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In the last 20 years, the application of high-precision isotopic analysis of essential mineral elements (Mg, K, Ca, Fe, Cu, and Zn) to biomedicine (sometimes referred to as isotope metallomics) has revealed that their stable isotopic compositions are altered by the metal dysregulation that is fundamental to the pathogenesis of many cancers and other diseases. Despite many published works showing the diagnostic and prognostic potential of this approach, a number of factors that may influence the stable isotopic composition of these essential mineral elements in healthy individuals remain unstudied. In this perspective article, we summarize the available evidence from trophic level studies, animal models, and ancient and modern humans, relating to physiological and lifestyle factors that appear likely (there is evidence indicating their influence) or unlikely (there is evidence indicating their lack of influence) to require controlling for when investigating variations in essential mineral element isotopic compositions in human subjects. We also discuss factors that require additional data to properly assess. There is evidence that sex, menopausal status, age, diet, vitamin and metal supplementation, genetic variation, and obesity influence the isotopic composition of at least one essential mineral element in the human body. The task of investigating potential influences on essential mineral element isotopic compositions in the human body is sizeable, but presents an exciting research opportunity, with each incremental advance helping to improve the quality of research output in the context of isotope metallomics., (© The Author(s) 2023. Published by Oxford University Press.)

As a component of many minerals and an essential trace element in most aerobic organisms, the transition metal element Cu is important for studying reduction-oxidation (redox) interactions and metal cycling in the total environment (lithosphere, atmosphere, biosphere, hydrosphere, and anthroposphere). The "fractionation" or relative partitioning of the naturally occurring "heavy" ( 65 Cu) and "light" ( 63 Cu) isotope between two coexisting phases in a system occurs according to bonding environment and/or as a result of a slight difference in the rate at which these isotopes take part in physical processes and chemical reactions (in absence of equilibrium). Due to this behaviour, Cu isotopic analysis can be used to study a range of geochemical and biological processes that cannot be elucidated with Cu concentrations alone. The shift between Cu + and Cu 2+ is accompanied by a large degree of Cu isotope fractionation, enabling the Cu isotope to be applied as a vector in mineral exploration, tracer of origin, transport, and fate of metal contaminants in the environment, biomonitor, and diagnostic/prognostic marker of disease, among other applications. In this contribution, we (1) discuss the analytical protocols that are currently available to perform Cu isotopic analysis, (2) provide a compilation of published δ 65 Cu values for matrix reference materials, (3) review Cu isotope fractionation mechanisms, (4) highlight emerging applications of Cu isotopic analysis, and (5) discuss future research avenues., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Due to the straightforward and non-invasive sampling, ease of transport and long-term storage and access to time-resolved information, determination of element concentrations and isotope ratios in hair and nails finds increasing use. Multi-isotopic information preserved in keratinous tissues allows one to reveal dietary, physiological and environmental influences, but progress in this area is still limited by complicated and time-consuming analytical procedures and challenges in accuracy assessment. In this study, longitudinal distributions of δ 34 S, 87 Sr/ 86 Sr, 207,208 Pb/ 206 Pb, δ 66 Zn, δ 56 Fe, δ 65 Cu, δ 26 Mg, and δ 114 Cd were obtained for hair and nails collected from nine subjects with different age, biological sex, diet and/or place of residence. For S and Zn, the distribution along hair strands revealed a trend towards a heavier isotopic signature from the proximal to the distal end, with a maximum difference within the hair of a single subject of 1.2‰ (Δ 34 S) and 0.4‰ (Δ 66 Zn). For Fe, Cu, Mg and Cd, a shift towards either a lighter (Cu) or heavier (Fe, Mg and Cd) isotopic composition is accompanied by increasing concentration towards the distal hair end, indicating