Publications by authors named "Douglas I Walker"

75 Publications

Exposure to Perfluoroalkyl Substances and Glucose Homeostasis in Youth.

Environ Health Perspect 2021 Sep 1;129(9):97002. Epub 2021 Sep 1.

Department of Population and Public Health Sciences, University of Southern California, Los Angeles, California, USA.

Background: Exposure to per- and polyfluoroalkyl substances (PFAS), a prevalent class of persistent pollutants, may increase the risk of type 2 diabetes.

Objective: We examined associations between PFAS exposure and glucose metabolism in youth.

Methods: Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; ) participated in annual visits for an average of . Generalizability of findings were tested in young adults from the Southern California Children's Health Study (CHS; ) who participated in a clinical visit with a similar protocol. At each visit, oral glucose tolerance tests were performed to estimate glucose metabolism and function via the insulinogenic index. Four PFAS were measured at baseline using liquid chromatography-high-resolution mass spectrometry; high levels were defined as concentrations percentile.

Results: In females from the SOLAR, high perfluorohexane sulfonate (PFHxS) levels () were associated with the development of dysregulated glucose metabolism beginning in late puberty. The magnitude of these associations increased postpuberty and persisted through 18 years of age. For example, postpuberty, females with high PFHxS levels had higher 60-min glucose (95% CI: ; ), higher 2-h glucose (95% CI: ; ), and 25% lower function () compared with females with low levels. Results were largely consistent in the CHS, where females with elevated PFHxS levels had higher 60-min glucose (95% CI: ; ) and higher 2-h glucose, which did not meet statistical significance (95% CI: ; ). In males, no consistent associations between PFHxS and glucose metabolism were observed. No consistent associations were observed for other PFAS and glucose metabolism.

Discussion: Youth exposure to PFHxS was associated with dysregulated glucose metabolism in females, which may be due to changes in function. These associations appeared during puberty and were most pronounced postpuberty. https://doi.org/10.1289/EHP9200.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1289/EHP9200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409228PMC
September 2021

Child serum metabolome and traffic-related air pollution exposure in pregnancy.

Environ Res 2021 Aug 19;203:111907. Epub 2021 Aug 19.

College of Health and Public Service, University of North Texas, Denton, TX, USA.

Background: Maternal exposure to traffic-related air pollution during pregnancy has been shown to increase the risk of adverse birth outcomes and childhood disorders. High-resolution metabolomics (HRM) has previously been employed to identify metabolic responses to traffic-related air pollution in adults, including pregnant women. Thus far, no studies have examined metabolic effects of air pollution exposure in utero on neonates.

Methods: We retrieved stored neonatal blood spots for 241 children born in California between 1998 and 2007. These children were randomly selected from all California birth rolls to serve as birth-year matched controls for children with retinoblastoma identified from the California cancer registry for a case control study of childhood cancer. We estimated prenatal traffic-related air pollution exposure (particulate matter less than 2.5 μm (PM)) during the third-trimester using the California Line Source Dispersion Model, version 4 (CALINE4) based on residential addresses recorded at birth. We employed untargeted HRM to obtain metabolic profiles, and metabolites associated with air pollution exposure were identified using partial least squares (PLS) regression and linear regressions. Biological effects were characterized using pathway enrichment analyses adjusting for potential confounders including maternal age, race/ethnicity, and education.

Results: In total we extracted 4038 and 4957 metabolite features from neonatal blood spots in hydrophilic interaction (HILIC) chromatography (positive ion mode) and C18 reverse phase columns (negative ion mode), respectively. After controlling for confounding factors, partial least square regression (Variable Importance in Projection (VIP) ≥ 2) selected 402 HILIC positive and 182 C18 negative features as statistically significantly associated with increasing third trimester PM exposure. Using pathway enrichment analysis, we identified metabolites in oxidative stress and inflammation pathways as being altered, primarily involving lipid metabolism.

Conclusion: The metabolite features and pathways associated with air pollution exposure in neonates suggest that maternal exposure during late pregnancy contributes to oxidative stress and inflammation in newborn children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2021.111907DOI Listing
August 2021

A randomized crossover trial of HEPA air filtration to reduce cardiovascular risk for near highway residents: Methods and approach.

Contemp Clin Trials 2021 Jul 28;108:106520. Epub 2021 Jul 28.

Department of Public Health and Community Medicine, Tufts University, Boston, MA 02111, United States of America.

Background: Near highway residents are exposed to elevated levels of traffic-related air pollution (TRAP), including ultrafine particles, which are associated with adverse health effects. The efficacy of using in-home air filtration units that reduce exposure and potentially yield health benefits has not been tested in a randomized controlled trial.

