Toenail zinc and risk of prostate cancer in the MCC-Spain case-control study.

BACKGROUND: Some researchers have suggested that zinc (Zn) could reduce the risk of prostate cancer (PC). However, research from observational studies on the relationship between PC risk and biomarkers of Zn exposure shows conflicting results. OBJECTIVES: To evaluate the association between toenail Zn and PC, considering tumour extension and aggressiveness, along with a gene-environment approach, exploring the interaction of individual genetic susceptibility to PC in the relationship between toenail Zn and PC. METHODS: In MCC-Spain study we invited all incident PC cases diagnosed in the study period (2008-2013) and recruited randomly selected general population controls. In this report we included 913 cases and 1198 controls with toenail Zn determined by inductively coupled plasma mass spectrometry. To measure individual genetic susceptibility, we constructed a polygenic risk score based on known PC-related single nucleotide polymorphisms. The association between toenail Zn and PC was explored with mixed logistic and multinomial regression models. RESULTS: Men with higher toenail Zn had higher risk of PC (OR quartile 4 vs.1: 1.41; 95% CI: 1.07-1.85). This association was slightly higher in high-grade PC [(ISUP≤2 Relative risk ratio (RRR) quartile 4 vs.1: 1.36; 1.01-1.83) vs. (ISUP3-5 RRR quartile 4 vs.1: 1.64; 1.06-2.54)] and in advanced tumours [(cT1-cT2a RRR quartile 4 vs.1: 1.40; 95% CI: 1.05-1.89) vs. (cT2b-cT4 RRR quartile 4 vs.1: 1.59; 1.00-2.53)]. Men with lower genetic susceptibility to PC were those at higher risk of PC associated with high toenail Zn (OR quartile 4 vs.1: 2.18; 95% CI: 1.08-4.40). DISCUSSION: High toenail Zn levels were related to a higher risk for PC, especially for more aggressive or advanced tumours. This effect was stronger among men with a lower genetic susceptibility to PC.

Untargeted Metabolomic Study of Lung Cancer Patients after Surgery with Curative Intent.

Lung cancer (LC) is a leading cause of mortality, claiming more than 1.8 million deaths per year worldwide. Surgery is one of the most effective treatments when the disease is in its early stages. The study of metabolic alterations after surgical intervention with curative intent could be used to assess the response to treatment or the detection of cancer recurrence. In this study, we have evaluated the metabolomic profile of serum samples (n = 110) from preoperative (PRE) and postoperative (POST) LC patients collected at two different time points (1 month, A; 3-6 months, B) with respect to healthy people. An untargeted metabolomic platform based on reversed phase (RP) and hydrophilic interaction chromatography (HILIC), using ultra-high performance liquid chromatography (UHPLC) and mass spectrometry (MS), was applied (MassIVE ID MSV000092213). Twenty-two altered metabolites were annotated by comparing all the different studied groups. DG(14,0/22:1), stearamide, proline, and E,e-carotene-3,3'-dione were found altered in PRE, and their levels returned to those of a baseline control group 3-6 months after surgery. Furthermore, 3-galactosyllactose levels remained altered after intervention in some patients. This study provides unique insights into the metabolic profiles of LC patients after surgery at two different time points by combining complementary analytical methods.

Metallomic Signatures of Lung Cancer and Chronic Obstructive Pulmonary Disease.

Lung cancer (LC) is the leading cause of cancer deaths, and chronic obstructive pulmonary disease (COPD) can increase LC risk. Metallomics may provide insights into both of these tobacco-related diseases and their shared etiology. We conducted an observational study of 191 human serum samples, including those of healthy controls, LC patients, COPD patients, and patients with both COPD and LC. We found 18 elements (V, Al, As, Mn, Co, Cu, Zn, Cd, Se, W, Mo, Sb, Pb, Tl, Cr, Mg, Ni, and U) in these samples. In addition, we evaluated the elemental profiles of COPD cases of varying severity. The ratios and associations between the elements were also studied as possible signatures of the diseases. COPD severity and LC have a significant impact on the elemental composition of human serum. The severity of COPD was found to reduce the serum concentrations of As, Cd, and Tl and increased the serum concentrations of Mn and Sb compared with healthy control samples, while LC was found to increase Al, As, Mn, and Pb concentrations. This study provides new insights into the effects of LC and COPD on the human serum elemental profile that will pave the way for the potential use of elements as biomarkers for diagnosis and prognosis. It also sheds light on the potential link between the two diseases, i.e., the evolution of COPD to LC.