possible isotope fractionation during deposition or external contamination with a different isotopic composition. Pb and Sr isotope ratios are relatively stable throughout the hair strands despite notable concentration increases towards the distal end, likely reflecting external contamination. The isotopic composition of Sr points to tap water as a probable main source, explaining the relative stability of the ratio for individuals from the same geographical location. For Pb, isotopic compositions suggest tap water and/or indoor dust as possible sources. Similar δ 34 S, 87 Sr/ 86 Sr, 207,208 Pb/ 206 Pb, δ 66 Zn, δ 56 Fe, and δ 65 Cu observed for hair, fingernails and toenails sampled from the same individual suggest that keratinous tissues are conservative receivers of internal and external inputs and can be used complementary. Seasonal variation in δ 34 S, 207,208 Pb/ 206 Pb, and δ 65 Cu was observed for fingernails., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A sequential chromatographic separation procedure for subsequent high-precision isotopic analysis of Mg and Ca via multi-collector ICP-mass spectrometry (MC-ICP-MS) from a single aliquot of sample was developed and used for a variety of animal/human biofluids and tissues. The procedure consists of a one-stage Mg isolation protocol (for most of the sample types) and a three-stage isolation protocol for Ca. AG50W-X8 strong cation exchange resin was used for the isolation of Mg and Ca, while Sr-resin was used to additionally purify the Ca fraction from Sr. Potential effects on the Mg isotope ratio measurement results caused by the possible presence of concomitant matrix elements (Cu, Fe, Zn, Ca) were systematically evaluated. δ 26 Mg values were biased for a Fe/Mg ratio > 0.13 and a Ca/Mg ratio > 1.5, resulting in a shift towards a lighter Mg isotopic composition. It was shown that the Mg isotope ratio data for Mg standards, the isotopic reference materials ERM-AE143 and IRMM 009 and the biological samples investigated are located on a mass-dependent fractionation line. Biological reference materials and commercially available serum samples were analyzed for both their Mg and Ca isotope ratios. For some of the biomaterials analyzed, the Ca isotope ratio data as obtained using MC-ICP-MS were further validated via their determination using double-spike thermal ionization mass spectrometry (DS-TIMS). The expanded uncertainty for δ 26 Mg was ≤ 0.12‰ and for δ 44 Ca ≤ 0.29‰. Biological fluids and tissues of mice were analyzed to characterize the body distribution of the stable isotopes of Mg and Ca. The isotopic variability among the body compartments was about 1.5‰ for Mg and 1.0‰ for Ca. Among the tissues explored, muscle tissue shows the lightest Mg and Ca isotopic compositions and liver the heaviest Mg and Ca isotopic compositions, respectively./42 Ca ≤ 0.29‰. Biological fluids and tissues of mice were analyzed to characterize the body distribution of the stable isotopes of Mg and Ca. The isotopic variability among the body compartments was about 1.5‰ for Mg and 1.0‰ for Ca. Among the tissues explored, muscle tissue shows the lightest Mg and Ca isotopic compositions and liver the heaviest Mg and Ca isotopic compositions, respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: The occurrence of non-alcoholic fatty liver disease (NAFLD) is globally increasing. To challenge the current incidence of NAFLD, non-invasive markers that could identify patients at risk or monitor disease progression are an important need. Copper intake and organ copper concentrations have earlier been linked to NAFLD progression, but serum copper does not adequately represent the disease state. Cu atoms occur under the form of two stable isotopes, 63 Cu and 65 Cu, and the ratio of both (expressed as δ 65 Cu, in  ‰) in blood serum has been shown to be altered in chronic liver disease. To assess whether the Cu isotope ratio might predict disease occurrence and progression of NAFLD, the serum Cu isotopic composition of patients with different stages of NAFLD was determined., Results: Our results showed that serum δ 65 Cu values were lower in NAFLD patients, already at the level of simple steatosis, and remained stable during further disease progression. ROC analysis shows an almost perfect diagnostic ability of serum δ 65 Cu values for NAFLD, but no discrimination between different severity degrees could be made. Therefore, the serum Cu isotopic composition might show potential for early diagnosis of NAFLD patients.

