Low-dose vanadium pentoxide perturbed lung metabolism associated with inflammation and fibrosis signaling in male animal and in vitro models.

Vanadium is available as a dietary supplement and also is known to be toxic if inhaled, yet little information is available concerning the effects of vanadium on mammalian metabolism when concentrations found in food and water. Vanadium pentoxide (V+5) is representative of the most common dietary and environmental exposures, and prior research shows that low-dose V+5 exposure causes oxidative stress measured by glutathione oxidation and protein S-glutathionylation. We examined the metabolic impact of V+5 at relevant dietary and environmental doses (0.01, 0.1, and 1 ppm for 24 h) in human lung fibroblasts (HLFs) and male C57BL/6J mice (0.02, 0.2, and 2 ppm in drinking water for 7 mo). Untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) showed that V+5 induced significant metabolic perturbations in both HLF cells and mouse lungs. We noted 30% of the significantly altered pathways in HLF cells, including pyrimidines and aminosugars, fatty acids, mitochondrial and redox pathways, showed similar dose-dependent patterns in mouse lung tissues. Alterations in lipid metabolism included leukotrienes and prostaglandins involved in inflammatory signaling, which have been associated with the pathogenesis of idiopathic pulmonary fibrosis (IPF) and other disease processes. Elevated hydroxyproline levels and excessive collagen deposition were also present in lungs from V+5-treated mice. Taken together, these results show that oxidative stress from environmental V+5, ingested at low levels, could alter metabolism to contribute to common human lung diseases.NEW & NOTEWORTHY We used relevant dietary and environmental doses of Vanadium pentoxide (V+5) to examine its metabolic impact in vitro and in vivo. Using liquid chromatography-high-resolution mass spectrometry (LC-HRMS), we found significant metabolic perturbations, with similar dose-dependent patterns observed in human lung fibroblasts and male mouse lungs. Alterations in lipid metabolism included inflammatory signaling, elevated hydroxyproline levels, and excessive collagen deposition were present in V+5-treated lungs. Our findings suggest that low levels of V+5 could trigger pulmonary fibrotic signaling.

Metabolomics of V2O5 nanoparticles and V2O5 nanofibers in human airway epithelial BEAS-2B cells.

Vanadium is a toxic metal listed by the IARC as possibly carcinogenic to humans. Manufactured nanosize vanadium pentoxide (V2O5) materials are used in a wide range of industrial sectors and recently have been developed as nanomedicine for cancer therapeutics, yet limited information is available to evaluate relevant nanotoxicity. In this study we used high-resolution metabolomics to assess effects of two V2O5 nanomaterials, nanoparticles and nanofibers, at exposure levels (0.01, 0.1, and 1 ppm) that did not cause cell death (i.e., non-cytotoxic) in a human airway epithelial cell line, BEAS-2B. As prepared, V2O5 nanofiber exhibited a fibrous morphology, with a width approximately 63 ± 12 nm and length in average 420 ± 70 nm; whereas, V2O5 nanoparticles showed a typical particle morphology with a size 36 ± 2 nm. Both V2O5 nanoparticles and nanofibers had dose-response effects on aminosugar, amino acid, fatty acid, carnitine, niacin and nucleotide metabolism. Differential effects of the particles and fibers included dibasic acid, glycosphingolipid and glycerophospholipid pathway associations with V2O5 nanoparticles, and cholesterol and sialic acid metabolism associations with V2O5 nanofibers. Examination by transmission electron microscopy provided evidence for mitochondrial stress and increased lysosome fusion by both nanomaterials, and these data were supported by effects on mitochondrial membrane potential and lysosomal activity. The results showed that non-cytotoxic exposures to V2O5 nanomaterials impact major metabolic pathways previously associated with human lung diseases and suggest that toxico-metabolomics may be useful to evaluate health risks from V2O5 nanomaterials.

Reference Standardization for Quantification and Harmonization of Large-Scale Metabolomics.