Single and joint effects of cadmium and selenium on bioaccumulation, oxidative stress and metabolomic responses in the clam Scrobicularia plana.

Selenium (Se) is a vital trace element for many living organisms inclusive of aquatic species. Although the antagonistic action of this element against other pollutants has been previously described for mammals and birds, limited information on the join effects in bivalves is available. To this end, bivalves of the species Scrobicularia plana were exposed to Se and Cd individually and jointly. Digestive glands were analysed to determine dose-dependent effects, the potential influence of Se on Cd bioaccumulationas well as the possible recover of the oxidative stress and metabolic alterations induced by Cd. Selenium co-exposure decreased the accumulation of Cd at low concentrations. Cd exposure significantly altered the metabolome of clams such as aminoacyltRNA biosynthesis, glycerophospholipid and amino acid metabolism, while Se co-exposure ameliorated several altered metabolites such asLysoPC (14:0), LysoPE (20:4), LysoPE (22:6), PE (14:0/18:0), PE (20:3/18:4) andpropionyl-l-carnitine.Additionally, Se seems to be able to regulate the redox status of the digestive gland of clams preventing the induction of oxidativedamage in this organ. This study shows the potential Se antagonism against Cd toxicity in S. plana and the importance to study join effects of pollutants to understand the mechanism underlined the effects.

Toenail zinc as a biomarker: Relationship with sources of environmental exposure and with genetic variability in MCC-Spain study.

BACKGROUND: Toenails are commonly used as biomarkers of exposure to zinc (Zn), but there is scarce information about their relationship with sources of exposure to Zn. OBJECTIVES: To investigate the main determinants of toenail Zn, including selected sources of environmental exposure to Zn and individual genetic variability in Zn metabolism. METHODS: We determined toenail Zn by inductively coupled plasma mass spectrometry in 3,448 general population controls from the MultiCase-Control study MCC-Spain. We assessed dietary and supplement Zn intake using food frequency questionnaires, residential proximity to Zn-emitting industries and residential topsoil Zn levels through interpolation methods. We constructed a polygenic score of genetic variability based on 81 single nucleotide polymorphisms in genes involved in Zn metabolism. Geometric mean ratios of toenail Zn across categories of each determinant were estimated from multivariate linear regression models on log-transformed toenail Zn. RESULTS: Geometric mean toenail Zn was 104.1 µg/g in men and 100.3 µg/g in women. Geometric mean toenail Zn levels were 7 % lower (95 % confidence interval 1-13 %) in men older than 69 years and those in the upper tertile of fibre intake, and 9 % higher (3-16 %) in smoking men. Women residing within 3 km from Zn-emitting industries had 4 % higher geometric mean toenail Zn levels (0-9 %). Dietary Zn intake and polygenic score were unrelated to toenail Zn. Overall, the available determinants only explained 9.3 % of toenail Zn variability in men and 4.8 % in women. DISCUSSION: Sociodemographic factors, lifestyle, diet, and environmental exposure explained little of the individual variability of toenail Zn in the study population. The available genetic variants related to Zn metabolism were not associated with toenail Zn.

Levels and determinants of urinary cadmium in general population in Spain: Metal-MCC-Spain study.

