% Ca, 39% Mg, 73% Cu, 37% Fe, 63% Mn, 45% Zn, 28% K, and 43% P. Correlations were observed between the majority of minerals tested suggesting strong interrelationships between mineral concentration levels. Hierarchical clustering identified fifteen accessions with high-ranking mineral concentrations. Thirty accessions could be compared to earlier inductively coupled optical emission spectrometry (ICP-OES) data, which revealed significant differences particularly for elements at extreme low or high levels of accumulation. These results improve our understanding of the range of variation in mineral content found in peas and provide additional mineral data resources for germplasm selection.

Copper is an essential micronutrient for humans. A cross-sectional and comparative study was done to assess serum Cu levels and serum copper/zinc (Cu/Zn) ratio and its association with nutritional indicators in a series of children and adolescents with chronic diseases. Anthropometric, biochemical, dietary, body composition, and bone densitometry assessments were carried out. Serum Cu and Zn were measured by atomic absorption spectrophotometry. Seventy-eight patients (55% women) participated. The mean serum Cu in the entire series and by nutritional status through body mass index (BMI) was normal. Serum Cu decreased significantly with age and was meaningfully higher in children than in adolescents. The risk of finding altered Cu levels in children and men was higher than in adolescents and women, respectively. Twenty-two per cent of patients had abnormal serum copper levels, 13 had hypercupremia, and four had hypocupremia. The Cu/Zn ratio was greater than 1.00 for 87% of the patients, which is an indicator of an inflammatory state. All patients with hypozincemia and hypocupremia had deficient Zn intake, but only 65% of the patients with hypercupremia had dietary Zn deficiency. Consequently, the Cu/Zn ratio could indicate an inflammatory state and a high risk of zinc deficiency in this specific child population.

Studies have evaluated the effect of copper (Cu) supplementation on blood lipid level. We therefore investigated whether the supplement of Cu on blood lipid level will have an impact in a meta-analysis on randomized controlled trials (RCTs). Literature search was conducted in Scopus, PubMed, Web of Science, and Cochrane Library (from database to January 2020). Randomized controlled trials of Cu supplementation on blood lipid level were retrieved according to the requirements of systematic review, and the quality of the included research was evaluated. Then the meta-analysis was performed. Data from 5 trials representing 176 participants were examined. Pooled mean net change in total cholesterol (TC) (standard mean difference(SMD) [95% CI] = - 0.05 [- 0.52, 0.43]), low density lipoprotein cholesterol (LDL-C) (SMD [95% CI] = 0.22 [- 0.46, 0.89]), and high density lipoprotein cholesterol (HDL-C) (SMD [95% CI] = 0.18 [- 0.14, 0.49]) for those treated with Cu supplementation had no significant difference when compared with control. Cu supplementation has not affected blood lipids in the result of meta-analysis. More research is needed to determine if this pattern will apply broadly.

Wilson's disease (WD) is a rare condition caused by copper accumulation primarily in the liver and secondly in other organs, such as the central nervous system. It is a hereditary autosomal recessive disease caused by a deficiency in the ATP7B transporter. This protein facilitates the incorporation of copper into ceruloplasmin. More than 800 mutations associated with WD have been described. The onset of the disease frequently includes manifestations related to the liver (as chronic liver disease or acute liver failure) and neurological symptoms, although it can sometimes be asymptomatic. Despite it being more frequent in young people, WD has been described in all life stages. Due to its fatal prognosis, WD should be suspected in all patients with unexplained biochemical liver abnormalities or neurological or psychiatric symptoms. The diagnosis is established with a combination of clinical signs and tests, including the measurement of ceruloplasmin, urinary copper excretion, copper quantification in liver biopsy, or genetic assessment. The pharmacological therapies include chelating drugs, such as D-penicillamine or trientine, and zinc salts, which are able to change the natural history of the disease, increasing the survival of these patients. In some cases of end-stage liver disease or acute liver failure, liver transplantation must be an option to increase survival. In this narrative review, we offer an overview of WD, focusing on the importance of clinical suspicion, the correct diagnosis, and treatment.