Reference standardization was developed to address quantification and harmonization challenges for high-resolution metabolomics (HRM) data collected across different studies or analytical methods. Reference standardization relies on the concurrent analysis of calibrated pooled reference samples at predefined intervals and enables a single-step batch correction and quantification for high-throughput metabolomics. Here, we provide quantitative measures of approximately 200 metabolites for each of three pooled reference materials (220 metabolites for Qstd3, 211 metabolites for CHEAR, 204 metabolites for NIST1950) and show application of this approach for quantification supports harmonization of metabolomics data collected from 3677 human samples in 17 separate studies analyzed by two complementary HRM methods over a 17-month period. The results establish reference standardization as a method suitable for harmonizing large-scale metabolomics data and extending capabilities to quantify large numbers of known and unidentified metabolites detected by high-resolution mass spectrometry methods.

Multigenerational metabolic profiling in the Michigan PBB registry.

Although polychlorinated biphenyls and polybrominated biphenyls are no longer manufactured the United States, biomonitoring in human populations show that exposure to these pollutants persist in human tissues. The objective of this study was to identify metabolic variations associated with exposure to 2,2'4,4',5,5'-hexabromobiphenyl (PBB-153) and 2,2'4,4',5,5'-hexachlorobiphenyl (PCB-153) in two generations of participants enrolled in the Michigan PBB Registry (http://pbbregistry.emory.edu/). Untargeted, high-resolution metabolomic profiling of plasma collected from 156 individuals was completed using liquid chromatography with high-resolution mass spectrometry. PBB-153 and PCB-153 levels were measured in the same individuals using targeted gas chromatography-tandem mass spectrometry and tested for dose-dependent correlation with the metabolome. Biological response to these exposures were evaluated using identified endogenous metabolites and pathway enrichment. When compared to lipid-adjusted concentrations for adults in the National Health and Nutrition Examination Survey (NHANES) for years 2003-2004, PCB-153 levels were consistent with similarly aged individuals, whereas PBB-153 concentrations were elevated (p<0.0001) in participants enrolled in the Michigan PBB Registry. Metabolic alterations were correlated with PBB-153 and PCB-153 in both generations of participants, and included changes in pathways related to catecholamine metabolism, cellular respiration, essential fatty acids, lipids and polyamine metabolism. These pathways were consistent with pathophysiological changes observed in neurodegenerative disease and included previously identified metabolomic markers of Parkinson's disease. To determine if the metabolic alterations detected in this study are replicated other cohorts, we evaluated correlation of PBB-153 and PCB-153 with plasma fatty acids measured in NHANES. Both pollutants showed similar associations with fatty acids previously linked to PCB exposure. Thus, the results from this study show metabolic alterations correlated with PBB-153 and PCB-153 exposure can be detected in human populations and are consistent with health outcomes previously reported in epidemiological and mechanistic studies.

Chronic Ethanol Metabolism Inhibits Hepatic Mitochondrial Superoxide Dismutase via Lysine Acetylation.

BACKGROUND: Chronic ethanol (EtOH) consumption is a major cause of liver disease worldwide. Oxidative stress is a known consequence of EtOH metabolism and is thought to contribute significantly to alcoholic liver disease (ALD). Therefore, elucidating pathways leading to sustained oxidative stress and downstream redox imbalances may reveal how EtOH consumption leads to ALD. Recent studies suggest that EtOH metabolism impacts mitochondrial antioxidant processes through a number of proteomic alterations, including hyperacetylation of key antioxidant proteins. METHODS: To elucidate mechanisms of EtOH-induced hepatic oxidative stress, we investigate a role for protein hyperacetylation in modulating mitochondrial superoxide dismutase (SOD2) structure and function in a 6-week Lieber-DeCarli murine model of EtOH consumption. Our experimental approach includes immunoblotting immunohistochemistry (IHC), activity assays, mass spectrometry, and in silico modeling. RESULTS: We found that EtOH metabolism significantly increased the acetylation of SOD2 at 2 functionally relevant lysine sites, K68 and K122, resulting in a 40% decrease in enzyme activity while overall SOD2 abundance was unchanged. In vitro studies also reveal which lysine residues are more susceptible to acetylation. IHC analysis demonstrates that SOD2 hyperacetylation occurs near zone 3 within the liver, which is the main EtOH-metabolizing region of the liver. CONCLUSIONS: Overall, the findings presented in this study support a role for EtOH-induced lysine acetylation as an adverse posttranslational modification within the mitochondria that directly impacts SOD2 charge state and activity. Last, the data presented here indicate that protein hyperacetylation may be a major factor contributing to an imbalance in hepatic redox homeostasis due to chronic EtOH metabolism.