BACKGROUND: Cadmium is a ubiquitous and persistent metal, associated with different harmful health effects and with increased morbidity and mortality. Understanding the main sources of exposure is essential to identify at risk populations and to design public health interventions. OBJECTIVE: To evaluate cadmium exposure in a random-sample of general adult population from three regions of Spain, assessed by the urinary cadmium (U-Cd) concentration, and to identify its potential determinants and sex-specific differences, including sociodemographic, lifestyle and dietary factors. MATERIALS AND METHODS: We measured U-Cd (µg/g creatinine) in single urine spot samples from 1282 controls enrolled in the multicase-control study in common tumors in Spain (MCC-Spain) with inductively coupling plasma-mass spectrometry equipped with an octopole reaction systems (ICP-ORS-MS). The association between sociodemographic, lifestyle, and dietary characteristics and U-Cd concentrations was evaluated using geometric mean ratios (GMR) estimated by multiple log-linear regression models. RESULTS: Overall, geometric mean U-Cd concentration was 0.40 (95%CI: 0.38, 0.41) µg/g creatinine. Levels were higher in women than in men (GMR]: 1.19; 95%CI: 1.07, 1.32), and increased with age in males (ptrend< 0.001). Cigarette smoking was clearly associated to U-Cd levels (GMRformer vs non-smokers: 1.16; 95%CI: 1.05, 1.29; GMRcurrent vs non-smokers: 1.42; 95%CI: 1.26, 1.60); the relationship with secondhand tobacco exposure in non-smokers, was restricted to women (pinteraction = 0.02). Sampling season and region also seemed to influence U-Cd concentrations, with lower levels in summer (GMRsummer vs average: 0.79; 95%CI: 0.71, 0.88), and higher levels in North-Spain Asturias (GMRAsturias vs average: 1.13; 95%CI: 1.04, 1.23). Regarding diet, higher U-Cd concentration was associated with eggs consumption only in men (pinteraction = 0.04), just as rice intake was associated in women (pinteraction = 0.03). CONCLUSION: These results confirmed that tobacco exposure is the main modifiable predictor of U-Cd concentrations, and remark that the role of dietary/sociodemographic factors on U-Cd levels may differ by sex.

Untargeted Gut Metabolomics to Delve the Interplay between Selenium Supplementation and Gut Microbiota.

Selenium (Se) is an essential trace element with important health roles due to the antioxidant properties of selenoproteins. To analyze the interplay between Se and gut microbiota, gut metabolomic profiles were determined in conventional (C) and microbiota depleted mice (Abx) after Se-supplementation (Abx-Se) by untargeted metabolomics, using an analytical multiplatform based on GC-MS and UHPLC-QTOF-MS (MassIVE ID MSV000087829). Gut microbiota profiling was performed by 16S rRNA gene amplicon sequencing. Significant differences in the levels of about 70% of the gut metabolites determined, including fatty acyls, glycerolipids, glycerophospholipids, and steroids, were found in Abx-Se compared to Abx, and only 30% were different between Abx-Se and C, suggesting an important effect of Se-supplementation on Abx mice metabolism. At genus level, the correlation analysis showed strong associations between metabolites and gut bacterial profiles. Likewise, higher abundance of Lactobacillus spp., a potentially beneficial genus enriched after Se-supplementation, was associated with higher levels of prenol lipids, phosphatidylglycerols (C-Se), steroids and diterpenoids (Abx-Se), and also with lower levels of fatty acids (Abx-Se). Thus, we observed a crucial interaction between Se intake-microbiota-metabolites, although further studies to clarify the specific mechanisms are needed. This is the first study about untargeted gut metabolomics after microbiota depletion and Se-supplementation.

Environmental metal toxicity assessment by the combined application of metallomics and metabolomics.

The growing interest of our society for the environment, climate change, and the assurance of the quality of life and health has been the motor of new methodological proposals that allow a more comprehensive knowledge of the problems to be solved. In this sense, the potential of omic methodologies to study these problems from a global perspective represents a milestone in environmental studies. Therefore, the study of essential and toxic metals has a special interest, particularly in relation to toxicity issues and their association to biological interactions, transport, binding to biomolecules, and behavior in biological interfaces. These studies have promoted new instrumental platforms and methodological approaches that allow addressing these problems. Furthermore, to encompass the reality of molecule-atoms interactions in their completeness, combinations of omics have been tried, focusing on environment, food, and health issues. In this sense, the present work is situated, with the objective of reviewing the most recent methodological proposals in the field of the environment and their applications, considering not only the analytical approaches but also how they have to be applied, the use of bioindicators' exposure experiments in the laboratory, and the potential transfer of the findings from the laboratory to the field. This latter point is a true touchstone, which makes these new analytical methodologies in the necessary tools for understanding the environment and the consequences of its imbalance.

