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.

Exposome Epidemiology for Suspect Environmental Chemical Exposures during Pregnancy Linked to Subsequent Breast Cancer Diagnosis.

Breast cancer is now the most common cancer globally, accounting for 12% of all new annual cancer cases worldwide. Despite epidemiologic studies having established a number of risk factors, knowledge of chemical exposure risks is limited to a relatively small number of chemicals. In this exposome research study, we used non-targeted, high-resolution mass spectrometry (HRMS) of pregnancy cohort biospecimens in the Child Health and Development Studies (CHDS) to test for associations with breast cancer identified via the California Cancer Registry. Second (T2) and third (T3) trimester archival samples were analyzed from 182 women who subsequently developed breast cancer and 384 randomly selected women who did not develop breast cancer. Environmental chemicals were annotated with the Toxin and Toxin-Target Database (T3DB) for chemical signals that were higher in breast cancer cases and used with an exposome epidemiology analytic framework to identify suspect chemicals and associated metabolic networks. Network and pathway enrichment analyses showed consistent linkage in both T2 and T3 to inflammation pathways, including linoleate, arachidonic acid and prostaglandins, and identified new suspect environmental chemicals associated with breast cancer, i.e., an N-substituted piperidine insecticide and a common commercial product, 2,4-dinitrophenol (DNP), linked to variations in amino acid and nucleotide pathways in T2 and benzo[a]carbazole and a benzoate derivative linked to glycan and amino sugar metabolism in T3. The results identify new suspect environmental chemical risk factors for breast cancer and provide an exposome epidemiology framework for discovery of suspect environmental chemicals and potential mechanistic associations with breast cancer.

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.

Per- and polyfluoroalkyl substance (PFAS) exposure, maternal metabolomic perturbation, and fetal growth in African American women: A meet-in-the-middle approach.

BACKGROUND: Prenatal exposures to per- and polyfluoroalkyl substances (PFAS) have been linked to reduced fetal growth. However, the detailed molecular mechanisms remain largely unknown. This study aims to investigate biological pathways and intermediate biomarkers underlying the association between serum PFAS and fetal growth using high-resolution metabolomics in a cohort of pregnant African American women in the Atlanta area, Georgia. METHODS: Serum perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) measurements and untargeted serum metabolomics profiling were conducted in 313 pregnant African American women at 8-14 weeks gestation. Multiple linear regression models were applied to assess the associations of PFAS with birth weight and small-for-gestational age (SGA) birth. A high-resolution metabolomics workflow including metabolome-wide association study, pathway enrichment analysis, and chemical annotation and confirmation with a meet-in-the-middle approach was performed to characterize the biological pathways and intermediate biomarkers of the PFAS-fetal growth relationship. RESULTS: Each log2-unit increase in serum PFNA concentration was significantly associated with higher odds of SGA birth (OR = 1.32, 95% CI 1.07, 1.63); similar but borderline significant associations were found in PFOA (OR = 1.20, 95% CI 0.94, 1.49) with SGA. Among 25,516 metabolic features extracted from the serum samples, we successfully annotated and confirmed 10 overlapping metabolites associated with both PFAS and fetal growth endpoints, including glycine, taurine, uric acid, ferulic acid, 2-hexyl-3-phenyl-2-propenal, unsaturated fatty acid C18:1, androgenic hormone conjugate, parent bile acid, and bile acid-glycine conjugate. Also, we identified 21 overlapping metabolic pathways from pathway enrichment analyses. These overlapping metabolites and pathways were closely related to amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolism perturbations. CONCLUSION: In this cohort of pregnant African American women, higher serum concentrations of PFOA and PFNA were associated with reduced fetal growth. Perturbations of biological pathways involved in amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolism were associated with PFAS exposures and reduced fetal growth, and uric acid was shown to be a potential intermediate biomarker. Our results provide opportunities for future studies to develop early detection and intervention for PFAS-induced fetal growth restriction.