Selective targeting of the cysteine proteome by thioredoxin and glutathione redox systems.

Thioredoxin (Trx) and GSH are the major thiol antioxidants protecting cells from oxidative stress-induced cytotoxicity. Redox states of Trx and GSH have been used as indicators of oxidative stress. Accumulating studies suggest that Trx and GSH redox systems regulate cell signaling and metabolic pathways differently and independently during diverse stressful conditions. In the current study, we used a mass spectrometry-based redox proteomics approach to test responses of the cysteine (Cys) proteome to selective disruption of the Trx- and GSH-dependent systems. Auranofin (ARF) was used to inhibit Trx reductase without detectable oxidation of the GSH/GSSG couple, and buthionine sulfoximine (BSO) was used to deplete GSH without detectable oxidation of Trx1. Results for 606 Cys-containing peptides (peptidyl Cys) showed that 36% were oxidized more than 1.3-fold by ARF, whereas BSO-induced oxidation of peptidyl Cys was only 10%. Mean fold oxidation of these peptides was also higher by ARF than BSO treatment. Analysis of potential functional pathways showed that ARF oxidized peptides associated with glycolysis, cytoskeleton remodeling, translation and cell adhesion. Of 60 peptidyl Cys oxidized due to depletion of GSH, 41 were also oxidized by ARF and included proteins of translation and cell adhesion but not glycolysis or cytoskeletal remodeling. Studies to test functional correlates showed that pyruvate kinase activity and lactate levels were decreased with ARF but not BSO, confirming the effects on glycolysis-associated proteins are sensitive to oxidation by ARF. These data show that the Trx system regulates a broader range of proteins than the GSH system, support distinct function of Trx and GSH in cellular redox control, and show for the first time in mammalian cells selective targeting peptidyl Cys and biological pathways due to deficient function of the Trx system.

First complete mitochondrial genome of the Alashan ground squirrel (Spermophilus alashanicus) (Rodentia: Sciuridae) from Ningxia, China.

The Alashan ground squirrel (Spermophilus alashanicus) is primarily distributed in the regions of Inner Mongolia and Ningxia, China. In this study, we present the first complete mitochondrial genome of S. alashanicus. The genome spans 16,464 base pairs and comprises 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and a single control region with a marked AT bias. The overall GC content is 35.4%. Phylogenetic analyses indicate that S. alashanicus clusters are closely associated with S. dauricus. This comprehensive characterization of the S. alashanicus mitochondrial genome serves as a foundational resource for future studies on mitochondrial evolution, species identification, population genomics, and phylogenetics.

[Characteristics of leaf stoichiometry and the driving factors of Ammopiptanthus mongolicus, China]. / æ²™å†¬é’å¶ç‰‡åŒ–å­¦è®¡é‡ç‰¹å¾åŠå ¶é©±åŠ¨å› ç´ .