The essential trace mineral copper plays important roles in human physiology and pathophysiology. Disruption of copper homeostasis may underlie the development of ischemic heart disease, and connective tissue and neurodegenerative disorders. Copper also likely participates in the host response to bacterial infection and is further implicated more broadly in regulating immunity. Recent studies further associate copper with disruption of lipid homeostasis, as is frequently seen in, for example, non-alcoholic fatty liver disease (NAFLD). Moreover, continuing investigation of copper chaperones has revealed new roles for these intracellular copper-binding proteins. Despite these (and many other) significant advances, many questions related to copper biology remain unanswered. For example, what are the most sensitive and specific biomarkers of copper status, and which ones are useful in marginal (or "sub-clinical" copper deficiency)? Further research on this topic is required to inform future investigations of copper metabolism in humans (so the copper status of study participants can be fully appreciated). Also, are current recommendations for copper intake adequate? Recent studies suggest that overt copper deficiency is more common than once thought, and further, some have suggested that the copper RDAs for adults may be too low. Additional human balance and interventional studies are necessary and could provide the impetus for reconsidering the copper RDAs in the future. These and myriad other unresolved aspects of copper nutrition will undoubtedly be the focus of future investigation.

Copper have been reported to be associated with metabolic diseases. However, results on copper exposure with blood lipid profiles are inconsistent, and the underlying mechanisms of this association remain unclear. This study focused on investigating associations between urinary copper and blood lipid profiles; and exploring the potential role of systemic inflammation in such relationships. Concentrations of urinary copper, plasma C-reactive protein (CRP), and four blood lipid parameters (e.g., Total cholesterol [TC], triglycerides [TG], low-density lipoprotein cholesterol [LDL-C], and high-density lipoprotein cholesterol [HDL-C]) were measured in the adult participants from Wuhan-Zhuhai cohort. The associations between copper, CRP, and four blood lipids were assessed by the multivariable linear regression models, and the 3D mesh graphs was used to examine the joint effects of copper exposure and CRP on four blood lipid parameters. In addition, we used mediation analysis to investigate the mediated effects of CRP in the relationships between copper exposure and blood lipid profiles. Each 1% increase in urinary copper was statistically significantly associated with a 5.32% (95% CI: 2.48%, 8.24%) increase in TG after adjusting for the confounders (P < 0.05). No significant associations were observed between urinary copper and the other three blood lipid parameters (all P > 0.05). In addition, urinary copper increased monotonically with plasma CRP elevation, which in turn, was positively associated with TC, TG, and LDL-C and negatively related to HDL-C (all P < 0.05). Results from 3D mesh graphs demonstrated that increased levels of plasma CRP with higher urinary copper corresponded to higher TC, TG, LDL-C, and lower HDL-C concentrations. Mediation analysis observed that CRP mediated 6.27% in the relationships of urinary copper and TG. These findings suggest that systemic inflammation partly mediated the association between copper exposure and abnormal blood lipid, and may contribute to the development of dyslipidemias.

Cystic fibrosis (CF) patients require a stable and sufficient supply of micronutrients. Since copper is an essential micronutrient for human development, a cross-sectional study was carried out to investigate the serum copper levels, serum copper/zinc (Cu/Zn) ratios, and their relationship with nutritional indicators in a group of CF patients. Anthropometric, biochemical, and dietary measurements, an abdominal ultrasound, and respiratory and pancreatic tests were conducted. Seventeen CF patients were studied (10 females, 59%), 76.5% of whom were ∆F580. Their mean serum copper (113 ± 23 μg/dL) was normal, and there was only one teenager with hypocupremia (6%) and two children with hypercupremia (18%). A significant association between serum copper and zinc levels was discovered. The Cu/Zn ratio was higher than 1.00 for 94% of patients, which is an indicator of an inflammation status. There was no significant correlation between the serum copper concentrations and respiratory and pancreatic function, respiratory colonization, and the results of the abdominal ultrasound. Linear regression analysis showed that serum copper had a positive association with both the Z-score body mass index (BMI) and mean bone conduction speed (BCS). Therefore, since 94% of CF patients had a Cu/Zn ratio > 1.00, this factor must alert us to consider the risk of zinc deficiency and high inflammatory response. The measurement of serum zinc alone does not show one's zinc status. However, the Cu/Zn ratio may be an indicator of zinc deficiency and the inflammatory status of CF patients.

