A nested case-control study of untargeted plasma metabolomics and lung cancer among never-smoking women within the prospective Shanghai Women's Health Study.

The etiology of lung cancer in never-smokers remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Here, we aimed to enhance our understanding of lung cancer pathogenesis among never-smokers using untargeted metabolomics. This nested case-control study included 395 never-smoking women who developed lung cancer and 395 matched never-smoking cancer-free women from the prospective Shanghai Women's Health Study with 15,353 metabolic features quantified in pre-diagnostic plasma using liquid chromatography high-resolution mass spectrometry. Recognizing that metabolites often correlate and seldom act independently in biological processes, we utilized a weighted correlation network analysis to agnostically construct 28 network modules of correlated metabolites. Using conditional logistic regression models, we assessed the associations for both metabolic network modules and individual metabolic features with lung cancer, accounting for multiple testing using a false discovery rate (FDR) < 0.20. We identified a network module of 121 features inversely associated with all lung cancer (p = .001, FDR = 0.028) and lung adenocarcinoma (p = .002, FDR = 0.056), where lyso-glycerophospholipids played a key role driving these associations. Another module of 440 features was inversely associated with lung adenocarcinoma (p = .014, FDR = 0.196). Individual metabolites within these network modules were enriched in biological pathways linked to oxidative stress, and energy metabolism. These pathways have been implicated in previous metabolomics studies involving populations exposed to known lung cancer risk factors such as traffic-related air pollution and polycyclic aromatic hydrocarbons. Our results suggest that untargeted plasma metabolomics could provide novel insights into the etiology and risk factors of lung cancer among never-smokers.

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.

Exposure to per- and polyfluoroalkyl substances and high-throughput proteomics in Hispanic youth.

BACKGROUND: Strong epidemiological evidence shows positive associations between exposure to per- and polyfluoroalkyl substances (PFAS) and adverse cardiometabolic outcomes (e.g., diabetes, hypertension, and dyslipidemia). However, the underlying cardiometabolic-relevant biological activities of PFAS in humans remain largely unclear. AIM: We evaluated the associations of PFAS exposure with high-throughput proteomics in Hispanic youth. MATERIAL AND METHODS: We included 312 overweight/obese adolescents from the Study of Latino Adolescents at Risk (SOLAR) between 2001 and 2012, along with 137 young adults from the Metabolic and Asthma Incidence Research (Meta-AIR) between 2014 and 2018. Plasma PFAS (i.e., PFOS, PFOA, PFHxS, PFHpS, PFNA) were quantified using liquid-chromatography high-resolution mass spectrometry. Plasma proteins (n = 334) were measured utilizing the proximity extension assay using an Olink Explore Cardiometabolic Panel I. We conducted linear regression with covariate adjustment to identify PFAS-associated proteins. Ingenuity Pathway Analysis, protein-protein interaction network analysis, and protein annotation were used to investigate alterations in biological functions and protein clusters. RESULTS: Results after adjusting for multiple comparisons showed 13 significant PFAS-associated proteins in SOLAR and six in Meta-AIR, sharing similar functions in inflammation, immunity, and oxidative stress. In SOLAR, PFNA demonstrated significant positive associations with the largest number of proteins, including ACP5, CLEC1A, HMOX1, LRP11, MCAM, SPARCL1, and SSC5D. After considering the mixture effect of PFAS, only SSC5D remained significant. In Meta-AIR, PFAS mixtures showed positive associations with GDF15 and IL6. Exploratory analysis showed similar findings. Specifically, pathway analysis in SOLAR showed PFOA- and PFNA-associated activation of immune-related pathways, and PFNA-associated activation of inflammatory response. In Meta-AIR, PFHxS-associated activation of dendric cell maturation was found. Moreover, PFAS was associated with common protein clusters of immunoregulatory interactions and JAK-STAT signaling in both cohorts. CONCLUSION: PFAS was associated with broad alterations of the proteomic profiles linked to pro-inflammation and immunoregulation. The biological functions of these proteins provide insight into potential molecular mechanisms of PFAS toxicity.

Repeated exposure to eucalyptus wood smoke alters pulmonary gene and metabolic profiles in male Long-Evans rats.