The stoichiometric characteristics of leaves can reflect environmental adaptation of plants, and thus the study of the relationship between them is helpful for exploring plant adaptation strategies. In this study, taking the national second-level key protection species, Ammopiptanthus mongolicus, as the research object, we set up 26 plots to collect samples, and measured the content of carbon (C), nitrogen (N), phosphorus (P) and water use efficiency (WUE) of leaves. We analyzed the relationship between leaf stoichiometric characteristics and WUE, and quantified the contributions of soil, climate, and water use efficiency to the variations of leaf stoichiometry. The results showed that C, N, and P contents in the leaves were (583.99±27.93), (24.31±2.09), and (1.83±0.06) mg·g-1, respectively. The coefficients of variation were 4.8%, 8.6%, and 3.2%, respectively, all belonging to weak variability, indicating that foliar contents of C, N and P tended to a certain stable value. The average value of N:P was 13.3, indicating that the growth of A. mongolicus was mainly limited by N. WUE was not correlated with leaf C content, but was significantly positively correlated with leaf N and P contents and N:P, and significantly negatively correlated with C:N and C:P, indicating that there was a linear synergistic trend between WUE and leaf nutrient content. The main factors influencing leaf C content and C:P were climatic factors, the leaf N content and N:P were mainly affected by soil factors, and the water use efficiency mainly affected leaf P content and C:N, indicating that the driving factors of different stoichiometric characteristics were different. The results could help eva-luate the habitat adaptation of desert plants, which would provide a theoretical basis for the conservation and management of A. mongolicus.

Factors influencing the distribution, risk, and transport of microplastics and heavy metals for wildlife and habitats in "island" landscapes: From source to sink.

Microplastics (MPs) and heavy metals (HMs) are important pollutants in terrestrial ecosystems. In particular, the "island" landscape's weak resistance makes it vulnerable to pollution. However, there is a lack of research on MPs and HMs in island landscapes. Therefore, we used Helan Mountain as the research area. Assess the concentrations, spatial distribution, ecological risks, sources, and transport of MPs and HMs in the soil and blue sheep (Pseudois nayaur) feces. Variations in geographical distribution showed a connection between human activity and pollutants. Risk assessment indicated soil and wildlife were influenced by long-term pollutant polarization and multi-element inclusion (Igeo, Class I; PHI, Class V; RI (MPs), 33 % Class II, and 17 % Class IV; HI = 452.08). Source apportionment showed that tourism and coal combustion were the primary sources of pollutants. Meanwhile, a new coupling model of PMF/Risk was applied to quantify the source contribution of various risk types indicated transportation roads and tourism sources were the main sources of ecological and health risks, respectively. Improve the traceability of pollution source risks. Furthermore, also developed a novel tracing model for pollutant transportation, revealing a unique "source-sink-source" cycle in pollutant transportation, which provides a new methodological framework for the division of pollution risk areas in nature reserves and the evaluation of spatial transport between sources and sinks. Overall, this study establishes a foundational framework for conducting comprehensive risk assessments and formulating strategies for pollution control and management.

Metabolic alterations and mitochondrial dysfunction in human airway BEAS-2B cells exposed to vanadium pentoxide.

Vanadium pentoxide (V+5) is a hazardous material that has drawn considerable attention due to its wide use in industrial sectors and increased release into environment from human activities. It poses potential adverse effects on animals and human health, with pronounced impact on lung physiology and functions. In this study, we investigated the metabolic response of human bronchial epithelial BEAS-2B cells to low-level V+5 exposure (0.01, 0.1, and 1 ppm) using liquid chromatography-high resolution mass spectrometry (LC-HRMS). Exposure to V+5 caused extensive changes to cellular metabolism in BEAS-2B cells, including TCA cycle, glycolysis, fatty acids, amino acids, amino sugars, nucleotide sugar, sialic acid, vitamin D3, and drug metabolism, without causing cell death. Altered mitochondrial structure and function were observed with as low as 0.01 ppm (0.2 µM) V+5 exposure. In addition, decreased level of E-cadherin, the prototypical epithelial marker of epithelial-mesenchymal transition (EMT), was observed following V+5 treatment, supporting potential toxicity of V+5 at low levels. Taken together, the present study shows that V+5 has adverse effects on mitochondria and the metabolome which may result in EMT activation in the absence of cell death. Furthermore, results suggest that high-resolution metabolomics could serve as a powerful tool to investigate metal toxicity at levels which do not cause cell death.

Diversity characteristics of arbuscular mycorrhizal fungi communities in the soil along successional altitudes of Helan Mountain, arid, and semi-arid regions of China.