Cu isotope fractionation was investigated in the human neuroblastoma SH-SY5Y cell line, in a proliferating/tumor phase (undifferentiated cells), and in a differentiated state (neuron-like cells), induced using retinoic acid (RA). The SH-SY5Y cell line displays genetic aberrations due to its cancerous origin, but differentiation drives the cell line towards phenotypes suitable for the research of neurological diseases (e.g., Alzheimer's disease or Parkinson's disease). Cellular Cu distribution was first explored by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging and, subsequently, Cu isotopic analysis was performed at cellular and sub-cellular levels via multi-collector inductively coupled plasma-mass spectrometry (MC-ICP-MS). The SH-SY5Y cells showed a re-distribution of intracellular Cu upon RA differentiation. Both undifferentiated and differentiated cells became systematically enriched in the light 63 Cu isotope with increasing intracellular Cu content. Differentiated neuron-like SH-SY5Y cells showed a heavier Cu isotopic composition (+ 0.3‰) than did the undifferentiated proliferating cells when exposed to Cu for 24 h. However, after a longer exposure time (72 h), no difference was observed between both cellular phenotypes. Mitochondrial fractions were enriched in the light 63 Cu isotope, compared to whole cells, for both undifferentiated and differentiated cells (no significant difference). The Cu isotopic composition of the remaining cell lysates was heavier than that of the whole cells and + 0.2‰ heavier in the differentiated cells than in the undifferentiated cells. These results indicate that neuronal differentiation affects the Cu isotope fractionation accompanying Cu uptake in the cells, but this effect does not seem to be associated with the mitochondrial Cu pathway. Cu isotope fractionation can be an interesting tool for studying Cu metabolism at a (sub)-cellular level in functional neurons. Graphical abstract.

Elemental and isotopic analysis via single-collector and multi-collector ICP-mass spectrometry, respectively, have been explored as a tool for identifying potential differences between non-tumor and oral squamous cell carcinoma tissues. Elemental concentrations of major and minor elements, known to be essential for different processes in the cell (i.e. Na, Ca, Mg, K, P, Fe, Cu and Zn), have been determined and results for cancerous and non-cancerous tissues collected from the same individual have been compared. Among the elements studied, only Mg, K and P turned out to be significantly higher in concentration in the tumor tissues. However, a shift towards higher and wider concentration ranges has also been observed for Cu and Zn in the tumor samples, whereas for Ca lower concentrations were established. Possible isotope ratio variations for Cu and Zn in both biological tissues have also been evaluated with the same goal. δ 66 Zn results did not provide an obvious trend, but in the case of Cu, a clear distinction between the tumor and non-tumor tissues was observed: δ 65 Cu values ranged between -0.68% and 0.03% in the non-tumor tissues, whereas tumor samples turned out to be enriched in 65 Cu, with δ 65 Cu values between 0.10% and 0.93%. These results confirm the considerable potential of isotopic and elemental studies for biomedical purposes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

End-stage liver disease (ESLD) is life-threatening and liver transplantation (LTx) is the definitive treatment with good outcomes. Given the essential role of hepatocytes in Cu homeostasis, the potential of the serum Cu isotopic composition for monitoring a patient's condition post-LTx was evaluated. For this purpose, high-precision Cu isotopic analysis of blood serum of ESLD patients pre- and post-LTx was accomplished via multi-collector ICP-mass spectrometry (MC-ICP-MS). The Cu isotopic composition of the ESLD patients was fractionated in favour of the lighter isotope (by about -0.50‰). Post-LTx, a generalized normalization of the Cu isotopic composition was observed for the patients with normal liver function, while it remained light when this condition was not reached. A strong decrease in the δ(65)Cu value a longer term post-LTx seems to indicate the recurrence of liver failure or cancer. The observed trend in favour of the heavier Cu isotopic composition post-LTx seems to be related with the restored biosynthetic capacity of the liver, the restored hepatic metabolism and/or the restored biliary secretion pathways. Thus, Cu isotopic analysis could be a valuable tool for the follow-up of liver transplant patients and for establishing the potential recurrence of liver failure.