Methods: We will conduct a randomized double-blind crossover trial of portable air filtration units for 200 adults 30 years and older who live in near-highway homes in Somerville, MA, USA. We will recruit participants from 172 households. The intervention periods will be one month of true or sham filtration, followed by a one-month wash out period and then a month of the alternate intervention. The primary health outcome will be systolic blood pressure (BP); secondary outcome measures will include diastolic and central BP, C-Reactive Protein (CRP) and D-dimer. Reasons for success or failure of the intervention will be evaluated in a subset of homes using indoor/outdoor monitoring for particulate pollution, personal monitoring, size and composition of particulate pollution, tracking of time spent in the room with the filter, and interviews for qualitative feedback.

Results: This trial has begun recruitment and is expected to take 2-3 years to be completed. Recruitment has been particularly challenging because of additional precautions required by the COVID-19 pandemic.

Discussion: This study has the potential to shed light on the value of using portable air filtration in homes close to highways to reduce exposure to TRAP and whether doing so has benefits for cardiovascular health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cct.2021.106520DOI Listing
July 2021

Elevated urinary mutagenicity among those exposed to bituminous coal combustion emissions or diesel engine exhaust.

Environ Mol Mutagen 2021 Jul 31. Epub 2021 Jul 31.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Urinary mutagenicity reflects systemic exposure to complex mixtures of genotoxic/carcinogenic agents and is linked to tumor development. Coal combustion emissions (CCE) and diesel engine exhaust (DEE) are associated with cancers of the lung and other sites, but their influence on urinary mutagenicity is unclear. We investigated associations between exposure to CCE or DEE and urinary mutagenicity. In two separate cross-sectional studies of nonsmokers, organic extracts of urine were evaluated for mutagenicity levels using strain YG1041 in the Salmonella (Ames) mutagenicity assay. First, we compared levels among 10 female bituminous (smoky) coal users from Laibin, Xuanwei, China, and 10 female anthracite (smokeless) coal users. We estimated exposure-response relationships using indoor air concentrations of two carcinogens in CCE relevant to lung cancer, 5-methylchrysene (5MC), and benzo[a]pyrene (B[a]P). Second, we compared levels among 20 highly exposed male diesel factory workers and 15 unexposed male controls; we evaluated exposure-response relationships using elemental carbon (EC) as a DEE-surrogate. Age-adjusted linear regression was used to estimate associations. Laibin smoky coal users had significantly higher average urinary mutagenicity levels compared to smokeless coal users (28.4 ± 14.0 SD vs. 0.9 ± 2.8 SD rev/ml-eq, p = 2 × 10 ) and a significant exposure-response relationship with 5MC (p = 7 × 10 ). DEE-exposed workers had significantly higher urinary mutagenicity levels compared to unexposed controls (13.0 ± 10.1 SD vs. 5.6 ± 4.4 SD rev/ml-eq, p = .02) and a significant exposure-response relationship with EC (p-trend = 2 × 10 ). Exposure to CCE and DEE is associated with urinary mutagenicity, suggesting systemic exposure to mutagens, potentially contributing to cancer risk and development at various sites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/em.22455DOI Listing
July 2021

Towards a comprehensive characterisation of the human internal chemical exposome: Challenges and perspectives.

Environ Int 2021 11 15;156:106630. Epub 2021 May 15.

Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.

The holistic characterisation of the human internal chemical exposome using high-resolution mass spectrometry (HRMS) would be a step forward to investigate the environmental ætiology of chronic diseases with an unprecedented precision. HRMS-based methods are currently operational to reproducibly profile thousands of endogenous metabolites as well as externally-derived chemicals and their biotransformation products in a large number of biological samples from human cohorts. These approaches provide a solid ground for the discovery of unrecognised biomarkers of exposure and metabolic effects associated with many chronic diseases. Nevertheless, some limitations remain and have to be overcome so that chemical exposomics can provide unbiased detection of chemical exposures affecting disease susceptibility in epidemiological studies. Some of these limitations include (i) the lack of versatility of analytical techniques to capture the wide diversity of chemicals; (ii) the lack of analytical sensitivity that prevents the detection of exogenous (and endogenous) chemicals occurring at (ultra) trace levels from restricted sample amounts, and (iii) the lack of automation of the annotation/identification process. In this article, we discuss a number of technological and methodological limitations hindering applications of HRMS-based methods and propose initial steps to push towards a more comprehensive characterisation of the internal chemical exposome. We also discuss other challenges including the need for harmonisation and the difficulty inherent in assessing the dynamic nature of the internal chemical exposome, as well as the need for establishing a strong international collaboration, high level networking, and sustainable research infrastructure. A great amount of research, technological development and innovative bio-informatics tools are still needed to profile and characterise the "invisible" (not profiled), "hidden" (not detected) and "dark" (not annotated) components of the internal chemical exposome and concerted efforts across numerous research fields are paramount.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envint.2021.106630DOI Listing
November 2021

High-Resolution Metabolomic Assessment of Pesticide Exposure in Central Valley, California.

Chem Res Toxicol 2021 May 29;34(5):1337-1347. Epub 2021 Apr 29.

Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California 90095, United States.