Introduction: Arbuscular mycorrhizal fungi (AMF) perform a vital role in terrestrial ecosystems. Methods: To investigate the diversity of AMF communities on the western slope of Helan Mountain at different altitudes and their influence factors, high-throughput sequencing was used to study the structure and diversity of soil AMF communities under different environments and their interrelationships between AMF and environmental factors. Results: The results revealed that there were significant differences (p < 0.05) in the physical and chemical properties of the soil along the different altitudes. A total of 1,145 OTUs were obtained by high-throughput sequencing, belonging to 1 phylum, 4 class, 6 orders, 13 families, 18 genera and 135 species, with the dominant genus being Glomus, which accounted for 75.27% of the relative abundance of the community. Soil AMF community structure was shown to be variable at the generic level according to NMDS analysis. Correlation analysis showed that soil pH, water content (WC), organic matter (OM), available K, available P and N were significantly correlated with AMF community diversity and species abundance (p < 0.05, p < 0.01). Based on redundancy analysis (RDA) and Monte Carlo test results, soil pH, WC and OM had highly significant effects (p < 0.01) on AMF community diversity and species abundance. Discussion: This study investigates the relationship between AMF community structure and diversity and soil physicochemical properties at different elevations on the western slope of Helan Mountain, which is of great significance to the study of the Helan Mountain ecosystem.

C:N:P stoichiometric characteristics of mosses in Picea crassifolia forest in Helan Mountains, Ningxia, China.

To explore the stoichiometric characteristics of C, N and P and adaptive mechanism of mosses in mountain forest ecosystems, we set up 15 plots along the altitude gradient in Picea crassifolia forest in Helan Mountains, Ningxia. We analyzed the C:N:P stoichiometry of moss aboveground tissues and its relationship with environmental factors. The results showed the mean values of C, N and P concentration in moss aboveground tissues were 336.67, 20.31 and 0.66 mg·g-1, respectively. The mean value of aboveground tissue N:P was 33.4, indicating that the growth of mosses was limited by P. The C concentration in the aboveground tissues of mosses was positively correlated with soil total nitrogen concentration and negatively correlated with soil total phosphorus concentration. The N concentration in aboveground tissues of mosses was significantly negatively correlated with soil organic carbon and soil total nitrogen concentrations. Results of redundancy analysis showed that the interpretation rate of environmental factors on the stoichiometry was 48.5%, with canopy closure, soil total nitrogen and soil total phosphorus as the main factors. Canopy closure was the main environmental factor affecting the growth of mosses in P. crassifolia forest in Helan Mountains. High canopy closure facilitated the growth of mosses.

Soil microbial community characteristics and the influencing factors at different elevations on the eastern slope of Helan Mountain, Northwest China.

As an important bridge connecting aboveground communities and belowground biological processes, soil microorganisms play an important role in regulating belowground ecological processes. The altitudinal changes and driving factors of soil microbial community in mountain ecosystem in arid region are still unclear. We measured soil physicochemical properties at seven altitudes in the range of 1300-2800 m in Helan Mountains, and investigated the understory community composition, soil physicochemical properties, and soil microbial community. The driving factor for soil microbial community was explored by variance partitioning analysis and redundancy analysis. The results showed that the total amount of soil microorganisms and bacterial biomass first increased and then decreased with the increases of altitude, fungi, actinomyces, arbuscular mycorrhizal fungi, Gram-positive bacteria, and Gram-negative bacteria groups showed a gradual increase. The variation of fungal-to-bacterial ratio (F/B) along the altitude showed that the cumulative ability of soil bacteria was stronger than that of fungi at low altitudes, while the pattern is opposite at high altitudes. The ratio of Gram-positive bacteria to Gram-negative bacteria (GP/GN) showed an overall decreasing trend with the increases of altitude, indicating that soil bacteria and organic carbon availability changed from "oligotrophic" to "eutrophication" and from "low" to "high" transition as the altitude increased. Vegetation properties, soil physical and chemical properties jointly accounted for 95.7% of the variation in soil microbial community. Soil organic carbon (SOC), soil water content (SWC), and total nitrogen (TN) were significantly correlated with soil microbial community composition. Our results revealed the distribution pattern and driving factors of soil microbial communities at different elevations on the eastern slope of Helan Mountain, which would provide theoretical basis and data support for further understanding the interaction between plant-soil-microorganisms in arid areas.