Mercury (Hg) isotopic analysis via multi-collector inductively coupled plasma (ICP)-mass spectrometry (MC-ICP-MS) can provide relevant biogeochemical information by revealing sources, pathways, and sinks of this highly toxic metal. In this work, the capabilities and limitations of two different sample introduction systems, based on pneumatic nebulization (PN) and cold vapor generation (CVG), respectively, were evaluated in the context of Hg isotopic analysis via MC-ICP-MS. The effect of (i) instrument settings and acquisition parameters, (ii) concentration of analyte element (Hg), and internal standard (Tl)-used for mass discrimination correction purposes-and (iii) different mass bias correction approaches on the accuracy and precision of Hg isotope ratio results was evaluated. The extent and stability of mass bias were assessed in a long-term study (18 months, n = 250), demonstrating a precision ≤0.006% relative standard deviation (RSD). CVG-MC-ICP-MS showed an approximately 20-fold enhancement in Hg signal intensity compared with PN-MC-ICP-MS. For CVG-MC-ICP-MS, the mass bias induced by instrumental mass discrimination was accurately corrected for by using either external correction in a sample-standard bracketing approach (SSB) or double correction, consisting of the use of Tl as internal standard in a revised version of the Russell law (Baxter approach), followed by SSB. Concomitant matrix elements did not affect CVG-ICP-MS results. Neither with PN, nor with CVG, any evidence for mass-independent discrimination effects in the instrument was observed within the experimental precision obtained. CVG-MC-ICP-MS was finally used for Hg isotopic analysis of reference materials (RMs) of relevant environmental origin. The isotopic composition of Hg in RMs of marine biological origin testified of mass-independent fractionation that affected the odd-numbered Hg isotopes. While older RMs were used for validation purposes, novel Hg isotopic data are provided for the latest generations of some biological RMs.

In this work, a novel approach to measure isotope ratios via multi-collector-inductively coupled plasma-mass spectrometry (MC-ICP-MS) for low amounts of target element is proposed. The methodology is based on mixing of the sample (target element isolate) with a non-enriched in-house standard, previously characterized for its isotopic composition. This methodology has been applied to isotopic analysis of Cu and of Fe in whole blood samples. For this purpose, different mixtures of sample + in-house standard were prepared and adjusted to a final concentration of 500 μg/L of the target elements for isotopic analysis. δ(65)Cu, δ(56)Fe, and δ(57)Fe varied linearly as a function of the amount of in-house standard (or of sample) present in the mixture. The isotopic composition of the sample was calculated considering the isotope ratios measured for (i) the mixture and (ii) the in-house standard and (iii) the relative concentrations of target element contributed by the sample and the standard to the mixture, respectively. For validation purposes, the isotopic analysis of whole blood Cu was carried out using both the conventional (using 2 mL of whole blood) and the newly developed approach (using 500 μL of whole blood). The δ(65)Cu values obtained using mixtures containing 40 % (200 μg/L) of Cu from the blood samples and 60 % (300 μg/L) of Cu from the in-house standard were in good agreement with the δ(65)Cu value obtained using the conventional approach (bias ≤0.15 ‰).

The provenancing of Roman natron glass is one of the most challenging problems in the field of archaeometry. Although the use of Sr and Nd isotope ratios and trace element signatures as an indication of provenance has proven promising, there are still many unknowns. In this study, the influence of the different raw materials on the final Sr isotopic composition of Roman natron glass is examined. It is shown that the 87Sr/86Sr ratio in natron glass is significantly influenced by the silicate fraction of the sand used and does not always provide a clear indication of the lime source used. [ABSTRACT FROM AUTHOR]

In this study analysis of major elements and Sr--Nd isotopes is performed on 33 colourless glass fragments from two Ro- man shipwrecks discovered in the Northern Mediterranean Sea, the Iulia Felix (irst half of the third century AD) and the Ouest-Embiez (end of the second--beginning of the third century AD). Two compositional groups are deined based upon the major elements analysis, suggesting the use of diferent raw materials, and possibly the production of the glass samples in two separate factories. Sr--Nd isotopes, promising indicators for provenancing geological resources used as raw materials 87 86 in glass manufacturing, conirm the compositional groups. The Sr/ Sr signature is very close to the modern sea water signature (0·7092) for all samples, likely due to the use of shell as glass raw material. The Nd signature further subdivides the compositional groups, suggesting the use of three diferent sand raw materials for the production of glass. [ABSTRACT FROM AUTHOR]

