Platinum-group elements and gold in silver coinage and the issue of salt cementation.

It has been proposed that gold purification by cementation could account for the low gold content of ancient Greek coinage from Attica and the Cyclades. In order to place new constraints on this suggestion, the concentrations of platinum-group elements (PGEs) and gold have been measured in 72 silver coins mostly from the Greek Archaic and Classical periods, but also from Rome, India, medieval Europe, and colonial Spanish Americas, by inductively coupled plasma mass spectrometry. A novel technique allowing these concentrations to be determined in silver coins is described. Variations are consistent with element position in the periodic table. The volatile elements Rh and Os are commonly at or below the detection level, which may reflect evaporation during smelting and cupellation. Ruthenium and Ir, which binary phase equilibrium experiments show to be insoluble in solid silver and gold, and soluble Pd and Pt, show variations in coinage consistent with these properties. The dichotomy of Ir/Au ratios is not consistent with Ir loss in gold during salt cementation (parting) and is better explained by the contrast between Au-rich and Au-poor ore districts. This contrast is suggested to reflect either regional differences or the variability of conditions during ore genesis, such as hydrothermal solution chlorinity.

A heavy metal baseline score predicts outcome in acute myeloid leukemia.

Despite abundant epidemiological data linking metals to leukemia and other cancers, baseline values of toxic and essential metals in patients with leukemia and the clinical impact of these metals remain unknown. Thus, we sought to quantify metal values in untreated patients with acute myeloid leukemia (AML) and controls and determine the impact of metal values on AML patients' survival. Serum samples from patients with untreated AML and controls at Hospices Civils de Lyon were analyzed and compared for trace metals and copper isotopic abundance ratios with inductively coupled plasma mass spectrometry. Survival analysis was performed as a function of metal values, and a multi-metal score was developed for patients with AML. Serum samples were collected from 67 patients with untreated AML and 94 controls. Most patients had intermediate-risk cytogenetics (63.1%) without FLT3 internal tandem duplication mutations (75.6%) or NPM1 mutations (68.1%). Most metal values differed significantly between AML and control groups. Patients with lower magnesium and higher cadmium values had the worst survival rates, with only 36% surviving at 6 months (P = .001). The adverse prognostic effect of this combination was maintained on multivariate analysis. Based on this, we developed a novel metal score, which accounts for multiple relative abnormalities in the values of five toxic and five essential metals. Patients with a higher metal score had significantly worse survival, which was maintained on multivariate analysis (P = .03). This baseline metal scoring system was also prognostic when we applied it to a separate population of front-line AML patients.

Geochemistry of Gold Ores Mined During Celtic Times from the North-Western French Massif Central.

The Celtic culture of Western Europe left magnificent gold objects, such as jewellery and weapons from nobility graves and hoarded coins, as well as field evidence of pre-Roman gold mining and metallurgical workshops that attest to the mining of local ores. This is the case of Central France where many precious metallic ores have been mined throughout the ages from the Prehistoric times onwards. One of the lingering problems in assessing the provenance of gold artefacts and coins is the lack of relevant data on the isotope geochemistry and mineralogy of ore sources. Forty gold ores samples were collected and studied from Limousin (French Massif Central), a very significant gold mining district from the Celtic times. Their Pb isotope compositions clearly show a local dichotomy i.e. two distinct groups of ores, one of Late Proterozoic to Early Paleozoic Pb model age and another associated to Variscan ages and consistent with field relationships, mineralogy and elemental analyses. The use of Cu and Ag isotopes, and their coupling with Pb isotopes, will refine the tracing of future metal provenance studies, but also highlight some metallurgical practices like deliberate metal additions to gold artefact or debasement of gold coins. The newly acquired Pb, Ag, and Cu isotopic data on gold ores improves our understanding of ore deposits geology and provide clarifications on the provenance of Celtic gold from this area and its economic importance.