This review summarizes the present knowledge on the toxicity of copper and copper nanoparticles (CuNPs) to various fish species. In previous decades, the excessive usage of metal and metallic nanoparticles has increased significantly, increasing the probability of the accumulation and discharge of metals in various trophic levels of the environment. Due to these concerns, it is important to understand the toxicity mechanisms of metals and metallic nanoparticles before they lead to unhealthy effects on human health. In this review paper, we specifically focus on the effect of metal copper and CuNPs on different fish organs under different physiochemical parameters of various water bodies. Nowadays, different forms of copper have distinctive and specific usages, e.g., copper sulfate is a well-established pesticide which is used to control the growth of algae in lakes and ponds. Deactivating the fungi enzymes prevents fungal spores from germinating. This process of deactivation is achieved via the free cupric ions, which are established as the most toxic forms of copper. Complexes of copper with other ligands may or may not be bioavailable for use in aquatic organisms. On the other hand, CuNPs have shown cost-effectiveness and numerous promising uses, but the toxicity and availability of copper in a nanoparticle form is largely unknown, Additionally, physiochemical factors such as the hardness of the water, alkalinity, presence of inorganic and organic ligands, levels of pH, and temperature in various different water bodies affect the toxicity caused by copper and CuNPs. However, comprehensive knowledge and data regarding the pattern of toxicity for copper metal ions and CuNPs in marine organisms is still limited. In this review, we carry out a critical analysis of the availability of the toxicological profiles of copper metal ions and CuNPs for different fishes in order to understand the toxicity mechanisms of copper and CuNPs. We believe that this review will provide valuable information on the toxicological profile of copper, which will further help in devising safe guidelines for the usage of copper and CuNPs in a sustainable manner.

Chile as a major international Cu producer faces serious soil contamination issues in mining areas. Currently Chile does not have any specific law governing the maximum permissible concentrations of metals in soils to protect ecosystems and human health. Chile heavily relies on the use of environmental laws of 14 foreign countries; the choice of the country depends on the similarity of its environmental conditions with those in Chile. In this study, we used an online database to compare the similarity of Chilean rocks to those in foreign countries. Likewise, we performed soil sampling and determined the background concentrations of Cu, As, Pb, and Zn in soils of the Aconcagua basin, the largest river basin in the Valparaiso Region of central Chile. The results showed that geochemical patterns in Chile have the greatest resemblance to New Zealand, Mexico, and Italy. The background Cu concentration in the Aconcagua basin (134 mg kg^-1) exceeded the legislated limits of New Zealand (100 mg kg^-1) and Italy (120 mg kg^-1), whereas the background Zn concentration (200 mg kg^-1) exceeded the legislated limit of Italy (150 mg kg^-1). Due to the elevated natural abundance of Cu and Zn in Chile, international laws should not be applied in Chile for the assessment of soil contamination. In addition, we assessed ecological risk using the results of our previous studies obtained by analyzing native field-contaminated soils of the Valparaiso region. In the Aconcagua basin, Cu posed high risk for plants in 11% of the samples, whereas As posed high risk for earthworms in 48% of the samples. We suggest that future studies are required to search for other organisms that can serve as biomarkers of metal toxicity because our previous studies were limited to plants and earthworms. Importantly, As posed high risk to human health in 25% of the samples in our study. There is a need for future studies to demonstrate empirically an association between soil As and children's blood As in order to establish the national threshold values of soil As to protect human health. We conclude that there is an urgent need in Chile to advance from the current approach of adapting foreign laws to developing Chilean sovereign environmental legislation.

Surface contamination by microbes leads to several detrimental consequences like hospital- and device-associated infections. One measure to inhibit surface contamination is to confer the surfaces with antimicrobial properties. Copper's antimicrobial properties have been known since ancient times, and the recent resurgence in exploiting copper for application as antimicrobial materials or coatings is motivated by the growing concern about antibiotic resistance and the pressure to reduce antibiotic use. Copper, unlike silver, demonstrates rapid and high microbicidal efficacy against pathogens that are in close contact under ambient indoor conditions, which enhances its range of applicability. This review highlights the mechanisms behind copper's potent antimicrobial property, the design and fabrication of different copper-based antimicrobial materials and coatings comprising metallic copper/copper alloys, copper nanoparticles or ions, and their potential for practical applications. Finally, as the antimicrobial coatings market is expected to grow, we offer our perspectives on the implications of increased copper release into the environment and the potential ecotoxicity effects and possibility of development of resistant genes in pathogens.