Environmental chemicals and endogenous metabolites in bile of USA and Norway patients with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a complex bile duct disorder. Its etiology is incompletely understood, but environmental chemicals likely contribute to risk. Patients with PSC have an altered bile metabolome, which may be influenced by environmental chemicals. This novel study utilized state-of-the-art high-resolution mass spectrometry (HRMS) with bile samples to provide the first characterization of environmental chemicals and metabolomics (collectively, the exposome) in PSC patients located in the United States of America (USA) (n = 24) and Norway (n = 30). First, environmental chemical- and metabolome-wide association studies were conducted to assess geographic-based similarities and differences in the bile of PSC patients. Nine environmental chemicals (false discovery rate, FDR < 0.20) and 3143 metabolic features (FDR < 0.05) differed by site. Next, pathway analysis was performed to identify metabolomic pathways that were similarly and differentially enriched by the site. Fifteen pathways were differentially enriched (P < .05) in the categories of amino acid, glycan, carbohydrate, energy, and vitamin/cofactor metabolism. Finally, chemicals and pathways were integrated to derive exposure-effect correlation networks by site. These networks demonstrate the shared and differential chemical-metabolome associations by site and highlight important pathways that are likely relevant to PSC. The USA patients demonstrated higher environmental chemical bile content and increased associations between chemicals and metabolic pathways than those in Norway. Polychlorinated biphenyl (PCB)-118 and PCB-101 were identified as chemicals of interest for additional investigation in PSC given broad associations with metabolomic pathways in both the USA and Norway patients. Associated pathways include glycan degradation pathways, which play a key role in microbiome regulation and thus may be implicated in PSC pathophysiology.

Vanadium pentoxide induced oxidative stress and cellular senescence in human lung fibroblasts.

Both environmental exposure to vanadium pentoxide (V2O5, V+5 for its ionic counterparts) and fibroblast senescence are associated with pulmonary fibrosis, but whether V+5 causes fibroblast senescence remains unknown. We found in a dose-response study that 2-40 µM V+5 caused human lung fibroblasts (HLF) senescence with increased senescence-associated ß-galactosidase activity and p16 expression, while cell death occurred at higher concentration (LC50, 82 µM V+5). Notably, measures of reactive oxygen species (ROS) production with fluorescence probes showed no association of ROS with V+5-dependent senescence. Preloading catalase (polyethylene-conjugated), a H2O2 scavenger, did not alleviate the cellular senescence induced by V+5. Analyses of the cellular glutathione (GSH) system showed that V+5 oxidized GSH, increased GSH biosynthesis, stimulated cellular GSH efflux and increased protein S-glutathionylation, and addition of N-acetyl cysteine inhibited V+5-elevated p16 expression, suggesting that thiol oxidation mediates V+5-caused senescence. Moreover, strong correlations between GSSG/GSH redox potential (Eh), protein S-glutathionylation, and cellular senescence (R2 > 0.99, p < 0.05) were present in V+5-treated cells. Studies with cell-free and enzyme-free solutions showed that V+5 directly oxidized GSH with formation of V+4 and GSSG in the absence of O2. Analyses of V+5 and V+4 in HLF and culture media showed that V+5 was reduced to V+4 in cells and that a stable V+4/V+5 ratio was rapidly achieved in extracellular media, indicating ongoing release of V+4 and reoxidation to V+5. Together, the results show that V+5-dependent fibroblast senescence is associated with a cellular/extracellular redox cycling mechanism involving the GSH system and occurring under conditions that do not cause cell death. These results establish a mechanism by which environmental vanadium from food, dietary supplements or drinking water, can cause or contribute to lung fibrosis in the absence of high-level occupational exposures and cytotoxic cell death.