Toxic metals in toenails as biomarkers of exposure: A review.

Toenails have been used as biomarkers of exposure to toxic metals, but their validity for this purpose is not yet clear and might differ depending on the specific agent. To evaluate this issue, we reviewed the literature on: a) the time-window of exposure reflected by toenails; b) the reproducibility of toenail toxic-metal levels in repeated measures over time; c) their relationship with other biomarkers of exposure, and; d) their association with potential determinants (i.e. sociodemographic, anthropometric, or lifestyle characteristics) or with sources of exposure like diet or environmental pollution. Thus, we performed a systematic review, searching for articles that provided original data for levels of any of the following toxic metals in toenails: aluminum, beryllium, cadmium, chromium, mercury, nickel, lead, thallium and uranium. We identified 88 articles, reporting data from 67 different research projects, which were quite heterogeneous with regard to population profile, sample size and analytical technique. The most commonly studied metal was mercury. Concerning the time-window of exposure explored by toenails, some reports indicate that toenail cadmium, nickel and lead may reflect exposures that occurred 7-12 months before sampling. For repeated samples obtained 1-6 years apart, the range of intraindividual correlation coefficients of aluminum, chromium and mercury was 0.33-0.56. The correlation of toxic metal concentrations between toenails and other matrices was higher for hair and fingernails than for urine or blood. Mercury levels were consistently associated with fish intake, while other toxic metals were occasionally associated with specific sources (e.g. drinking water, place of residence, environmental pollution, and occupation). The most frequently evaluated health endpoints were cardiovascular diseases, cancer, and central nervous system diseases. Available data suggest that toenail mercury levels reflected long-term exposures and showed positive associations with fish intake. The lack of standardization in sample collection, quality control, analytical techniques and procedures - along with the heterogeneity and conflicting results among studies - mean it is still difficult to conclude that toenails are a good biomarker of exposure to toxic metals. Further studies are needed to draw solid conclusions about the suitability of toenails as biomarkers of exposure to toxic metals.

Advances in lung cancer biomarkers: The role of (metal-) metabolites and selenoproteins.

Lung cancer (LC) is the second most common cause of death in men after prostate cancer, and the third most recurrent type of tumor in women after breast and colon cancers. Unfortunately, when LC symptoms begin to appear, the disease is already in an advanced stage and the survival rate only reaches 2%. Thus, there is an urgent need for early diagnosis of LC using specific biomarkers, as well as effective therapies and strategies against LC. On the other hand, the influence of metals on more than 50% of proteins is responsible for their catalytic properties or structure, and their presence in molecules is determined in many cases by the genome. Research has shown that redox metal dysregulation could be the basis for the onset and progression of LC disease. Moreover, metals can interact between them through antagonistic, synergistic and competitive mechanisms, and for this reason metals ratios and correlations in LC should be explored. One of the most studied antagonists against the toxic action of metals is selenium, which plays key roles in medicine, especially related to selenoproteins. The study of potential biomarkers able to diagnose the disease in early stage is conditioned by the development of new analytical methodologies. In this sense, omic methodologies like metallomics, proteomics and metabolomics can greatly assist in the discovery of biomarkers for LC early diagnosis.

Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice.