Exposure to wildfire smoke is associated with both acute and chronic cardiopulmonary illnesses, which are of special concern for wildland firefighters who experience repeated exposure to wood smoke. It is necessary to better understand the underlying pathophysiology by which wood smoke exposure increases pulmonary disease burdens in this population. We hypothesize that wood smoke exposure produces pulmonary dysfunction, lung inflammation, and gene expression profiles associated with future pulmonary complications. Male Long-Evans rats were intermittently exposed to smoldering eucalyptus wood smoke at two concentrations, low (11.0 ± 1.89 mg/m3) and high (23.7 ± 0.077 mg/m3), over a 2-week period. Whole body plethysmography was measured intermittently throughout. Lung tissue and lavage fluid were collected 24 hours after the final exposure for transcriptomics and metabolomics. Increasing smoke exposure upregulated neutrophils and select cytokines in the bronchoalveolar lavage fluid. In total, 3,446 genes were differentially expressed in the lungs of rats in the high smoke exposure and only one gene in the low smoke exposure (Cd151). Genes altered in the high smoke group reflected changes to the Eukaryotic Initiation Factor 2 (EIF2) stress and oxidative stress responses, which mirrored metabolomics analyses. xMWAS-integrated analysis revealed that smoke exposure significantly altered pathways associated with oxidative stress, lung morphogenesis, and tumor proliferation pathways. These results indicate that intermittent, 2-week exposure to eucalyptus wood smoke leads to transcriptomic and metabolic changes in the lung that may predict future lung disease development. Collectively, these findings provide insight into cellular signaling pathways that may contribute to the chronic pulmonary conditions observed in wildland firefighters.

Redox organization of living systems.

Redox organization governs an underlying simplicity in living systems. Critically, redox reactions enable the essential characteristics of life: extraction of energy from the environment, use of energy to support metabolic and structural organization, use of dynamic redox responses to defend against environmental threats, and use of redox mechanisms to direct differentiation of cells and organ systems essential for reproduction. These processes are sustained through a redox context in which electron donor/acceptor couples are poised at substantially different steady-state redox potentials, some with relatively reducing steady states and others with relatively oxidizing steady states. Redox-sensitive thiols of the redox proteome, as well as low molecular weight redox-active molecules, are maintained individually by the kinetics of oxidation-reduction within this redox system. Recent research has revealed opposing network interactions of the metallome, redox proteome, metabolome and transcriptome, which appear to be an evolved redox response structure to maintain stability of an organism in the presence of variable oxidative environments. Considerable opportunity exists to improve human health through detailed understanding of these redox networks so that targeted interventions can be developed to support new avenues for redox medicine.

Associations of dietary intake and longitudinal measures of per- and polyfluoroalkyl substances (PFAS) in predominantly Hispanic young Adults: A multicohort study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are pollutants linked to adverse health effects. Diet is an important source of PFAS exposure, yet it is unknown how diet impacts longitudinal PFAS levels. OBJECTIVE: To determine if dietary intake and food sources were associated with changes in blood PFAS concentrations among Hispanic young adults at risk of metabolic diseases. METHODS: Predominantly Hispanic young adults from the Children's Health Study who underwent two visits (CHS; n = 123) and young adults from NHANES 2013-2018 who underwent one visit (n = 604) were included. Dietary data at baseline was collected using two 24-hour dietary recalls to measure individual foods and where foods were prepared/consumed (home/restaurant/fast-food). PFAS were measured in blood at both visits in CHS and cross-sectionally in NHANES. In CHS, multiple linear regression assessed associations of baseline diet with longitudinal PFAS; in NHANES, linear regression was used. RESULTS: In CHS, all PFAS except PFDA decreased across visits (all p < 0.05). In CHS, A 1-serving higher tea intake was associated with 24.8 %, 16.17 %, and 12.6 % higher PFHxS, PFHpS, and PFNA at follow-up, respectively (all p < 0.05). A 1-serving higher pork intake was associated with 13.4 % higher PFOA at follow-up (p < 0.05). Associations were similar in NHANES, including unsweetened tea, hot dogs, and processed meats. For food sources, in CHS each 200-gram increase in home-prepared food was associated with 0.90 % and 1.6 % lower PFOS at baseline and follow-up, respectively, and in NHANES was associated with 0.9 % lower PFDA (all p < 0.05). CONCLUSION: Results suggest that beverage consumption habits and food preparation are associated with differences in PFAS levels in young adults. This highlights the importance of diet in determining PFAS exposure and the necessity of public monitoring of foods and beverages for PFAS contamination.