Decades of study indicate that copper oral exposures are typically not a human health concern. Ingesting high levels of soluble copper salts can cause acute gastrointestinal symptoms and, in uncommon cases, liver toxicity in susceptible individuals with repeated exposure. This focused toxicological review evaluated the current literature since the last comprehensive reviews (2007-2010). Our review identified limitations in the existing United States and international guidance for determining an oral reference dose (RfD) for essential metals like copper. Instead, an alternative method using categorical regression analysis to develop an optimal dose that considers deficiency, toxicity, and integrates information from human and animal studies was reviewed for interpreting an oral RfD for copper. We also considered subchronic or chronic toxicity from genetic susceptibility to copper dysregulation leading to rare occurrences of liver and other organ toxicity with elevated copper exposure. Based on this approach, an oral RfD of 0.04 mg Cu/kg/day would be protective of acute or chronic toxicity in adults and children. This RfD is also protective for possible genetic susceptibility to elevated copper exposure and allows for background dietary exposures. This dose is not intended to be protective of patients with rare genetic disorders for copper sensitivity within typical nutritional intake ranges, nor is it protective for those with excessive supplement intake. Less soluble mineral forms of copper in soil have reduced bioavailability as compared with more soluble copper in water and diet, which should be considered in using this RfD for risk assessments of copper.

Dietary copper restriction has long been considered an important aspect of treatment for Wilson's disease (WD). However, evidence supporting this approach is limited. There are no published randomised controlled trials examining this recommendation due to rarity of the disease and variable presentation. This review summarises current knowledge on the absorption and regulation of copper in humans and its relevance to patients with WD. Studies have demonstrated that as the level of dietary copper increases, the proportion absorbed decreases. This observation implies that 'high copper' foods that WD patients are generally advised to avoid would need to be consumed in large amounts to impact markedly on the quantity absorbed. Dietary copper restriction is unlikely to reduce the amount absorbed significantly and is not only difficult to manage but restricts food groups unnecessarily, detracting from the provision of substrates essential for improving nutritional status in a nutritionally compromised group. Medical management for WD is effective in compliant patients, allowing stabilisation of the liver disease. Based on current evidence, dietary copper restrictions in stable WD patients who are adherent to medical therapy are unnecessary with two food exceptions (shellfish and liver).

There are theoretical and empirical reasons to consider a potential role for copper metabolism in the brain in how it could influence stuttering. However, a link between stuttering and dietary intake has never been researched in a systematic way. This pilot study therefore aimed to explore a possible association between ingested amounts of copper and thiamine (vitamin B1) with stuttering frequency using a double blind cross-over longitudinal paradigm.

19 adults who stutter between 20 and 51 years old filled out an online survey for 9 consecutive weeks. The survey consisted of self-assessed fluency and mood state scales, as well as food journals. After 4 weeks, the participants consumed either copper or thiamine supplements for 2 weeks, followed by a 1-week washout period, and another period of two weeks taking the other supplement. Formal speech assessments were done pre/post baseline and at the end of each supplement intake. Participants were not informed about the nature of the supplements during the experiment and the investigators were blinded to the order of the supplements.

The results demonstrated that copper and thiamine had no measurable effect on the amount of stuttering (self and formal assessments) but there was a moderate, significant correlation between mood state and fluency.

The findings do not support notions of dietary influences of ingested copper or thiamine on stuttering but do provide modest support for a relationship between variations in stuttering and self-perceived anxiety.

Between 1938 and 1975, the city of Chañaral, located in the north of Chile, received 200 megatons of unregulated mining waste, which created an artificial beach 10 kilometers long and covering an area larger than 4 km2. In 1983, this deposit was classified as a serious case of marine pollution in the Pacific Ocean, according to the Organization for Economic Cooperation and Development. In 1989, dumping ceased due to a judicial order. Until now, the effects of this pollution on the population living around these mine tailings has been unknown.

To determine the prevalence of exposure to metals by dust from mine tailings in Chañaral, a city located in the northern mining area of Chile.

The level of urinary metals in a representative sample of adults from Chanaral was determined.

Urinary levels of total arsenic (44.6 μg/L), inorganic arsenic (17.0 μg/L) and nickel (2.8 μg/L) were higher than in other areas of Chile. Levels of copper (17.9 μg/L), mercury (1.6 μg/L) and lead (0.9 μg/L) exceeded international values. Of the total subjects, 67.5%, 30.4%, 29.4%, 16.9%, 13.2 and 9.3% presented with high levels of copper, nickel, total arsenic, inorganic arsenic, mercury and lead, respectively.

Thirty-one years after suspension of the discharge of mining waste, the local population in this area remains exposed to metals from the mine tailings. Surveillance and remedial actions addressing the Chañaral mine tailings are needed.