High-Resolution Exposomics and Metabolomics Reveals Specific Associations in Cholestatic Liver Diseases.

Progress in development of prognostic and therapeutic options for the rare cholestatic liver diseases, primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), is hampered by limited knowledge of their pathogeneses. In particular, the potential role of hepatotoxic and/or metabolism-altering environmental chemicals in the pathogenesis of these diseases remains relatively unstudied. Moreover, the extent to which metabolic pathways are altered due to ongoing cholestasis and subsequent liver damage or possibly influenced by hepatotoxic chemicals is poorly understood. In this study, we applied a comprehensive exposomics-metabolomics approach to uncover potential pathogenic contributors to PSC and PBC. We used untargeted high-resolution mass spectrometry to characterize a wide range of exogenous chemicals and endogenous metabolites in plasma and tested them for association with disease. Exposome-wide association studies (EWAS) identified environmental chemicals, including pesticides, additives and persistent pollutants, that were associated with PSC and/or PBC, suggesting potential roles for these compounds in disease pathogenesis. Metabolome-wide association studies (MWAS) found disease-associated alterations to amino acid, eicosanoid, lipid, co-factor, nucleotide, mitochondrial and microbial metabolic pathways, many of which were shared between PSC and PBC. Notably, this analysis implicates a potential role of the 5-lipoxygenase pathway in the pathogenesis of these diseases. Finally, EWAS × MWAS network analysis uncovered linkages between environmental agents and disrupted metabolic pathways that provide insight into potential mechanisms for PSC and PBC. Conclusion: This study establishes combined exposomics-metabolomics as a generalizable approach to identify potentially pathogenic environmental agents and enumerate metabolic alterations that may impact PSC and PBC, providing a foundation for diagnostic and therapeutic strategies.

Environmental chemicals and metabolic disruption in primary and secondary human parathyroid tumors.

BACKGROUND: The incidence of primary hyperparathyroidism has increased 300% in the United States in the past 30 years, and secondary hyperparathyroidism is almost universal in patients with end-stage renal disease. We assessed the presence of environmental chemicals in human hyperplastic parathyroid tumors as possible contributing factors to this increase. METHODS: Cryopreserved hyperplastic parathyroid tumors and normal human parathyroids were analyzed by gas chromatography and liquid chromatography coupled to ultra-high-resolution mass spectrometry, bioinformatics, and biostatistics. RESULTS: Detected environmental chemicals included polychlorinated biphenyls, polybrominated diphenyl ethers, dichloro-diphenyl-trichloroethane derivatives, and other insecticides. A total of 99% had p,p'-dichlorodiphenyldichloroethylene. More than 50% contained other environmental chemicals, and many classified as endocrine disruptors. Polychlorinated biphenyl-28 and polychlorinated biphenyl-49 levels correlated positively with parathyroid tumor mass. Polybrominated diphenyl ether-47 concentrations in tumors were inversely correlated with patients' serum calcium levels. Cellular metabolites in pathways of purine and pyrimidine synthesis and mitochondrial energy production were associated with tumor growth and with p,p'-dichlorodiphenyldichloroethylene in primary hyperparathyroidism tumors. In normal parathyroids, p,p'-dichlorodiphenyldichloroethylene , polychlorinated biphenyl-28, polychlorinated biphenyl-74, and polychlorinated biphenyl-153, but not p,p'-dichlorodiphenyldichloroethylene or polychlorinated biphenyl-49, were detected. CONCLUSION: Environmental chemicals are present in human parathyroid tumors and warrant detailed epidemiologic and mechanistic studies to test for causal links to the growth of human parathyroid tumors.

A scalable workflow to characterize the human exposome.