Protein S-palmitoylation enhances profibrotic signaling in response to cadmium.

Cadmium (Cd) is a naturally occurring, toxic environmental metal found in foods. Humans do not have an efficient mechanism for Cd elimination; thus, Cd burden in humans increases with age. Cell and mouse studies show that Cd burden from low environmental levels of exposure impacts lung cell metabolism, proliferation signaling and cell growth as part of disease-promoting profibrotic responses in the lungs. Prior integrative analysis of metabolomics and transcriptomics identified the zDHHC11 transcript as a central functional hub in response to Cd dose. zDHHC11 encodes a protein S-palmitoyltransferase, but no evidence is available for effects of Cd on protein S-palmitoylation. In the present research, we studied palmitoylation changes in response to Cd and found increased protein S-palmitoylation in human lung fibroblasts that was inhibited by 2-bromopalmitate (2-BP), an irreversible palmitoyltransferase inhibitor. Mass spectrometry-based proteomics showed palmitoylation of proteins involved in divalent metal transport and in fibrotic signaling. Mechanistic studies showed that 2-BP inhibited palmitoylation of divalent metal ion transporter ZIP14 and also inhibited cellular Cd uptake. Transcription analyses showed that Cd stimulated transforming growth factor (TGF)-ß1 and ß3 expression within 8 h and lung fibrotic markers α-smooth muscle actin, matrix metalloproteinase-2, and collagen 1α1 gene expression and that these effects were blocked by 2-BP. Because 2-BP also blocked palmitoylation of proteins controlled by TGFß1, these results show that palmitoylation impacts Cd-dependent fibrotic signaling both by enhancing cellular Cd accumulation and by supporting post-translational processing of TGFß1-dependent proteins.

Metabolomic signatures of ideal cardiovascular health in black adults.

Plasma metabolomics profiling is an emerging methodology to identify metabolic pathways underlying cardiovascular health (CVH). The objective of this study was to define metabolomic profiles underlying CVH in a cohort of Black adults, a population that is understudied but suffers from disparate levels of CVD risk factors. The Morehouse-Emory Cardiovascular (MECA) Center for Health Equity study cohort consisted of 375 Black adults (age 53 ± 10, 39% male) without known CVD. CVH was determined by the AHA Life's Simple 7 (LS7) score, calculated from measured blood pressure, body mass index (BMI), fasting blood glucose and total cholesterol, and self-reported physical activity, diet, and smoking. Plasma metabolites were assessed using untargeted high-resolution metabolomics profiling. A metabolome wide association study (MWAS) identified metabolites associated with LS7 score after adjusting for age and sex. Using Mummichog software, metabolic pathways that were significantly enriched in metabolites associated with LS7 score were identified. Metabolites representative of these pathways were compared across clinical domains of LS7 score and then developed into a metabolomics risk score for prediction of CVH. We identified novel metabolomic signatures and pathways associated with CVH in a cohort of Black adults without known CVD. Representative and highly prevalent metabolites from these pathways included glutamine, glutamate, urate, tyrosine and alanine, the concentrations of which varied with BMI, fasting glucose, and blood pressure levels. When assessed in conjunction, these metabolites were independent predictors of CVH. One SD increase in the novel metabolomics risk score was associated with a 0.88 higher LS7 score, which translates to a 10.4% lower incident CVD risk. We identified novel metabolomic signatures of ideal CVH in a cohort of Black Americans, showing that a core group of metabolites central to nitrogen balance, bioenergetics, gluconeogenesis, and nucleotide synthesis were associated with CVH in this population.