BACKGROUND: The apolipoprotein E (APOE) gene exists in three isoforms in humans: APOE2, APOE3 and APOE4. APOE4 causes structural and functional alterations in normal brains, and is the strongest genetic risk factor of the sporadic form of Alzheimer's disease (LOAD). Research on APOE4 has mainly focused on the neuronal damage caused by defective cholesterol transport and exacerbated amyloid-ß and Tau pathology. The impact of APOE4 on non-neuronal cell functions has been overlooked. Astrocytes, the main producers of ApoE in the healthy brain, are building blocks of neural circuits, and Ca2+ signaling is the basis of their excitability. Because APOE4 modifies membrane-lipid composition, and lipids regulate Ca2+ channels, we determined whether APOE4 dysregulates Ca2+signaling in astrocytes. METHODS: Ca2+ signals were recorded in astrocytes in hippocampal slices from APOE3 and APOE4 gene targeted replacement male and female mice using Ca2+ imaging. Mechanistic analyses were performed in immortalized astrocytes. Ca2+ fluxes were examined with pharmacological tools and Ca2+ probes. APOE3 and APOE4 expression was manipulated with GFP-APOE vectors and APOE siRNA. Lipidomics of lysosomal and whole-membranes were also performed. RESULTS: We found potentiation of ATP-elicited Ca2+responses in APOE4 versus APOE3 astrocytes in male, but not female, mice. The immortalized astrocytes modeled the male response, and showed that Ca2+ hyperactivity associated with APOE4 is caused by dysregulation of Ca2+ handling in lysosomal-enriched acidic stores, and is reversed by the expression of APOE3, but not of APOE4, pointing to loss of function due to APOE4 malfunction. Moreover, immortalized APOE4 astrocytes are refractory to control of Ca2+ fluxes by extracellular lipids, and present distinct lipid composition in lysosomal and plasma membranes. CONCLUSIONS: Immortalized APOE4 versus APOE3 astrocytes present: increased Ca2+ excitability due to lysosome dysregulation, altered membrane lipidomes and intracellular cholesterol distribution, and impaired modulation of Ca2+ responses upon changes in extracellular lipids. Ca2+ hyperactivity associated with APOE4 is found in astrocytes from male, but not female, targeted replacement mice. The study suggests that, independently of Aß and Tau pathologies, altered astrocyte excitability might contribute to neural-circuit hyperactivity depending on APOE allele, sex and lipids, and supports lysosome-targeted therapies to rescue APOE4 phenotypes in LOAD.

Absolute quantification of selenoproteins and selenometabolites in lung cancer human serum by column switching coupled to triple quadrupole inductively coupled plasma mass spectrometry.

One of the most important causes of the high mortality rate and low life expectancy of lung cancer is the detection at advanced stages. Thus, there is an urgent need for early diagnosis and the search of new selective biomarkers. Selenium is an important constituent of selenoproteins and a powerful antioxidant able to protect against cancer. In this work, the absolute quantification of selenium in selenoproteins and the total content in selenometabolites has been performed for the first time in serum from lung cancer patients (LC) and healthy controls (HC). To this end, a method for the simultaneous speciation of selenoproteins using size exclusion chromatography (SEC) and affinity chromatography (AF) with detection by ICP-QQQ-MS, and quantification by isotopic dilution (IDA) (SEC-AF-HPLC-SUID-ICP-QQQ-MS) was developed to determine the selenium concentration in eGPx, SEPP1 and SeAlb, as well as total selenometabolites, to find alterations that may serve as biomarkers of this disease. In the same way, a method based on anion-exchange chromatography coupled to ICP-QQQ-MS was developed to quantify selenometabolites (SeCys2, SeMeSeCys, SeMet, selenite and selenate) in the same LC and HC serum samples. The results showed that the averaged concentrations of selenium in eGPx, SeAlb and selenite were significantly higher in LC patients (LC (eGPx: 21.24 ± 0.77 ng g-1; SeAlb: 49.56 ± 3.16 ng g-1 and Se(IV): 6.20 ± 1.22 ng g-1) than in HC group (eGPx: 16.96 ± 0.53 ng g-1; SeAlb: 38.33 ± 2.66 ng g-1 and Se(IV): 3.56 ± 0.55 ng g-1). In addition, the ratios between selenoproteins and selenometabolites have been calculated for the first to study their potential use as LC biomarkers. The rates eGPx/SEPP1, SEPP1/SeAlb, eGPx/Se(IV) and SEPP1/Se(IV) were significantly different between LC and HC groups.

Metabolic impairments, metal traffic, and dyshomeostasis caused by the antagonistic interaction of cadmium and selenium using organic and inorganic mass spectrometry.