Although copper (Cu) is recognized as an essential trace element, uncertainties remain regarding Cu reference values for humans, as illustrated by discrepancies between recommendations issued by different national authorities. This review examines human studies published since 1990 on relationships between Cu intake, Cu balance, biomarkers of Cu status, and health. It points out several gaps and unresolved issues which make it difficult to assess Cu requirements. Results from balance studies suggest that daily intakes below 0.8 mg/day lead to net Cu losses, while net gains are consistently observed above 2.4 mg/day. However, because of an incomplete collection of losses in all studies, a precise estimation of Cu requirements cannot be derived from available data. Data regarding the relationship between Cu intake and potential biomarkers are either too preliminary or inconclusive because of low specificity or low sensitivity to change in dietary Cu over a wide range of intakes. Results from observation and intervention studies do not support a link between Cu and a risk of cardiovascular disease, cognitive decline, arthritis or cancer for intakes ranging from 0.6 to 3mg/day, and limited evidence exists for impaired immune function in healthy subjects with a very low (0.38 mg/day) Cu intake. However, data from observation studies should be regarded with caution because of uncertainties regarding Cu concentration in various foods and water. Further studies that accurately evaluate Cu exposure based on reliable biomarkers of Cu status are needed.

Ceruloplasmin, the main copper binding protein in blood plasma, has been of particular interest for its role in efflux of iron from cells, but has additional functions. Here we tested the hypothesis that it releases its copper for cell uptake by interacting with a cell surface reductase and transporters, producing apoceruloplasmin. Uptake and transepithelial transport of copper from ceruloplasmin was demonstrated with mammary epithelial cell monolayers (PMC42) with tight junctions grown in bicameral chambers, and purified human (64)Cu-labeled ceruloplasmin secreted by HepG2 cells. Monolayers took up virtually all the (64)Cu over 16h and secreted half into the apical (milk) fluid. This was partly inhibited by Ag(I). The (64)Cu in ceruloplasmin purified from plasma of (64)Cu-injected mice accumulated linearly in mouse embryonic fibroblasts (MEFs) over 3-6h. Rates were somewhat higher in Ctr1+/+ versus Ctr1-/- cells, and 3-fold lower at 2 °C. The ceruloplasmin-derived (64)Cu could not be removed by extensive washing or trypsin treatment, and most was recovered in the cytosol. Actual cell copper (determined by furnace atomic absorption) increased markedly upon 24h exposure to holoceruloplasmin. This was accompanied by a conversion of holo to apoceruloplasmin in the culture medium and did not occur during incubation in the absence of cells. Four different endocytosis inhibitors failed to prevent 64Cu uptake from ceruloplasmin. High concentrations of non-radioactive Cu(II)- or Fe(III)-NTA (substrates for cell surface reductases), or Cu(I)-NTA (to compete for transporter uptake) almost eliminated uptake of (64)Cu from ceruloplasmin. MEFs had cell surface reductase activity and expressed Steap 2 (but not Steaps 3 and 4 or dCytB). However, six-day siRNA treatment was insufficient to reduce activity or uptake. We conclude that ceruloplasmin is a circulating copper transport protein that may interact with Steap2 on the cell surface, forming apoceruloplasmin, and Cu(I) that enters cells through CTR1 and an unknown copper uptake transporter.

Copper is an essential element, and either a copper deficiency or excess can be life threatening. Recent studies have indicated that alteration of copper metabolism is one of the pathogenetic mechanisms of Alzheimer's disease (AD). In light of these findings, many researchers have proposed preventive strategies to reduce AD risk. Because the general population comes in contact with copper mainly through dietary intake, that is, food 75% and drinking water 25%, a low-copper diet can reduce the risk of AD in individuals with an altered copper metabolism. We suggest that a diet-gene interplay is at the basis of the "copper phenotype" of sporadic AD. Herein, we describe the pathways regulating copper homeostasis, the adverse sequelae related to its derangements, the pathogenic mechanism of the AD copper phenotype, indications for a low-copper diet, and future perspectives to improve this preventive strategy.