Exposure to perfluoroalkyl substances and longitudinal changes in bone mineral density in adolescents and young adults: A multi-cohort study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) may impair bone development in adolescence, which impacts life-long bone health. No previous studies have examined prospective associations of individual PFAS and their mixture with bone mineral density (BMD) changes in Hispanic young persons, a population at high risk of osteoporosis in adulthood. OBJECTIVES: To examine associations of individual PFAS and PFAS mixtures with longitudinal changes in BMD in an adolescent Hispanic cohort and examine generalizability of findings in a mixed-ethnicity young adult cohort (58.4% Hispanic). METHODS: Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; n = 304; mean follow-up = 1.4 years) and young adults from the Southern California Children's Health Study (CHS; n = 137; mean follow-up = 4.1 years) were included in this study. Plasma PFAS were measured at baseline and dual x-ray absorptiometry scans were performed at baseline and follow-up to measure BMD. We estimated longitudinal associations between BMD and five PFAS via separate covariate-adjusted linear mixed effects models, and between BMD and the PFAS mixture via quantile g-computation. RESULTS: In SOLAR adolescents, baseline plasma perfluorooctanesulfonic acid (PFOS) was associated with longitudinal changes in BMD. Each doubling of PFOS was associated with an average -0.003 g/cm2 difference in change in trunk BMD per year over follow-up (95% CI: -0.005, -0.0002). Associations with PFOS persisted in CHS young adults, where each doubling of plasma PFOS was associated with an average -0.032 g/cm2 difference in total BMD at baseline (95% CI -0.062, -0.003), though longitudinal associations were non-significant. We did not find associations of other PFAS with BMD; associations of the PFAS mixture with BMD outcomes were primarily negative though non-significant. DISCUSSION: PFOS exposure was associated with lower BMD in adolescence and young adulthood, important periods for bone development, which may have implications on future bone health and risk of osteoporosis in adulthood.

Postprandial Metabolite Profiles and Risk of Prediabetes in Young People: A Longitudinal Multicohort Study.

OBJECTIVE: Prediabetes in young people is an emerging epidemic that disproportionately impacts Hispanic populations. We aimed to develop a metabolite-based prediction model for prediabetes in young people with overweight/obesity at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS: In independent, prospective cohorts of Hispanic youth (discovery; n = 143 without baseline prediabetes) and predominately Hispanic young adults (validation; n = 56 without baseline prediabetes), we assessed prediabetes via 2-h oral glucose tolerance tests. Baseline metabolite levels were measured in plasma from a 2-h postglucose challenge. In the discovery cohort, least absolute shrinkage and selection operator regression with a stability selection procedure was used to identify robust predictive metabolites for prediabetes. Predictive performance was evaluated in the discovery and validation cohorts using logistic regression. RESULTS: Two metabolites (allylphenol sulfate and caprylic acid) were found to predict prediabetes beyond known risk factors, including sex, BMI, age, ethnicity, fasting/2-h glucose, total cholesterol, and triglycerides. In the discovery cohort, the area under the receiver operator characteristic curve (AUC) of the model with metabolites and known risk factors was 0.80 (95% CI 0.72-0.87), which was higher than the risk factor-only model (AUC 0.63 [0.53-0.73]; P = 0.001). When the predictive models developed in the discovery cohort were applied to the replication cohort, the model with metabolites and risk factors predicted prediabetes more accurately (AUC 0.70 [95% CI 40.55-0.86]) than the same model without metabolites (AUC 0.62 [0.46-0.79]). CONCLUSIONS: Metabolite profiles may help improve prediabetes prediction compared with traditional risk factors. Findings suggest that medium-chain fatty acids and phytochemicals are early indicators of prediabetes in high-risk youth.

A prediction model for classifying maternal pregnancy smoking using California state birth certificate information.