Cadmium (Cd) has become one of the most important environmental pollutants in the world, derived from natural and industrial sources, which is known to be accumulated in the human body, producing serious health effects. On the other hand, Selenium (Se) is an essential element for mammals, which is well known for its antagonistic interaction against Cd toxicity, such as the prevention of oxidative stress induced by this element. For this reason, the use of complementary analytical methods to study the homeostasis of metals, "traffic" between different organs and massive information about metabolites altered by the exposure, is of great interest. To this end, a metabolomic workflow based on the use of direct infusion mass spectrometry (DIMS) and gas chromatography mass spectrometry (GC-MS) was applied in mice serum. On the other hand, metal homeostasis and traffic between different organs and serum of mice exposed to Cd and Se have been evaluated by determining the concentration of metals by inductively coupled plasma mass spectrometry. This work demonstrates for the first time that Cd exposure causes a decrease of all the elements studied in the lung except itself. On the other hand, Se provokes As trafficking from metabolically less active organs (brain, lung, and testes) to others with greater metabolic activity (kidney), which also facilitates its excretion. Moreover, when mice are only exposed to Se, it provokes the accumulation of almost all the elements in the kidney, except Cd that increases also in the liver and brain. However, when both elements are simultaneously administered, Se increases Cd concentration in all the organs except in the serum and especially in the testis. On the other hand, important metabolic alterations have been detected in the energy and amino acid metabolism, as well as degradation of phospholipidic membranes, and in free fatty acids. In summary, the results show the high potential of the combined use of organic and inorganic mass spectrometry to establish Cd and Se interaction and the biological impairments caused and to provide information about metal traffic and metabolomic changes in exposure experiments.

Toenails as biomarker of exposure to essential trace metals: A review.

Health problems associated with essential trace metals can result from both inadequate (i.e., low intake) and excessive exposures (i.e., from environmental and/or occupational source). Thus, measuring the exposure level is a real challenge for epidemiologists. Among non-invasive biomarkers that intend to measure long-term exposure to essential trace metals, the toenail is probably the biological matrix with the greatest potential. This systematic review collects the current evidence regarding the validity of toenail clippings as exposure biomarker for trace metals such as boron, cobalt, copper, iron, manganese, molybdenum, selenium, silicon, vanadium and zinc. Special attention was paid to the time-window of exposure reflected by the toenail, the intraindividual variability in exposure levels over time in this matrix, and the relationship of toenail with other biomarkers, personal characteristics and environmental sources. Our search identified 139 papers, with selenium and zinc being the most studied elements. The variability among studies suggests that toenail levels may reflect different degrees of exposure and probably correspond to exposures occurred 3-12 months before sampling (i.e., for manganese/selenium). Few studies assessed the reproducibility of results over time and, for samples obtained 1-6 years apart, the correlation coefficient were between 0.26 and 0.66. Trace metal levels in toenails did not correlate well with those in the blood and urine and showed low-moderate correlation with those in the hair and fingernails. Available data suggests that for some elements (Se, Mn, Zn) toenail concentrations reflect long-term external exposures in fairly reproducible levels, while for other metals, this association has not yet been assessed. Among dietary factors, only toenail selenium showed clear associations with the intake of supplements or specific foods. The toenail levels could also represent occupational exposure, for instance, Mn exposure in welders. The scarcity of information on other essential trace elements, together with the great heterogeneity among studies makes the validation of the usage of toenails as biomarkers of exposure to these elements difficult. Standardization of sample collection, quality control, analytical techniques and reporting procedures might facilitate further research focused on the clear understanding of the significance of essential levels in this promising matrix and would enhance its utility in epidemiological research.

Insights into cancer and neurodegenerative diseases through selenoproteins and the connection with gut microbiota - current analytical methodologies.