Recent longitudinal studies in dietary daily intake in human centenarians have shown that a satisfactory content of some micronutrients within the cells maintain several immune functions, a low grade of inflammation and preserve antioxidant activity. Micronutrients (zinc, copper, selenium) play a pivotal role in maintaining and reinforcing the performances of the immune and antioxidant systems as well as in affecting the complex network of the genes (nutrigenomic) with anti- and pro-inflammatory tasks. Genes of pro- and anti-inflammatory cytokines and some key regulators of trace elements homeostasis, such as Metallothioneins (MT), are involved in the susceptibility to major geriatric disease/disorders. Moreover, the genetic inter-individual variability may affect the nutrients' absorption (nutrigenetic) with altered effects on inflammatory/immune response and antioxidant activity. The interaction between genetic factors and micronutrients (nutrigenomic and nutrigenetic approaches) may influence ageing and longevity because the micronutrients may become also toxic. This review reports the micronutrient-gene interactions in ageing and their impact on the healthy state with a focus on the method of protein-metal speciation analysis. The association between micronutrient-gene interactions and the protein-metal speciation analysis can give a complete picture for a personalized nutrient supplementation or chelation in order to reach healthy ageing and longevity.

In ageing, alterations in inflammatory/immune response and antioxidant capacity lead to increased susceptibility to diseases and loss of mobility and agility. Various essential micronutrients in the diet are involved in age-altered biological functions. Micronutrients (zinc, copper, iron) play a pivotal role either in maintaining and reinforcing the immune and antioxidant performances or in affecting the complex network of genes (nutrigenomic approach) involved in encoding proteins for a correct inflammatory/immune response. By the other side, the genetic inter-individual variability may affect the absorption and uptake of the micronutrients (nutrigenetic approach) with subsequent altered effects on inflammatory/immune response and antioxidant activity. Therefore, the individual micronutrient-gene interactions are fundamental to achieve healthy ageing. In this review, we report and discuss the role of micronutrients (Zn, Cu, Fe)-gene interactions in relation to the inflammatory status and the possibility of a supplement in the event of a micronutrient deficiency or chelation in presence of micronutrient overload in relation to specific polymorphisms of inflammatory proteins or proteins related of the delivery of the micronutriemts to various organs and tissues. In this last context, we report the protein-metal speciation analysis in order to have, coupled with micronutrient-gene interactions, a more complete picture of the individual need in micronutrient supplementation or chelation to achieve healthy ageing and longevity.

This article reviews recent evidence, much of which has been generated by my group's research programme, which has identified for the first time a previously unknown copper-overload state that is central to the pathogenesis of diabetic organ damage. This state causes tissue damage in the blood vessels, heart, kidneys, retina and nerves through copper-mediated oxidative stress. This author now considers this copper-overload state to provide an important new target for therapeutic intervention, the objective of which is to prevent or reverse the diabetic complications. Triethylenetetramine (TETA) has recently been identified as the first in a new class of anti-diabetic molecules through the original work reviewed here, thus providing a new use for this molecule, which was previously approved by the US FDA in 1985 as a second-line treatment for Wilson's disease. TETA acts as a highly selective divalent copper (Cu(II)) chelator that prevents or reverses diabetic copper overload, thereby suppressing oxidative stress. TETA treatment of diabetic animals and patients has identified and quantified the interlinked defects in copper metabolism that characterize this systemic copper overload state. Copper overload in diabetes mellitus differs from that in Wilson's disease through differences in their respective causative molecular mechanisms, and resulting differences in tissue localization and behaviour of the excess copper. Elevated pathogenetic tissue binding of copper occurs in diabetes. It may well be mediated by advanced-glycation endproduct (AGE) modification of susceptible amino-acid residues in long-lived fibrous proteins, for example, connective tissue collagens in locations such as blood vessel walls. These AGE modifications can act as localized, fixed endogenous chelators that increase the chelatable-copper content of organs such as the heart and kidneys by binding excessive amounts of catalytically active Cu(II) in specific vascular beds, thereby focusing the related copper-mediated oxidative stress in susceptible tissues. In this review, summarized evidence from our clinical studies in healthy volunteers and diabetic patients with left-ventricular hypertrophy, and from nonclinical models of diabetic cardiac, arterial, renal and neural disease is used to construct descriptions of the mechanisms by which TETA treatment prevents injury and regenerates damaged organs. Our recent phase II proof-of-principle studies in patients with type 2 diabetes and in nonclinical models of diabetes have helped to define the pathogenetic defects in copper regulation, and have shown that they are reversible by TETA. The drug tightly binds and extracts excess systemic Cu(II) into the urine whilst neutralizing its catalytic activity, but does not cause systemic copper deficiency, even after prolonged use. Its physicochemical properties, which are pivotal for its safety and efficacy, clearly differentiate it from all other clinically available transition metal chelators, including D-penicillamine, ammonium tetrathiomolybdate and clioquinol. The studies reviewed here show that TETA treatment is generally effective in preventing or reversing diabetic organ damage, and support its ongoing development as a new medicine for diabetes. Trientine (TETA dihydrochloride) has been used since the mid-1980s as a second-line treatment for Wilson's disease, and our recent clinical studies have reinforced the impression that it is likely to be safe for long-term use in patients with diabetes and related metabolic disorders. There is substantive evidence to support the view that diabetes shares many pathogenetic mechanisms with Alzheimer's disease and vascular dementia. Indeed, the close epidemiological and molecular linkages between them point to Alzheimer's disease/vascular dementia as a further therapeutic target where experimental pharmacotherapy with TETA could well find further clinical application.