Homogeneous sulfur isotope signature in East Antarctica and implication for sulfur source shifts through the last glacial-interglacial cycle.

Sulfate aerosol (SO42-) preserved in Antarctic ice cores is discussed in the light of interactions between marine biological activity and climate since it is mainly sourced from biogenic emissions from the surface ocean and scatters solar radiation during traveling in the atmosphere. However, there has been a paradox between the ice core record and the marine sediment record; the former shows constant non-sea-salt (nss-) SO42- flux throughout the glacial-interglacial changes, and the latter shows a decrease in biogenic productivity during glacial periods compared to interglacial periods. Here, by ensuring the homogeneity of sulfur isotopic compositions of atmospheric nss-SO42- (δ34Snss) over East Antarctica, we established the applicability of the signature as a robust tool for distinguishing marine biogenic and nonmarine biogenic SO42-. Our findings, in conjunction with existing records of nss-SO42- flux and δ34Snss in Antarctic ice cores, provide an estimate of the relative importance of marine biogenic SO42- during the last glacial period to be 48 ± 10% of nss-SO42-, slightly lower than 59 ± 11% during the interglacial periods. Thus, our results tend to reconcile the ice core and sediment records, with both suggesting the decrease in marine productivity around Southern Ocean under the cold climate.

Dynamic homeostasis modeling of Zn isotope ratios in the human body.

Recent research performed on volunteers and patients suggested that diet, health, and basal metabolic rates (BMR) are factors controlling the bodily Zn isotope compositions (isotopic homeostasis). However, our poor understanding of the variability of Zn distribution among the different organs and fluids of the human body, and the ensuing isotope fractionation, limits the use of this isotopic system as a typical diagnostic tool for cancers and for past hominin diet reconstructions. Using box model calculations, we investigated the dynamics of Zn isotope variability in blood and other body tissues as well as the consistency of the hypothesis of heavy Zn isotope accumulation through time in the human body. We compare the results of the model with data obtained from control feeding experiments and from archeological samples. Model simulations indicate that the absence of an aging drift in non-circumpolar populations cannot be explained by their lower BMR. We argue that the drift observed in the blood of a circumpolar population results from a differential diet between young and older individuals in this population. When applied to the δ66Zn measured in blood, bones, or teeth, the present box model also offers insight into the isotope composition of the human diet, and therefore into its nature. Applying the model to isotopic observations on the remains of past hominins is a promising tool for diet reconstruction.

Differential effects of TNF-α and IL-1ß on the control of metal metabolism and cadmium-induced cell death in chronic inflammation.

OBJECTIVE: Interleukin-1-beta (IL-1ß) and tumour necrosis factor-alpha (TNF-α) are both monocyte-derived cytokines. Both cytokines have been previously described to exert a role in rheumatoid arthritis (RA) pathogenesis synergizing with other pro-inflammatory mediators, such as interleukin-17 (IL-17) on target cells, for the perpetuation of the inflammatory response (e.g. IL-6 production). In the context of experimental RA, Cd addition has an anti-proliferative and anti-inflammatory effect when associated to IL-17/TNF-α stimulation, due to its accumulation in synoviocytes. The aim of this work was to evaluate if IL-1ß interaction with IL-17 also contributes to metal-import mechanisms and its effects on cell viability and inflammation. METHODS: IL-17 and IL-1ß were added to synoviocyte cultures with or without exogenous Cd addition (0.1 ppm, 0.89 µM). IL-6 production, Cd import kinetics, gene expression of ZIP-8 importer and metallothioneins (MTs) and cell viability were evaluated by ELISA, inductively-coupled mass spectrometry (ICP-MS), q-RT-PCR and viability assays (neutral red and annexin V) respectively. RESULTS: IL-17 and IL-1ß acted in synergy on synoviocytes to induce IL-6 production similarly to the IL-17/TNF-α combination. Metal import was lower with IL17/ IL-1ß in comparison to IL-17/TNF-α exposed-synoviocytes, as the expression of ZIP-8 and MT-1F was less induced. Monocyte and PBMCs exposure to Cd resulted in a reduced production of IL-1ß and an increased production of TNF-α and this result was confirmed in co-cultures of synoviocytes and PBMCs. The IL-17/IL-1ß combination with Cd slightly reduced cell viability in comparison to the IL-17/TNF-α combination and resulted in a strong induction of IL-6 production. CONCLUSION: IL-17/TNF-α combination but not IL-17/IL-1ß combination mainly drives the accumulation of Cd in synoviocytes and its effects on cell viability and inflammation.

