Objective:
A study was conducted to identify metabolic-related effects of benzo(ghi)perylene (BghiP) and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), on primary human fibroblasts to verify biological associations previously found in occupational health research.
Methods:
Human lung fibroblasts were exposed to BghiP or HpCDD and extracts were analyzed with a metabolome-wide association study to test for pathways and metabolites altered relative to controls. Gene expression was measured by quantitative-real time polymerase chain reaction.
Results:
Metabolic perturbations in amino-acid, oxidative stress, and fatty-acid pathways were observed for BghiP and HpCDD. HpCDD but not BghiP exposure increased gene expression of the amino acid transporters SLC7A5 and SLC7A11.
Conclusions:
Exposure to polycyclic aromatic hydrocarbons (PAH) or dioxins perturbs amino acid pathways at physiologically relevant concentrations with different mechanisms. These findings imply an effect on central homeostatic systems by environmental exposures which could have implications on disease susceptibility.
Thioredoxin-2 (Trx2) is a multifunctional, mitochondria-specific protein, which inhibits cell death. The mitochondrial permeability transition (MPT) is a distinct mechanism for cell death activated by oxidants and linked to both necrotic and apoptotic morphologies. We studied mitochondria from Trx2 transgenic mice to determine whether Trx2 protects against oxidant-induced MPT. All experiments were performed in isolated mitochondria. Results showed that Trx2 protected against MPT induced by exogenously added peroxide. Unexpectedly, Trx2 also protected against the MPT induced by Ca2+ in the absence of added peroxide. The results indicate that in addition to protecting against oxidative stress, Trx2 is an endogenous regulator of the MPT.
Obesity and obesity-related metabolic disorders are linked to the intestinal microbiome. However, the causality of changes in the microbiome–host interaction affecting energy metabolism remains controversial. Here, we show the microbiome-derived metabolite δ-valerobetaine (VB) is a diet-dependent obesogen that is increased with phenotypic obesity and is correlated with visceral adipose tissue mass in humans. VB is absent in germ-free mice and their mitochondria but present in ex-germ-free conventionalized mice and their mitochondria. Mechanistic studies in vivo and in vitro show VB is produced by diverse bacterial species and inhibits mitochondrial fatty acid oxidation through decreasing cellular carnitine and mitochondrial long-chain acyl-coenzyme As. VB administration to germ-free and conventional mice increases visceral fat mass and exacerbates hepatic steatosis with a western diet but not control diet. Thus, VB provides a molecular target to understand and potentially manage microbiome–host symbiosis or dysbiosis in diet-dependent obesity.
The redox potential of the major thiol/disulfide couple, cysteine (Cys) and its disulfide cystine (CySS), in plasma (EhCys) is oxidized in association with oxidative stress, and oxidized EhCys is associated with cardiovascular disease risk. In vitro exposure of monocytes to oxidized EhCys increases expression of the proinflammatory cytokine, interleukin-1β (IL-1β), suggesting that EhCys could be a mechanistic link between oxidative stress and chronic inflammation. Because cell membranes contain multiple Cys-rich proteins, which could be sensitive to EhCys, we sought to determine whether EhCys specifically affects proinflammatory signaling or has other effects on monocytes. We used microarray analysis and mass spectrometry–based proteomics to evaluate global changes in protein redox state, gene expression, and protein abundance in monocytes in response to EhCys. Pathway analysis results revealed that in addition to IL-1β-related pathways, components of stress/detoxification and cell death pathways were increased by oxidized EhCys, while components of cell growth and proliferation pathways were increased by a reduced potential. Phenotypic studies confirmed that a cell stress response occurred with oxidized Eh and that cell proliferation was stimulated with reduced Eh. Therefore, plasma EhCys provides a control over monocyte phenotype, which could contribute to cardiovascular disease risk and provide a novel therapeutic target for disease prevention.
The retinal pigment epithelium (RPE) is a particularly vulnerable tissue to age-dependent degeneration. Over the life span, the RPE develops an expanded endo-lysosomal compartment to maintain the high efficiency of phagocytosis and degradation of photoreceptor outer segments (POS) necessary for photoreceptor survival. As the assembly and activation of the mechanistic target of rapamycin complex 1 (mTORC1) occur on the lysosome surface, increased lysosome mass with aging leads to higher mTORC1 activity. The functional consequences of hyperactive mTORC1 in the RPE are unclear. In the current study, we used integrated high-resolution metabolomic and genomic approaches to examine mice with RPE-specific deletion of the tuberous sclerosis 1 (Tsc1) gene which encodes an upstream suppressor of mTORC1. Our data show that RPE cells with constitutively high mTORC1 activity were reprogramed to be hyperactive in glucose and lipid metabolism. Lipolysis was suppressed, mitochondrial carnitine shuttle was inhibited, while genes involved in fatty acid (FA) biosynthesis were upregulated. The metabolic changes occurred prior to structural changes of RPE and retinal degeneration. These findings have revealed cellular events and intrinsic mechanisms that contribute to lipid accumulation in the RPE cells during aging and age-related degeneration.