Copper (Cu), an essential element required as a cofactor and/or structural component of numerous metalloenzymes, is uniquely positioned as a case study for issues associated with the essential metals health risk assessment, because of its extensive database. Essential elements pose distinct challenges when establishing regulatory guidelines because too little as well as too much intake can produce adverse health consequences and the dose-response curve is roughly U-shaped. Thus, conventional health risk assessment paradigms do not apply to essential elements; the dose-response assessment needs to define an acceptable range of oral intake (AROI) which prevents deficiency by meeting nutritional requirements while avoiding toxicity due to high intakes. The conceptual framework for this type of risk assessment includes consideration of biological processes that are unique to essential elements-homeostasis, basal and normative nutritional requirements, bioavailability, and nutrient-nutrient interactions. In this paper, the Cu database on physiology, deficiency, and excess is briefly reviewed in order to establish the range of potential health hazards associated with varying levels of intake. Issues discussed include the (1) development of suitable dose-response methodologies, including appropriate dose and response metrics, for Cu; (2) categorization of severity of response and functional significance; (3) use of endpoints of similar severity and functionality for deficiency and excess in dose-response assessment; (4) development of valid biomarkers for subclinical effects, exposures and susceptibilities. Guideline values for Cu intake have been established by nutritional and toxicologic regulatory or advisory boards. Although regulators are more concerned with the potential human toxicity arising from excessive Cu intake, the preponderance of evidence suggests that deficiency is more of a public health concern than excess.

The assessment of dietary adequacy of copper is constrained by the absence of recognized copper status biomarkers.

The objectives were to systematically review the usefulness of copper status biomarkers and identify those that reflected changes in status over > or =4 wk.

The methods included a structured search on Ovid MEDLINE, EMBASE (Ovid), and Cochrane databases to October 2007, followed by the use of formal inclusion/exclusion criteria, data extraction, validity assessment, and meta-analysis.

A total of 16 studies (288 participants) were included in the review, with data on 16 possible copper biomarkers. All of the included studies were small and at high risk of bias. Data for serum copper suggested its value as a biomarker, reflecting changes in status in both depleted and replete individuals, although these changes were smaller in the latter. Total ceruloplasmin protein is related to copper status but reflects changes in highly depleted individuals only. Erythrocyte superoxide dismutase and urinary deoxypyridinoline are not useful biomarkers, but there were insufficient data to draw firm conclusions about plasma, erythrocyte, and platelet copper; leukocyte superoxide dismutase; erythrocyte, platelet, and plasma glutathione peroxidase; platelet and leukocyte cytochrome-c oxidase; total glutathione; diamine oxidase; and urinary pyridinoline. The paucity of data prevented detailed subgroup analysis.

Despite limited data, serum copper appears to be a useful biomarker of copper status at the population level. Further large studies with low risk of bias are needed to explore the effectiveness of other biomarkers of copper status and the relation between biomarker responsiveness, dose, and period of supplementation.

Previous studies showed that responses to chronic administration of copper were significantly associated with gender, raising the need to better characterize the relation between the effects observed and stradiols. The objective of this study was to measure copper and liver function indicators and the sex hormone binding globulin (SHBG) serum concentrations in healthy adults exposed to copper, grouped by sex and phase of the female hormonal cycle. Healthy females on day 7 (follicular phase, Group 1, n = 39), on day 21 (secretory phase, Group 2, n = 34) and males (comparison group, Group 3, n = 34) received 8 mg Cu/day (as copper sulfate), orally, for 6 months. On days 0, 30, 60, 120, and 180, the serum concentration of copper, ceruloplasmin, liver aminotransferases, and SHBG were measured. Analysis of results included analysis of variance (ANOVA; repeated measures) and the post hoc Bonferroni correction. Participants remained healthy throughout the study period, including aminotransferases below the cut off in all measures. GGT, AST, and ALT activities were significantly different by group and by time (ANOVA repeated measures P < 0.05). Six-month curves of serum copper and ceruloplasmin concentrations were different by group, by time and interaction group x time (all P < 0.001). SHBG curves were different by group and time (P < 0.01), and interaction group x time (P < 0.009). Serum copper, ceruloplasmin, and liver aminotranferases are influenced by estrogens/progesterone, something that should be considered when these indicators are used as outcomes of effects. Time of sampling was also significantly associated with the indicators and deserves further study.