Introduction: Selenium plays many key roles in health especially in connection with cancer and neurodegenerative diseases. However, it needs to be appreciated that the essentiality/toxicity of selenium depends on both, a narrow range of concentration and the chemical specie involved. In this context, selenoproteins are essential biomolecules against these disorders, mainly due to its antioxidant action. To this end, analytical methodologies may allow identifying and quantifying individual selenospecies in human biofluids and tissues. Areas covered: This review focus on the role of selenoproteins in medicine, with special emphasis in cancer and neurodegenerative diseases, considering the possible link with gut microbiota. In particular, this article reviews the analytical techniques and procedures recently developed for the absolute quantification of selenoproteins and selenometabolites in human biofluids and tissues. Expert commentary: The beneficial role of selenium in human health has been extensively studied and reviewed. However, several challenges remain unsolved as discussed in this article: (i) speciation of selenium (especially selenoproteins) in cancer and neurodegenerative disease patients; (ii) supplementation of selenium in humans using functional foods and nutraceuticals; (iii) the link between selenium and selenoproteins expression and the gut microbiota and (iv) analytical methods and pitfalls for the absolute quantification of selenoproteins and selenometabolites.

Metabolic Impairments Caused by a "Chemical Cocktail" of DDE and Selenium in Mice Using Direct Infusion Triple Quadrupole Time-of-Flight and Gas Chromatography-Mass Spectrometry.

Among organic contaminants, pesticides are one of the most important groups of chemicals due to their persistent character and toxicity. However, the biological systems are exposed to a complex environment in which the contaminants can interact in a synergistic/antagonistic fashion, and for this reason, the study of "chemical cocktails" is of great interest to fully understand the final biological effect. In this way, selenium is known for its antagonistic action against several toxicants. In this paper, metabolic impairments caused by the joint exposure of p,p'-dichloro diphenyl trichloroethane (DDE) and selenium (Se) have been issued for the first time. A metabolomic workflow was applied to mice fed DDE and DDE with Se diet, on the basis of the complementary use of two organic mass spectrometric techniques, combining direct infusion mass spectrometry (DI-ESI-QqQ-TOF MS) and gas chromatography-mass spectrometry (GC-MS). The results show a good classification between the studied groups caused by about 70 altered metabolites in the liver, kidney, or brain, including the pathways of energy metabolism, degradation of phospholipidic membrane, ß-oxidation, and oxidative stress, which confirm the potential of combined metabolomic platforms in environmental studies.

The Metallome of Lung Cancer and its Potential Use as Biomarker.

Carcinogenesis is a very complex process in which metals have been found to be critically involved. In this sense, a disturbed redox status and metal dyshomeostasis take place during the onset and progression of cancer, and it is well-known that trace elements participate in the activation or inhibition of enzymatic reactions and metalloproteins, in which they usually participate as cofactors. Until now, the role of metals in cancer have been studied as an effect, establishing that cancer onset and progression affects the disturbance of the natural chemical form of the essential elements in the metabolism. However, it has also been studied as a cause, giving insights related to the high exposure of metals giving a place to the carcinogenic process. On the other hand, the chemical species of the metal or metallobiomolecule is very important, since it finally affects the biological activity or the toxicological potential of the element and their mobility across different biological compartments. Moreover, the importance of metal homeostasis and metals interactions in biology has also been demonstrated, and the ratios between some elements were found to be different in cancer patients; however, the interplay of elements is rarely reported. This review focuses on the critical role of metals in lung cancer, which is one of the most insidious forms of cancer, with special attention to the analytical approaches and pitfalls to extract metals and their species from tissues and biofluids, determining the ratios of metals, obtaining classification profiles, and finally defining the metallome of lung cancer.

Metabolomic study of serum, urine and bronchoalveolar lavage fluid based on gas chromatography mass spectrometry to delve into the pathology of lung cancer.

This study explores for the first time the combination of serum, urine and bronchoalveolar lavage fluid (BALF) to deep insight into the pathology of lung cancer (LC) using a metabolomic platform based on gas chromatography mass spectrometry (GCMS). The study includes LC patients, healthy control group (HC) and a group of patients with noncancerous lung diseases (NCC) used as a control group respect to BALF because of the invasive nature this fluid collection. The metabolomic platform was applied to serum, urine and BALF samples in order to compare the metabolomic profiles of these biological fluids and establish metabolic similarities and differences between them. The application of PLS-DA presented a clear classification of groups for all types of samples, indicating the existence of altered metabolites in LC. Twenty six and thirty one perturbed metabolites in the LC were annotated in the comparison of serum and urine samples. On the other hand, sixteen metabolites were altered in BALF of LC patients compared to NCC. The pathway analysis indicated that several amino acid metabolic routes were the most affected in LC. Finally, ROC curves were applied to the dataset and metabolites with an AUC value higher than 0.75 were considered as relevant in the progression of LC.