BACKGROUND: Systematically recorded smoking data are not always available in vital statistics records, and even when available it can underestimate true smoking rates. OBJECTIVE: To develop a prediction model for maternal tobacco smoking in late pregnancy based on birth certificate information using a combination of self- or provider-reported smoking and biomarkers (smoking metabolites) in neonatal blood spots as the alloyed gold standard. METHODS: We designed a case-control study where childhood cancer cases were identified from the California Cancer Registry and controls were from the California birth rolls between 1983 and 2011 who were cancer-free by the age of six. In this analysis, we included 894 control participants and performed high-resolution metabolomics analyses in their neonatal dried blood spots, where we extracted cotinine [mass-to-charge ratio (m/z) = 177.1023] and hydroxycotinine (m/z = 193.0973). Potential predictors of smoking were selected from California birth certificates. Logistic regression with stepwise backward selection was used to build a prediction model. Model performance was evaluated in a training sample, a bootstrapped sample, and an external validation sample. RESULTS: Out of seven predictor variables entered into the logistic model, five were selected by the stepwise procedure: maternal race/ethnicity, maternal education, child's birth year, parity, and child's birth weight. We calculated an overall discrimination accuracy of 0.72 and an area under the receiver operating characteristic curve (AUC) of 0.81 (95% confidence interval [CI] 0.77, 0.84) in the training set. Similar accuracies were achieved in the internal (AUC 0.81, 95% CI 0.77, 0.84) and external (AUC 0.69, 95% CI 0.64, 0.74) validation sets. CONCLUSIONS: This easy-to-apply model may benefit future birth registry-based studies when there is missing maternal smoking information; however, some smoking status misclassification remains a concern when only variables from the birth certificate are used to predict maternal smoking.

Combined cerebrospinal fluid metabolomic and cytokine profiling in tuberculosis meningitis reveals robust and prolonged changes in immunometabolic networks.

Much of the high mortality in tuberculosis meningitis (TBM) is attributable to excessive inflammation, making it imperative to identify targets for host-directed therapies that reduce pathologic inflammation and mortality. In this study, we investigate how cytokines and metabolites in the cerebral spinal fluid (CSF) associate with TBM at diagnosis and during TBM treatment. At diagnosis, TBM patients (n = 17) demonstrate significant increases of cytokines and chemokines that promote inflammation and cell migration including IL-17A, IL-2, TNFα, IFNγ, and IL-1ß versus asymptomatic controls without known central nervous system pathology (n = 20). Inflammatory immune signaling had a strong positive correlation with immunomodulatory metabolites including kynurenine, lactic acid, and carnitine and strong negative correlations with tryptophan and itaconate. Inflammatory immunometabolic networks were only partially reversed with two months of effective TBM treatment and remained significantly different compared to CSF from controls. Together, these data highlight a critical role for host metabolism in regulating the inflammatory response to TBM and indicate the timeline for restoration of immune homeostasis in the CSF is prolonged.

Metabolomic Effects of Folic Acid Supplementation in Adults: Evidence from the FACT Trial.

BACKGROUND: Folic acid (FA) is the oxidized form of folate found in supplements and FA-fortified foods. Most FA is reduced by dihydrofolate reductase to 5-methyltetrahydrofolate (5mTHF); the latter is the form of folate naturally found in foods. Ingestion of FA increases the plasma levels of both 5mTHF and unmetabolized FA (UMFA). Limited information is available on the downstream metabolic effects of FA supplementation, including potential effects associated with UMFA. OBJECTIVE: We aimed to assess the metabolic effects of FA-supplementation, and the associations of plasma 5mTHF and UMFA with the metabolome in FA-naïve Bangladeshi adults. METHODS: Sixty participants were selected from the Folic Acid and Creatine Trial; half received 800 µg FA/day for 12 weeks and half placebo. Plasma metabolome profiles were measured by high-resolution mass spectrometry, including 170 identified metabolites and 26,541 metabolic features. Penalized regression methods were used to assess the associations of targeted metabolites with FA-supplementation, plasma 5mTHF, and plasma UMFA. Pathway analyses were conducted using Mummichog. RESULTS: In penalized models of identified metabolites, FA-supplementation was associated with higher choline. Changes in 5mTHF concentrations were positively associated with metabolites involved in amino acid metabolism (5-hydroxyindoleacetic acid, acetylmethionine, creatinine, guanidinoacetate, hydroxyproline/n-acetylalanine) and 2 fatty acids (docosahexaenoic acid and linoleic acid). Changes in 5mTHF concentrations were negatively associated with acetylglutamate, acetyllysine, carnitine, propionyl carnitine, cinnamic acid, homogentisate, arachidonic acid, and nicotine. UMFA concentrations were associated with lower levels of arachidonic acid. Together, metabolites selected across all models were related to lipids, aromatic amino acid metabolism, and the urea cycle. Analyses of nontargeted metabolic features identified additional pathways associated with FA supplementation. CONCLUSION: In addition to the recapitulation of several expected metabolic changes associated with 5mTHF, we observed additional metabolites/pathways associated with FA-supplementation and UMFA. Further studies are needed to confirm these associations and assess their potential implications for human health. TRIAL REGISTRATION NUMBER: This trial was registered at https://clinicaltrials.gov as NCT01050556.