Rome's urban history inferred from Pb-contaminated waters trapped in its ancient harbor basins.

Heavy metals from urban runoff preserved in sedimentary deposits record long-term economic and industrial development via the expansion and contraction of a city's infrastructure. Lead concentrations and isotopic compositions measured in the sediments of the harbor of Ostia-Rome's first harbor-show that lead pipes used in the water supply networks of Rome and Ostia were the only source of radiogenic Pb, which, in geologically young central Italy, is the hallmark of urban pollution. High-resolution geochemical, isotopic, and 14C analyses of a sedimentary core from Ostia harbor have allowed us to date the commissioning of Rome's lead pipe water distribution system to around the second century BC, considerably later than Rome's first aqueduct built in the late fourth century BC. Even more significantly, the isotopic record of Pb pollution proves to be an unparalleled proxy for tracking the urban development of ancient Rome over more than a millennium, providing a semiquantitative record of the water system's initial expansion, its later neglect, probably during the civil wars of the first century BC, and its peaking in extent during the relative stability of the early high Imperial period. This core record fills the gap in the system's history before the appearance of more detailed literary and inscriptional evidence from the late first century BC onward. It also preserves evidence of the changes in the dynamics of the Tiber River that accompanied the construction of Rome's artificial port, Portus, during the first and second centuries AD.

Regulatory effects of zinc on cadmium-induced cytotoxicity in chronic inflammation.

OBJECTIVES: Zinc (Zn) has major effects on immune system activation while Cadmium (Cd) has anti-inflammatory and anti-proliferative effects in several chronic inflammatory contexts. The aim of this work was to investigate by which mechanisms Zn could compete with Cd and eventually counteract its deleterious effects. Rheumatoid arthritis (RA) synoviocytes exposed to cytokines were used as a model of chronic inflammation; osteoarthritis (OA) synoviocytes were used as control. METHODS: Cell/medium fractionation constants were analyzed for different metals by inductively-coupled-plasma mass-spectrometry by comparison to the 70Zn spike. Interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α) were used to mimic inflammation. Gene expression of ZIP-8 importer, metallothioneins-1 (MT-1s) and the ratio between metalloprotease-3 and the tissue inhibitor of metalloproteinases (MMP-3)/TIMP-1) were evaluated after pre-exposure to cytokines and Cd, with or without the addition of exogenous Zn (0.9 ppm). Cell viability was measured by neutral red assay and IL-6 production by ELISA. RESULTS: Synoviocytes selectively absorbed and retained Cd in comparison to Zn. Metal import increased with IL-17/TNF-α exposure, through the enhanced ZIP-8 expression. Zn did not modify ZIP-8 expression, while Cd reduced it (p<0.05). Zn induced a reduction of Cd-induced MT-1s expression, in particular of MT-1X (3-fold), and subsequently the final intra-cellular content of Cd. By reducing Cd accumulation in cells, Zn reversed Cd anti-proliferative and anti-inflammatory effects but preserved the low MMP-3/TIMP-1 ratio induced by Cd, which was enhanced by inflammatory conditions. CONCLUSION: Zinc counteracts the deleterious effect of Cd by reducing its import and accumulation in the cell, without the reactivation of destructive pathways such as MMPs.