Metabolomic study of bioactive compounds in strawberries preserved under controlled atmosphere based on GC-MS and DI-ESI-QqQ-TOF-MS.

INTRODUCTION: The storage of the vegetables products in a controlled atmosphere (CA) with low O2 and high CO2 concentrations, reduces respiration rates and delays the ripening process, and in some cases, improves their quality and organoleptic properties. OBJECTIVE: To obtain deep insight into strawberry fruit metabolic changes caused by these CA treatments. METHODOLOGY: Freshly harvested strawberries were preserved under different atmospheres enriched with 10%, 20% and 30% of CO2 , for 2 days at 0°C, containing in all the cases 5% of O2 and were subjected to a metabolomic analysis based on gas chromatography-mass spectrometry (GC-MS) and direct-infusion with electrospray ionisation source equipped with triple quadrupole coupled to time of flight mass spectrometry (DI-ESI-QqQ-TOF-MS). Partial least square discriminant analysis (PLS-DA) was employed to compare the control and treated samples for the identification of altered metabolites. RESULTS: Several metabolites related to CA treatment could be identified by databases and literature, which are mainly sugars, organic acids and phenolic compounds (bioactive compounds). CONCLUSIONS: Good correlation coefficients were obtained between discriminant metabolites and fruit quality parameters. These results suggest that treated strawberries under CA could be considered as bioactive healthy compounds, suggesting that treated strawberries under CA could be used as raw material for the preparation and formulation of food supplements and nutraceutical products.

Metal dyshomeostasis based biomarkers of lung cancer using human biofluids.

Lung cancer (LC) is one of the most common causes of cancer-related deaths in the world and it is well known that trace elements play important roles in the carcinogenic process activating and inhibiting enzymatic reactions and metalloproteins, in which they usually participate as cofactors. A cross-sectional study was conducted on 48 lung cancer patients and 39 controls (56 men and 31 women), aged 44-76 years between March 2011 and June 2012. Eleven elements have been included in the study: V, Cr, Mn, Fe, Co, Cu, Zn, Se, Mo, Cd, and Pb, some of them considered toxic (V, Cd, Cr and Pb), while others are essential (Co, Mo, Se, Fe and Zn), and they have been analyzed by ICP-QQQ-MS in serum, urine and for the first time in bronchoalveolar lavage fluid (BALF). In order to understand the involvement of metals in this process, an analytical metallomic approach based on non-denaturing precipitation of proteins (NDPP) has been optimized for the fractionation of high molecular mass (HMM) and low molecular mass (LMM) metal species, in order to distinguish between metal species that affect the biological activity and toxicological potential of the elements. In this work, the NDPP followed by the analysis of metals by ICP-QQQ-MS has been applied for the first time to serum, urine and BALF samples from lung cancer patients and controls in order to get metal-size molecule profiles (MSMP), which can be used as metal-based biomarkers of altered metabolic processes such as oxidative stress and homeostasis. In this sense, we have demonstrated that several metals are good biomarkers when they are related to labile complexes, complexed with low molecular mass ligands, or in the form of metalloproteins (i.e. V and Cr in HMM and Cu in LMM), which has been described for the first time. On the other hand, metal dyshomeostasis biomarkers are proposed using metal ratios and correlations. Finally, the ratios between elements were shown to be important biomarkers for lung cancer in serum (V/Mn, V/Pb, V/Zn, Cr/Pb), urine (Cr/Cd, Mn/Cd, V/Cd, Co/Cd, Cd/Pb) and BALF (V/Cu), which reflects the dyshomeostasis of metals in lung cancer. In this sense, several metals are correlated to others suggesting also the existence of an interconnected homeostasis in lung cancer.