Neonatal per- and polyfluoroalkyl substance exposure in relation to retinoblastoma.

BACKGROUND: Neonatal per- and polyfluoroalkyl substance (PFAS) exposure can disrupt hormonal homeostasis and induce neuro- and immunotoxicity in children. In this exploratory study, we investigated associations between PFAS levels in neonatal dried blood spots and retinoblastoma risk. MATERIALS AND METHODS: This study included 501 retinoblastoma cases born from 1983 to 2011 and 899 controls frequency-matched by birth year (20:1 matching ratio), born to 755 US-born and 366 Mexico-born mothers in California. Perfluorooctanesulfonic acid (PFOS), perflurooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) feature intensities were identified from neonatal blood spots from California newborn Genetic Disease Screening Program. Using logistic regression, we assessed whether an interquartile range (IQR) increase of PFAS levels or having above-mean levels of PFAS in blood affects retinoblastoma risk overall or its subtypes (i.e., unilateral, bilateral). We assessed children of US-born and Mexico-born mothers, separately. RESULTS AND DISCUSSION: Among all children, above-mean PFOS levels at birth increased the odds of retinoblastoma overall by 29% (95% Confidence Interval (CI): 1.00, 1.67) and unilateral retinoblastoma by 42% (95% CI: 1.03, 1.97). For children of Mexico-born mothers, we estimated the highest odds of retinoblastoma overall (adjusted odds ratio (aOR): 1.67; 95% CI: 1.06, 2.66) and bilateral retinoblastoma (aOR: 2.06; 95% CI: 1.12, 3.92) with above-mean PFOS levels. Among children of US-born mothers, higher PFOS levels increased the odds of unilateral retinoblastoma by 15% (95% CI: 0.99, 1.35) for each IQR increase and by 71% among children with above-mean PFOS levels (95% CI: 1.04, 2.90). In addition, for children of US-born mothers, PFOA increased the odds of retinoblastoma overall (aOR: 1.41; 95% CI: 1.00, 2.02 for above-mean levels, aOR: 1.06; 95% CI: 0.98, 1.16 per IQR increase). PFNA was not associated with retinoblastoma risk. CONCLUSIONS: Our results suggested that PFOS and PFOA might contribute to retinoblastoma risk in children born in California.

Dioxin(-like)-Related Biological Effects through Integrated Chemical-wide and Metabolome-wide Analyses.

Dioxin(-like) exposures are linked to adverse health effects, including cancer. However, metabolic alterations induced by these chemicals remain largely unknown. Beyond known dioxin(-like) compounds, we leveraged a chemical-wide approach to assess chlorinated co-exposures and parent compound products [termed dioxin(-like)-related compounds] among 137 occupational workers. Endogenous metabolites were profiled by untargeted metabolomics, namely, reversed-phase chromatography with negative electrospray ionization (C18-negative) and hydrophilic interaction liquid chromatography with positive electrospray ionization (HILIC-positive). We performed a metabolome-wide association study to select dioxin(-like) associated metabolic features using a 20% false discovery rate threshold. Metabolic features were then characterized by pathway enrichment analyses. There are no significant features associated with polychlorinated dibenzo-p-dioxins (PCDDs), a subgroup of known dioxin(-like) compounds. However, 3,110 C18-negative and 2,894 HILIC-positive features were associated with at least one of the PCDD-related compounds. Abundant metabolic changes were also observed for polychlorinated dibenzofuran-related and polychlorinated biphenyl-related compounds. These metabolic features were primarily enriched in pathways of amino acids, lipid and fatty acids, carbohydrates, cofactors, and nucleotides. Our study highlights the potential of chemical-wide analysis for comprehensive exposure assessment beyond targeted chemicals. Coupled with advanced endogenous metabolomics, this approach allows for an in-depth exploration of metabolic alterations induced by environmental chemicals.