Protective effect of low dose intra-articular cadmium on inflammation and joint destruction in arthritis.

Synovium hyperplasia characterizes joint diseases, such as rheumatoid arthritis (RA). The cytotoxic effect of low-dose Cadmium (Cd) was tested in vitro and ex vivo on synoviocytes, the mesenchymal key effector cells of inflammation and proliferation in arthritis. The anti-inflammatory and anti-proliferative effects of Cd were tested in vivo by intra-articular injection in the adjuvant induced arthritis rat joints, where the clinical scores and the consequences of arthritis were evaluated. Cell death through apoptosis was highly induced by Cd in inflammatory synoviocytes (80% reduction of cell viability, p < 0.01). TNF plus IL-17 cytokine combination induced a two-fold increase of Cd cell content by enhancing the ZIP-8 importer and the MT-1 homeostasis regulator expression. Addition of Cd reduced IL-6 production in TNF plus IL-17-activated synoviocytes (up to 83%, p < 0.05) and in ex-vivo synovium biopsies (up to 94%, p < 0.01). Cd-injection in rat joints improved arthritis, reducing clinical scores (arthritic score reduced from 4 to 2, p < 0.01), inflammatory cell recruitment (up to 50%, p < 0.01) and protecting from bone/cartilage destruction. This proof of concept study is supported by the limited Cd spread in body reservoirs, with low-dose Cd providing a safe risk/benefit ratio, without toxic effects on other cell types and organs.

Copper transporters are responsible for copper isotopic fractionation in eukaryotic cells.

Copper isotopic composition is altered in cancerous compared to healthy tissues. However, the rationale for this difference is yet unknown. As a model of Cu isotopic fractionation, we monitored Cu uptake in Saccharomyces cerevisiae, whose Cu import is similar to human. Wild type cells are enriched in 63Cu relative to 65Cu. Likewise, 63Cu isotope enrichment in cells without high-affinity Cu transporters is of slightly lower magnitude. In cells with compromised Cu reductase activity, however, no isotope fractionation is observed and when Cu is provided solely in reduced form for this strain, copper is enriched in 63Cu like in the case of the wild type. Our results demonstrate that Cu isotope fractionation is generated by membrane importers and that its amplitude is modulated by Cu reduction. Based on ab initio calculations, we propose that the fractionation may be due to Cu binding with sulfur-rich amino acids: methionine and cysteine. In hepatocellular carcinoma (HCC), lower expression of the STEAP3 copper reductase and heavy Cu isotope enrichment have been reported for the tumor mass, relative to the surrounding tissue. Our study suggests that copper isotope fractionation observed in HCC could be due to lower reductase activity in the tumor.

Medical applications of Cu, Zn, and S isotope effects.

This review examines recent applications of stable copper, zinc and sulfur isotopes to medical cases and notably cancer. The distribution of the natural stable isotopes of a particular element among coexisting molecular species varies as a function of the bond strength, the ionic charge, and the coordination, and it also changes with kinetics. Ab initio calculations show that compounds in which a metal binds to oxygen- (sulfate, phosphate, lactate) and nitrogen-bearing moieties (histidine) favor heavy isotopes, whereas bonds with sulfur (cysteine, methionine) favor light isotopes. Oxidized cations (e.g., Cu(ii)) and low coordination numbers are expected to favor heavy isotopes relative to their reduced counterparts (Cu(i)) and high coordination numbers. Here we discuss the first observations of Cu, Zn, and S isotopic variations, three elements closely related along multiple biological pathways, with emphasis on serum samples of healthy volunteers and of cancer patients. It was found that heavy isotopes of Zn and to an even greater extent Cu are enriched in erythrocytes relative to serum, while the difference is small for sulfur. Isotopic variations related to age and sex are relatively small. The 65Cu/63Cu ratio in the serum of patients with colon, breast, and liver cancer is conspicuously low relative to healthy subjects. The characteristic time over which Cu isotopes may change with disease progression (a few weeks) is consistent with both the turnover time of the element and albumin half-life. A parallel effect on sulfur isotopes is detected in a few un-medicated patients. Copper in liver tumor tissue is isotopically heavy. In contrast, Zn in breast cancer tumors is isotopically lighter than in healthy breast tissue. 66Zn/64Zn is very similar in the serum of cancer patients and in controls. Possible reasons for Cu isotope variations may be related to the cytosolic storage of Cu lactate (Warburg effect), release of intracellular copper from cysteine clusters (metallothionein), or the hepatocellular and biosynthetic dysfunction of the liver. We suggest that Cu isotope metallomics will help evaluate the homeostasis of this element during patient treatment, notably by chelates and blockers of Cu trafficking, and understand the many biochemical pathways in which this element is essential.