Copper is an essential trace element involved, among other functions, in enzymatic antioxidative defense systems. However, nonprotein bound copper ions have been shown to generate reactive oxygen species. To gain insight into the discrepancy between the protective properties of copper on the one hand and its toxicity on the other hand, we examined the genotoxic effects of CuSO(4) in cultured human cells. Here we report that copper, at cytotoxic concentrations, induces oxidative DNA base modifications and DNA strand breaks. However, at lower noncytotoxic concentrations, copper inhibits the repair of oxidative DNA damage induced by visible light. As a first mechanistic hint, inhibition of H(2)O(2)-induced poly(ADP-ribosyl)ation was identified in cultured cells and further experiments demonstrated a strong inhibition of the activity of isolated poly(ADP-ribose)polymerase-1 (PARP-1) by copper. Bioavailability studies of copper showed a dose-dependent uptake in cells and pointed out the relevance of the applied concentrations. Taken together, the results indicate that copper, under conditions of either disturbed homeostasis or overload due to high exposure, exerts defined genotoxic effects. Hence, a balance needs to be maintained to ensure sufficient uptake and to prevent overload.

Wilson's disease carriers constitute 1% of the human population. It is unknown whether Wilson's disease carriers are at increased susceptibility to copper overload when exposed to chronically high levels of ingested copper. This study investigated the effect of chronic excess copper in drinking water on the heterozygous form of the Wilson's disease mouse model--the toxic milk (tx) mouse. Mice were provided with drinking water containing 300 mg/l copper for 4-7, 8-11, 12-15 or 16-20 months. At the completion of the study liver, spleen, kidney and brain tissue were analyzed by atomic absorption spectroscopy to determine copper concentration. Plasma ceruloplasmin oxidase activity and liver histology were also assessed. Chronic copper loading resulted in significantly increased liver copper in both tx heterozygous and tx homozygous mice, while wild type mice were resistant to the effects of copper loading. Copper loading effects were greatest in tx homozygous mice, with increased extrahepatic copper deposition in spleen and kidney - an effect absent in heterozygote and wild type mice. Although liver histology in homozygous mice was markedly abnormal, no histological differences were noted between heterozygous and wild type mice with copper loading. Tx heterozygous mice have a reduced ability to excrete excess copper, indicating that half of the normal liver Atp7b copper transporter activity is insufficient to deal with large copper intakes. Our results suggest that Wilson's disease carriers in the human population may be at increased risk of copper loading if chronically exposed to elevated copper in food or drinking water.

Definitive data on mineral bioavailability in humans and animals can be obtained by using isotopic tracers. The use of stable isotope tracers to study important issues in mineral nutrition has expanded rapidly in the past two decades, particularly in human nutrition studies. Stable isotopes have a number of advantages over radioisotopes. There is no exposure to radiation with stable isotopes, and some minerals have no radioisotope that can be used satisfactorily as a tracer. Multiple stable isotopes of one mineral and isotopes of multiple minerals can be administered simultaneously or sequentially. The analytical methods of choice for stable isotopes are thermal ionization mass spectrometry and inductively coupled plasma mass spectrometry (ICPMS). Thermal ionization mass spectrometry offers the greatest precision and accuracy, but it is slower, more labor intensive, and more costly than ICPMS. Bioavailability data are critical to establishing reliable dietary mineral requirements and recommendations. Combined with a computer program for compartmental modeling, mineral kinetics can be studied, including mineral turnover, pool sizes, and transfer rates between compartments. Our laboratory conducts studies using stable isotopes of Zn, Cu, Fe, Ca, Mg, and Mo. We have studied the effect of the amount of dietary intake of minerals on bioavailability and use, pregnancy and aging, and interactions among minerals. The research resulted in establishing new dietary recommendations for Cu and Mo and developing compartmental models for these minerals. Although stable isotopes have been used more extensively to date in humans than in animals, the techniques applied to humans can be used to study a number of issues important to optimizing feeding strategies for animal production.