Maternal and newborn metabolomic changes associated with urinary polycyclic aromatic hydrocarbon metabolite concentrations at delivery: an untargeted approach.

INTRODUCTION: Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse human health outcomes. To explore the plausible associations between maternal PAH exposure and maternal/newborn metabolomic outcomes, we conducted a cross-sectional study among 75 pregnant people from Cincinnati, Ohio. METHOD: We quantified 8 monohydroxylated PAH metabolites in maternal urine samples collected at delivery. We then used an untargeted high-resolution mass spectrometry approach to examine alterations in the maternal (n = 72) and newborn (n = 63) serum metabolome associated with PAH metabolites. Associations between individual maternal urinary PAH metabolites and maternal/newborn metabolome were assessed using linear regression adjusted for maternal and newborn factors while accounting for multiple testing with the Benjamini-Hochberg method. We then conducted functional analysis to identify potential biological pathways. RESULTS: Our results from the metabolome-wide associations (MWAS) indicated that an average of 1% newborn metabolome features and 2% maternal metabolome features were associated with maternal urinary PAH metabolites. Individual PAH metabolite concentrations in maternal urine were associated with maternal/newborn metabolome related to metabolism of vitamins, amino acids, fatty acids, lipids, carbohydrates, nucleotides, energy, xenobiotics, glycan, and organic compounds. CONCLUSION: In this cross-sectional study, we identified associations between urinary PAH concentrations during late pregnancy and metabolic features associated with several metabolic pathways among pregnant women and newborns. Further studies are needed to explore the mediating role of the metabolome in the relationship between PAHs and adverse pregnancy outcomes.

The redox code of plants.

Central metabolism is organised through high-flux, Nicotinamide Adenine Dinucleotide (NAD+ /NADH) and NADP+ /NADPH systems operating at near equilibrium. As oxygen is indispensable for aerobic organisms, these systems are also linked to the levels of reactive oxygen species, such as H2 O2 , and through H2 O2 to the regulation of macromolecular structures and activities, via kinetically controlled sulphur switches in the redox proteome. Dynamic changes in H2 O2 production, scavenging and transport, associated with development, growth and responses to the environment are, therefore, linked to the redox state of the cell and regulate cellular function. These basic principles form the 'redox code' of cells and were first defined by D. P. Jones and H. Sies in 2015. Here, we apply these principles to plants in which recent studies have shown that they can also explain cell-to-cell and even plant-to-plant signalling processes. The redox code is, therefore, an integral part of biological systems and can be used to explain multiple processes in plants at the subcellular, cellular, tissue, whole organism and perhaps even community and ecosystem levels. As the environmental conditions on our planet are worsening due to global warming, climate change and increased pollution levels, new studies are needed applying the redox code of plants to these changes.

Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson's disease.

BACKGROUND: Untargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands of metabolites. Metabolic networks based on these data can help uncover disease-related perturbations across interconnected pathways. OBJECTIVE: Identify metabolic disturbances associated with Parkinson's disease (PD) in two population-based studies using untargeted metabolomics. METHODS: We performed a metabolome-wide association study (MWAS) of PD using serum-based untargeted metabolomics data derived from liquid chromatography with high-resolution mass spectrometry (LC-HRMS) using two distinct population-based case-control populations. We also combined our results with a previous publication of 34 metabolites linked to PD in a large-scale, untargeted MWAS to assess external validation. RESULTS: LC-HRMS detected 4,762 metabolites for analysis (HILIC: 2716 metabolites; C18: 2046 metabolites). We identified 296 features associated with PD at FDR<0.05, 134 having a log2 fold change (FC) beyond ±0.5 (228 beyond ±0.25). Of these, 104 were independently associated with PD in both discovery and replication studies at p<0.05 (170 at p<0.10), while 27 were associated with levodopa-equivalent dose among the PD patients. Intriguingly, among the externally validated features were the microbial-related metabolites, p-cresol glucuronide (FC=2.52, 95% CI=1.67, 3.81, FDR=7.8e-04) and p-cresol sulfate. P-cresol glucuronide was also associated with motor symptoms among patients. Additional externally validated metabolites associated with PD include phenylacetyl-L-glutamine, trigonelline, kynurenine, biliverdin, and pantothenic acid. Novel associations include the anti-inflammatory metabolite itaconate (FC=0.79, 95% CI=0.73, 0.86; FDR=2.17E-06) and cysteine-S-sulfate (FC=1.56, 95% CI=1.39, 1.75; FDR=3.43E-11). Seventeen pathways were enriched, including several related to amino acid and lipid metabolism. CONCLUSIONS: Our results revealed PD-associated metabolites, confirming several previous observations, including for p-cresol glucuronide, and newly implicating interesting metabolites, such as itaconate. Our data also suggests metabolic disturbances in amino acid and lipid metabolism and inflammatory processes in PD.