Hypoxia induces copper stable isotope fractionation in hepatocellular carcinoma, in a HIF-independent manner.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, with increasing incidence worldwide. The unrestrained proliferation of tumour cells leads to tumour hypoxia which in turn promotes cancer aggressiveness. While changes in the concentration of copper (Cu) have long been observed upon cancerization, we have recently reported that the isotopic composition of copper is also altered in several types of cancer. In particular, we showed that in hepatocellular carcinoma, tumour tissue contains heavier copper compared to the surrounding parenchyma. However, the reasons behind such isotopic signature remained elusive. Here we show that hypoxia causes heavy copper enrichment in several human cell lines. We also demonstrate that this effect of hypoxia is pH, HIF-1 and -2 independent. Our data identify a previously unrecognized cellular process associated with hypoxia, and suggests that in vivo tumour hypoxia determines copper isotope fractionation in HCC and other solid cancers.

A lead isotope perspective on urban development in ancient Naples.

The influence of a sophisticated water distribution system on urban development in Roman times is tested against the impact of Vesuvius volcanic activity, in particular the great eruption of AD 79, on all of the ancient cities of the Bay of Naples (Neapolis). Written accounts on urbanization outside of Rome are scarce and the archaeological record sketchy, especially during the tumultuous fifth and sixth centuries AD when Neapolis became the dominant city in the region. Here we show that isotopic ratios of lead measured on a well-dated sedimentary sequence from Neapolis' harbor covering the first six centuries CE have recorded how the AD 79 eruption was followed by a complete overhaul of Neapolis' water supply network. The Pb isotopic signatures of the sediments further reveal that the previously steady growth of Neapolis' water distribution system ceased during the collapse of the fifth century AD, although vital repairs to this critical infrastructure were still carried out in the aftermath of invasions and volcanic eruptions.

A Feedback Loop between Inflammation and Zn Uptake.

OBJECTIVE: Zinc (Zn) has major effects on the immune system and inflammation is associated with systemic Zn deficiency. The aim of this work was to investigate how inflammation modifies Zn metabolism at the cellular level. Rheumatoid arthritis (RA) synoviocytes exposed to cytokines were used as a model of chronic inflammation. Osteoarthritis (OA) synoviocytes were used as control. METHODS: Zn levels were measured in medium and inside cells by Induced Coupled Plasma-Mass Spectrometry (ICP-MS), in the presence of minute quantities of stable spike 70Zn isotope and the addition or not of the pro-inflammatory cytokines interleukin-17 (IL-17) and tumor necrosis factor alpha (TNF-α). Gene expression of ZIP-8 importer, ZnT1 exporter and the homeostasis regulators metallothioneins (MTs) was evaluated after pre-exposure to cytokines, with or without exogenous Zn addition at increasing concentrations. IL-6 production was used as a marker of inflammation and measured by ELISA. RESULTS: Exposure to IL-17 and TNF-α enhanced expression of the Zn-importer ZIP-8, regardless of the concentration of Zn in the culture medium. In contrast, the expression of the Zn-exporter ZnT1 and of the MTs was primarily dependent on Zn levels. Addition of Zn also increased the production of IL-6, thus further stimulating the inflammatory response. CONCLUSION: IL-17/TNF-mediated inflammation enhanced the intracellular Zn uptake by synoviocytes, further increasing inflammation. These observations document the existence of a feedback loop between inflammation and Zn uptake. Based on these results, a mathematical model was developed to represent the cytokine-mediated Zn homeostasis alterations.