Phytochelatins (PyCs) are metal-binding compounds produced by plants. PyCs may reduce bioavailability of dietary toxic metals such as cadmium. However, the PyC concentrations in foods are unknown. The objective of this study was to analyze PyC contents in a subset of commonly consumed plant foods. Foods (20) across five groups were analyzed and PyCs quantified using liquid chromatography-mass spectrometry (LC-MS/MS). The impact of factors such as food processing were also explored. PyCs were in all 20 foods. Five PyC types were detected with PyC2-Gly, PyC3-Gly and PyC2-Ala at quantifiable concentrations. PyC2-Gly was found at the highest concentrations and most widely distributed. PyC2-Gly concentrations were highest in fruits and root vegetables. Foods with increased processing tended to have reduced PyC concentrations. This survey of commonly consumed plant foods in the United States demonstrates PyCs are widely distributed and provides a foundation for understanding their concentrations and impact in the human diet.
Abstract
Proteins with oxidizable thiols are essential to many functions of cell nuclei, including transcription, chromatin stability, nuclear protein import and export, and DNA replication and repair. Control of the nuclear thiol-disulfide redox states involves both the elimination of oxidants to prevent oxidation and the reduction of oxidized thiols to restore function. These processes depend on the common thiol reductants, glutathione (GSH) and thioredoxin-1 (Trx1). Recent evidence shows that these systems are controlled independent of the cytoplasmic counterparts. In addition, the GSH and Trx1 couples are not in redox equilibrium, indicating that these reductants have nonredundant functions in their support of proteins involved in transcriptional regulation, nuclear protein trafficking, and DNA repair. Specific isoforms of glutathione peroxidases, glutathione S-transferases, and peroxiredoxins are enriched in nuclei, further supporting the interpretation that functions of the thiol-dependent systems in nuclei are at least quantitatively distinct, and probably also qualitatively distinct, from similar processes in the cytoplasm. Elucidation of the distinct nuclear functions and regulation of the thiol redox pathways in nuclei can be expected to improve understanding of nuclear processes and also to provide the basis for novel approaches to treat aging and disease processes associated with oxidative stress in the nuclei. Antioxid. Redox Signal. 13, 489–509.
Objective:A study was conducted using serum samples and high-resolution metabolomics (HRM) to test for changes in abundance of environmental chemicals in deployment in high-risk areas (Balad, Iraq; Bagram, Afghanistan).Methods:Pre and Post-deployment serum samples for deployment (cases) and matched controls stationed domestically were analyzed by HRM and bioinformatics for the relative abundance of 271 environmental chemicals.Results:Of the 271 chemicals, 153 were measurable in at least 80% of the samples in one of the pre- or post-deployment groups. Several pesticides and other chemicals were modestly elevated post-deployment in the Control as well as the Bagram and Balad samples. Similarly, small decreases were seen for some chemicals.Conclusion:These results using serum samples show that for the 271 environmental chemicals studied, 56% were detected and small differences occurred with deployment to high-risk areas.
Objective:A study was conducted to identifymetabolic-related effects of benzo[a]pyrene (BaP) on human lung epithelial cells and validate these findings using human sera.Methods:Human lung epithelial cells were treated with BaP, and extracts were analyzed with a global metabolome-wide association study (MWAS) to test for pathways and metabolites altered relative to vehicle controls.Results:MWAS results showed that BaP metabolites were among the top metabolites differing between BaP-treated cells and controls. Pathway enrichment analysis further confirmed that fatty acid, lipid, and mitochondrial pathways were altered by BaP. Human sera analysis showed that lipids varied with BaP concentration. BaP associations with amino acid metabolism were found in both models.Conclusions:These findings show that BaP has broad metabolic effects, and suggest that air pollution exacerbates disease processes by altered mitochondrial and amino acid metabolism.
Objective:To develop a computational approach to link clinical outcomes with environmental exposures and molecular variations measured in Department of Defense (DOD) serum-repository samples.Methods:International Classification of Diseases, Ninth Division codes which corresponded to cardiopulmonary symptoms for service personnel were selected to test for associations with deployment-related inhalation hazards and metabolomics, micro-RNA, cytokine, plasma markers, and environmental exposure analyses for corresponding samples. xMWAS and Mummichog were used for integrative network and pathway analysis.Results:Comparison between 41 personnel exhibiting new cardio-pulmonary diagnoses after deployment start-date to 25 personnel exhibiting no symptoms identified biomarkers associated with cardiopulmonary conditions. Integrative network and pathway analysis showed communities of clinical, molecular, and environmental markers associated with fatty acid, lipid, nucleotide, and amino acid metabolism pathways.Conclusions:The current proof of principle study establishes a computational framework for integrative analysis of deployment-related exposures, molecular responses, and health outcomes.