The neonatal blood spot metabolome in retinoblastoma.

Background: Retinoblastoma is rare but nevertheless the most common pediatric eye cancer that occurs in children under age 5. High-resolution metabolomics (HRM) is a powerful analytical approach to profile metabolic features and pathways or identify metabolite biomarkers. To date, no studies have used pre-diagnosis blood samples from retinoblastoma cases and compared them to healthy controls to elucidate early perturbations in tumor pathways. Objectives: Here, we report on metabolic profiles of neonatal blood comparing cases later in childhood diagnosed with retinoblastoma and controls. Methods: We employed untargeted metabolomics analysis using neonatal dried blood spots for 1327 children (474 retinoblastoma cases and 853 healthy controls) born in California from 1983 to 2011. Cases were selected from the California Cancer Registry and controls, frequency matched to cases by birth year, from California birth rolls. We performed high-resolution metabolomics to extract metabolic features, partial least squares discriminant analysis (PLS-DA) and logistic regression to identify features associated with disease, and Mummichog pathway analysis to characterize enriched biological pathways. Results: PLS-DA identified 1917 discriminative features associated with retinoblastoma and Mummichog identified 14 retinoblastoma-related enriched pathways including linoleate metabolism, pentose phosphate pathway, pyrimidine metabolism, fructose and mannose metabolism, vitamin A metabolism, as well as fatty acid and lipid metabolism. Interpretation: Our findings linked a retinoblastoma diagnosis in early life to newborn blood metabolome perturbations indicating alterations in inflammatory pathways and energy metabolism. Neonatal blood spots may provide a venue for early detection for this or potentially other childhood cancers.

Fecal microbiota transplantation promotes reduction of antimicrobial resistance by strain replacement.

Multidrug-resistant organism (MDRO) colonization is a fundamental challenge in antimicrobial resistance. Limited studies have shown that fecal microbiota transplantation (FMT) can reduce MDRO colonization, but its mechanisms are poorly understood. We conducted a randomized, controlled trial of FMT for MDRO decolonization in renal transplant recipients called PREMIX (NCT02922816). Eleven participants were enrolled and randomized 1:1 to FMT or an observation period followed by delayed FMT if stool cultures were MDRO positive at day 36. Participants who were MDRO positive after one FMT were treated with a second FMT. At last visit, eight of nine patients who completed all treatments were MDRO culture negative. FMT-treated participants had longer time to recurrent MDRO infection versus PREMIX-eligible controls who were not treated with FMT. Key taxa (Akkermansia muciniphila, Alistipes putredinis, Phocaeicola dorei, Phascolarctobacterium faecium, Alistipes species, Mesosutterella massiliensis, Barnesiella intestinihominis, and Faecalibacterium prausnitzii) from the single feces donor used in the study that engrafted in recipients and metabolites such as short-chain fatty acids and bile acids in FMT-responding participants uncovered leads for rational microbiome therapeutic and diagnostic development. Metagenomic analyses revealed a previously unobserved mechanism of MDRO eradication by conspecific strain competition in an FMT-treated subset. Susceptible Enterobacterales strains that replaced baseline extended-spectrum ß-lactamase-producing strains were not detectable in donor microbiota manufactured as FMT doses but in one case were detectable in the recipient before FMT. These data suggest that FMT may provide a path to exploit strain competition to reduce MDRO colonization.