Complementing the genome with an understanding of the human exposome is an important challenge for contemporary science and technology. Tens of thousands of chemicals are used in commerce, yet cost for targeted environmental chemical analysis limits surveillance to a few hundred known hazards. To overcome limitations which prevent scaling to thousands of chemicals, we develop a single-step express liquid extraction and gas chromatography high-resolution mass spectrometry analysis to operationalize the human exposome. We show that the workflow supports quantification of environmental chemicals in human plasma (200 µL) and tissue (≤100 mg) samples. The method also provides high resolution, sensitivity and selectivity for exposome epidemiology of mass spectral features without a priori knowledge of chemical identity. The simplicity of the method can facilitate harmonization of environmental biomonitoring between laboratories and enable population level human exposome research with limited sample volume.

Postprandial cysteine/cystine redox potential in human plasma varies with meal content of sulfur amino acids.

Few data are available on plasma redox responses to sulfur amino acid (SAA) loads. In this study, we had 2 aims: to determine whether the SAA content of a meal affected postprandial plasma cysteine (Cys), cystine (CySS), or redox potential (E(h)CySS) in humans and whether SAA intake level (adequate or inadequate) in the days preceding the meal challenge affected these postprandial levels. Eight healthy individuals aged 18-36 y were equilibrated for 3 d to adequate SAA, fed chemically defined meals without SAA for 5 d (inadequate SAA) and then fed isoenergetic, isonitrogenous meals with adequate SAA for 5 d. On the first and last days with the chemically defined meals, a morning meal containing 60% of the daily food intake was given, and plasma Cys, CySS, and E(h)CySS were determined over an 8-h postprandial time course. Following equilibration to adequate intake, provision of the meal with SAA resulted in increased plasma Cys and CySS concentrations and more reduced plasma E(h)CySS compared with the postprandial values following the same meal without SAA. Equilibration to inadequate SAA intake for the days preceding the meal challenge did not affect this response. The magnitude of the difference in postprandial plasma E(h)CySS (10 mV) due to meal content of SAA was comparable to those which alter physiologic signaling and/or are associated with disease risk. Consequently, the SAA content of meals could affect physiologic signaling and associated disease mechanisms in the postprandial period by changes in Cys, CySS, or E(h)CySS.

Environmental chemical burden in metabolic tissues and systemic biological pathways in adolescent bariatric surgery patients: A pilot untargeted metabolomic approach.

BACKGROUND: Advances in untargeted metabolomic technologies have great potential for insight into adverse metabolic effects underlying exposure to environmental chemicals. However, important challenges need to be addressed, including how biological response corresponds to the environmental chemical burden in different target tissues. AIM: We performed a pilot study using state-of-the-art ultra-high-resolution mass spectrometry (UHRMS) to characterize the burden of lipophilic persistent organic pollutants (POPs) in metabolic tissues and associated alterations in the plasma metabolome. METHODS: We studied 11 adolescents with severe obesity at the time of bariatric surgery. We measured 18 POPs that can act as endocrine and metabolic disruptors (i.e. 2 dioxins, 11 organochlorine compounds [OCs] and 5 polybrominated diphenyl ethers [PBDEs]) in visceral and subcutaneous abdominal adipose tissue (vAT and sAT), and liver samples using gas chromatography with UHRMS. Biological pathways were evaluated by measuring the plasma metabolome using high-resolution metabolomics. Network and pathway enrichment analysis assessed correlations between the tissue-specific burden of three frequently detected POPs (i.e. p,p'-dichlorodiphenyldichloroethene [DDE], hexachlorobenzene [HCB] and PBDE-47) and plasma metabolic pathways. RESULTS: Concentrations of 4 OCs and 3 PBDEs were quantifiable in at least one metabolic tissue for > 80% of participants. All POPs had the highest median concentrations in adipose tissue, especially sAT, except for PBDE-154, which had comparable average concentrations across all tissues. Pathway analysis showed high correlations between tissue-specific POPs and metabolic alterations in pathways of amino acid metabolism, lipid and fatty acid metabolism, and carbohydrate metabolism. CONCLUSIONS: Most of the measured POPs appear to accumulate preferentially in adipose tissue compared to liver. Findings of plasma metabolic pathways potentially associated with tissue-specific POPs concentrations merit further investigation in larger populations.