Natural variations of copper and sulfur stable isotopes in blood of hepatocellular carcinoma patients.

The widespread hypoxic conditions of the tumor microenvironment can impair the metabolism of bioessential elements such as copper and sulfur, notably by changing their redox state and, as a consequence, their ability to bind specific molecules. Because competing redox state is known to drive isotopic fractionation, we have used here the stable isotope compositions of copper ((65)Cu/(63)Cu) and sulfur ((34)S/(32)S) in the blood of patients with hepatocellular carcinoma (HCC) as a tool to explore the cancer-driven copper and sulfur imbalances. We report that copper is (63)Cu-enriched by ∼0.4‰ and sulfur is (32)S-enriched by ∼1.5‰ in the blood of patients compared with that of control subjects. As expected, HCC patients have more copper in red blood cells and serum compared with control subjects. However, the isotopic signature of this blood extra copper burden is not in favor of a dietary origin but rather suggests a reallocation in the body of copper bound to cysteine-rich proteins such as metallothioneins. The magnitude of the sulfur isotope effect is similar in red blood cells and serum of HCC patients, implying that sulfur fractionation is systemic. The (32)S-enrichment of sulfur in the blood of HCC patients is compatible with the notion that sulfur partly originates from tumor-derived sulfides. The measurement of natural variations of stable isotope compositions, using techniques developed in the field of Earth sciences, can provide new means to detect and quantify cancer metabolic changes and provide insights into underlying mechanisms.

Copper isotope effect in serum of cancer patients. A pilot study.

The isotope effect describes mass-dependent variations of natural isotope abundances for a particular element. In this pilot study, we measured the (65)Cu/(63)Cu ratios in the serums of 20 breast and 8 colorectal cancer patients, which correspond to, respectively, 90 and 49 samples taken at different times with molecular biomarker documentation. Copper isotope compositions were determined by multiple-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). When compared with the literature data from a control group of 50 healthy blood donors, abundances of Cu isotopes predict mortality in the colorectal cancer group with a probability p = 0.018. For the breast cancer patients and the group of control women the probability goes down to p = 0.0006 and the AUC under the ROC curve is 0.75. Most patients considered in this preliminary study and with serum δ(65)Cu lower than the threshold value of -0.35‰ (per mil) did not survive. As a marker, a drop in δ(65)Cu precedes molecular biomarkers by several months. The observed decrease of δ(65)Cu in the serum of cancer patients is assigned to the extensive oxidative chelation of copper by cytosolic lactate. The potential of Cu isotope variability as a new diagnostic tool for breast and colorectal cancer seems strong. Shifts in Cu isotope compositions fingerprint cytosolic Cu chelation by lactate mono- and bidentates. This simple scheme provides a straightforward explanation for isotopically light Cu in the serum and isotopically heavy Cu in cancer cells: Cu(+) escaping chelation by lactate and excreted into the blood stream is isotopically light. Low δ(65)Cu values in serum therefore reveal the strength of lactate production by the Warburg effect.

Zinc and its role in immunity and inflammation.