This article overviews recent developments in the use of multicollector inductively coupled plasma mass spectrometry (MC-ICPMS) in studies of mass-independent isotope chemistry of heavy elements. Origins of mass-independent isotope effects and their relevance to isotope ratio measurements by MC-ICPMS are briefly described. The extent to which these effects can affect instrumental mass bias in MC-ICPMS is critically discussed on the basis of the experimental observations. Furthermore, key findings reported in studies of mass-independent isotope fractionation (MIF) of mercury in the field of environmental sciences are reviewed. MIF of heavy elements is not only of interest from a fundamental point of view, but also provides scientists with a new and effective means of studying the biogeochemistry of these elements. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: Since considerable time, isotopic analysis of different elements present in a sample, material or object (such as the ‘light’ elements H, C, N, O and S and ‘heavy’ elements, such as Sr and Pb), has been used in provenancing studies, as several factors — defined by “the environment” or origin of the sample — can lead to measurable differences in their isotopic composition. For the light elements, traditionally, (gas source) isotope ratio mass spectrometry (IR-MS) is used, while for a long period of time, thermal ionization mass spectrometry (TIMS) was considered as the only technique capable of detecting subtle variations in the isotopic composition of the ‘heavier’ elements. However, since the introduction of the first inductively coupled plasma mass spectrometers (ICP-MS), considerable attention has been devoted to the development of methodologies and strategies to perform isotopic analysis by means of ICP-MS. While the relatively modest isotope ratio precision offered by single-collector ICP-MS may already be fit-for-purpose under some circumstances, especially the introduction of multi-collector ICP-MS instruments, equipped with an array of Faraday detectors instead of a single electron multiplier, has lead to tremendous improvements in the field of isotopic analysis. As a result, MC-ICP-MS can be seen as a very strong competitor of TIMS nowadays, while it even provides information on the small isotopic variations shown by some elements, that are not or hardly accessible by means of TIMS (e.g., elements with a high ionization energy). Owing to these new instrumental developments, the application field of isotopic analysis by means of ICP-MS is continuously growing, also in the field of provenance determination. This paper is intended as a review of the developments in and the recent applications of isotopic analysis by means of ICP-MS in this specific research field. [ABSTRACT FROM AUTHOR]

In the northeastern part of France, around the city of Metz, lichens (Hypogymnia physodes) have been transplanted from a single reference site to five different sites: (i) the reference site itself, (ii and iii) two pen-urban sites, (iv) a site in the proximity of a highway, and (v) a final one close to an industrial site. The dynamics of two different system set-ups (one covered and one uncovered) were evaluated. Samples have been collected 14,34, and 68 days after transplantation. Lead concentrations already accumulated in the thallus, and the corresponding Pb isotopic compositions have been measured by quadrupole-based ICP-mass spectrometry. A systematic difference between the two setups is found for Pb concentrations, with the higher concentrations measured in lichens from the uncovered devices. Lead concentrations in lichens from the covered devices were found to be lower than or equal to the original concentration. Also the Pb isotopic compositions show a systematic difference between the devices, with the Pb isotopic composition present in lichens from the uncovered device being more radiogenic. Substantial changes in the isotopic composition of Pb are recorded for lichens from the uncovered device (from about 1.15 up to 1.22 for the 206Pb/207Pb ratio), in some cases already after only 34 days of exposure. The increases in the Pb concentration and the 206Pb/207Pb ratio and the differences between the devices are explained by hypothesizing that (i) different Pb sources give rise to a different size distribution of aerosol particles and (ii) in the lichens present in the covered setup, a part of the aerosol particles cannot be incorporated. Also the influence of the source of the aerosols to lichens after transplantation is evaluated and the potential influence of biological reactions is discussed. [ABSTRACT FROM AUTHOR]