Zinc (Zn) nutritional importance has been known for a long time, but in the last decades its importance in immune modulation has arisen. This review aims at describing the mechanisms involved in the regulation of Zn homeostasis and their effects on the immune response focusing on those which are implicated in the physiopathology of rheumatoid arthritis. Zn functions as a modulator of the immune response through its availability, which is tightly regulated by several transporters and regulators. When this mechanism is disturbed, Zn availability is reduced, altering survival, proliferation and differentiation of the cells of different organs and systems and, in particular, cells of the immune system. Zn deficiency affects cells involved in both innate and adaptive immunity at the survival, proliferation and maturation levels. These cells include monocytes, polymorphonuclear-, natural killer-, T-, and B-cells. T cell functions and the balance between the different T helper cell subsets are particularly susceptible to changes in Zn status. While acute Zn deficiency causes a decrease in innate and adaptive immunity, chronic deficiency increases inflammation. During chronic deficiency, the production of pro-inflammatory cytokines increases, influencing the outcome of a large number of inflammatory diseases, including rheumatoid arthritis.

Lead in ancient Rome's city waters.

It is now universally accepted that utilization of lead for domestic purposes and water distribution presents a major health hazard. The ancient Roman world was unaware of these risks. How far the gigantic network of lead pipes used in ancient Rome compromised public health in the city is unknown. Lead isotopes in sediments from the harbor of Imperial Rome register the presence of a strong anthropogenic component during the beginning of the Common Era and the Early Middle Ages. They demonstrate that the lead pipes of the water distribution system increased Pb contents in drinking water of the capital city by up to two orders of magnitude over the natural background. The Pb isotope record shows that the discontinuities in the pollution of the Tiber by lead are intimately entwined with the major issues affecting Late Antique Rome and its water distribution system.

Contrasting Cu, Fe, and Zn isotopic patterns in organs and body fluids of mice and sheep, with emphasis on cellular fractionation.

We report Cu, Fe, and Zn natural isotope compositions in organs, body fluids, diets and feces of mice and sheep. Large and systematic isotope variability is observed, notably in the δ(66)Zn in liver and δ(65)Cu in kidneys, but significant differences exist between mice, sheep and humans, especially in the δ(66)Zn value of blood. The results are interpreted with reference to current knowledge of metal trafficking and redox conditions in cells. In general, the light isotopes preferentially fractionate into 'softer' bonds involving sulfur such as cysteine and glutathione, whereas heavy isotopes fractionate into 'harder' bonds involving nitrogen (histidine) and even more oxygen, notably hydroxides, phosphates, and carbonates. Bonds involving the reduced forms Cu(+) and Fe(2+) are enriched in the light isotopes relative to bonds involving the oxidized Cu(2+) and Fe(3+) forms. Differences in blood Zn isotope abundances between mice, sheep and humans may reflect a different prevalence of Zn ZIP transporters. The isotopically heavy Cu in the kidneys may reflect isotope fractionation during redox processes and may be relevant to ascorbate degradation into oxalate.

Is aging recorded in blood Cu and Zn isotope compositions?

Recent isotopic observations of animal samples indicate body accumulation of heavy zinc and light copper throughout life. This hypothesis has never been tested for humans, but the existence of a relationship between blood isotopic composition and age could be promising for age assessment methodologies. Dietary habits can also influence the blood zinc isotope composition, being an additional source of isotopic variation. In order to reduce this putative source of variation, we selected a population living in an isolated area (Sakha Republic, Russia) where diverse foods are of limited availability. We sampled blood from 8 male and 31 female Yakut volunteers between the ages of 18 and 74. Zinc, iron and copper were purified by liquid chromatography on ion exchange resin and their stable isotope ratios were measured using multiple-collector inductively coupled plasma mass spectrometry. According to observations of animal samples, the (66)Zn/(64)Zn ratio increases with age. We also observe that the (65)Cu/(63)Cu ratio decreases with age, whereas iron isotopic compositions are unrelated to age. The copper and zinc isotope compositions of the Yakut's blood are significantly lighter and heavier, respectively, than in samples of European and Japanese populations. The Yakut is a circumpolar population in which individuals have an elevated basal metabolic rate in response to cold stress. This elevated basal metabolic rate could enhance copper and zinc isotopic fractionation by accelerating the turnover of the copper and zinc stores.