Pesticides are widely used in the agricultural Central Valley region of California. Historically, this has included organophosphates (OPs), organochlorines (OCs), and pyrethroids (PYRs). This study aimed to identify perturbations of the serum metabolome in response to each class of pesticide and mutual associations between groups of metabolites and multiple pesticides. We conducted high-resolution metabolomic profiling of serum samples from 176 older adults living in the California Central Valley using liquid chromatography with high-resolution mass spectrometry. We estimated chronic pesticide exposure (from 1974 to year of blood draw) to OPs, OCs, and PYRs from ambient sources at homes and workplaces with a geographic information system (GIS)-based model. Based on partial least-squares regression and pathway enrichment analysis, we identified metabolites and metabolic pathways associated with one or multiple pesticide classes, including mitochondrial energy metabolism, fatty acid and lipid metabolism, and amino acid metabolism. Utilizing an integrative network approach, we found that the fatty acid β-oxidation pathway is a common pathway shared across all three pesticide classes. The disruptions of the serum metabolome suggested that chronic pesticide exposure might result in oxidative stress, inflammatory reactions, and mitochondrial dysfunction, all of which have been previously implicated in a wide variety of diseases. Overall, our findings provided a comprehensive view of the molecular mechanisms of chronic pesticide toxicity, and, for the first time, our approach informs exposome research by moving from macrolevel population exposures to microlevel biologic responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.chemrestox.0c00523DOI Listing
May 2021

An annotation database for chemicals of emerging concern in exposome research.

Environ Int 2021 07 24;152:106511. Epub 2021 Mar 24.

Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, the Netherlands. Electronic address:

Background: Chemicals of Emerging Concern (CECs) include a very wide group of chemicals that are suspected to be responsible for adverse effects on health, but for which very limited information is available. Chromatographic techniques coupled with high-resolution mass spectrometry (HRMS) can be used for non-targeted screening and detection of CECs, by using comprehensive annotation databases. Establishing a database focused on the annotation of CECs in human samples will provide new insight into the distribution and extent of exposures to a wide range of CECs in humans.

Objectives: This study describes an approach for the aggregation and curation of an annotation database (CECscreen) for the identification of CECs in human biological samples.

Methods: The approach consists of three main parts. First, CECs compound lists from various sources were aggregated and duplications and inorganic compounds were removed. Subsequently, the list was curated by standardization of structures to create "MS-ready" and "QSAR-ready" SMILES, as well as calculation of exact masses (monoisotopic and adducts) and molecular formulas. The second step included the simulation of Phase I metabolites. The third and final step included the calculation of QSAR predictions related to physicochemical properties, environmental fate, toxicity and Absorption, Distribution, Metabolism, Excretion (ADME) processes and the retrieval of information from the US EPA CompTox Chemicals Dashboard.

Results: All CECscreen database and property files are publicly available (DOI: https://doi.org/10.5281/zenodo.3956586). In total, 145,284 entries were aggregated from various CECs data sources. After elimination of duplicates and curation, the pipeline produced 70,397 unique "MS-ready" structures and 66,071 unique QSAR-ready structures, corresponding with 69,526 CAS numbers. Simulation of Phase I metabolites resulted in 306,279 unique metabolites. QSAR predictions could be performed for 64,684 of the QSAR-ready structures, whereas information was retrieved from the CompTox Chemicals Dashboard for 59,739 CAS numbers out of 69,526 inquiries. CECscreen is incorporated in the in silico fragmentation approach MetFrag.

Discussion: The CECscreen database can be used to prioritize annotation of CECs measured in non-targeted HRMS, facilitating the large-scale detection of CECs in human samples for exposome research. Large-scale detection of CECs can be further improved by integrating the present database with resources that contain CECs (metabolites) and meta-data measurements, further expansion towards in silico and experimental (e.g., MassBank) generation of MS/MS spectra, and development of bioinformatics approaches capable of using correlation patterns in the measured chemical features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envint.2021.106511DOI Listing
July 2021

Metabolomics analysis of maternal serum exposed to high air pollution during pregnancy and risk of autism spectrum disorder in offspring.

Environ Res 2021 05 4;196:110823. Epub 2021 Feb 4.

Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, 90095, USA; Department of Community Health Sciences, Fielding School of Public Health, University of California, Los Angeles, CA, 90095, USA; Department of Neurology, Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. Electronic address:

Background: Previously, numerous epidemiologic studies reported an association between autism spectrum disorder (ASD) and exposure to air pollution during pregnancy. However, there have been no metabolomics studies investigating the impact of pregnancy pollution exposure to ASD risk in offspring.

Objectives: To identify differences in maternal metabolism that may reflect a biological response to exposure to high air pollution in pregnancies of offspring who later did or did not develop ASD.

Methods: We obtained stored mid-pregnancy serum from 214 mothers who lived in California's Central Valley and experienced the highest levels of air pollution during early pregnancy. We estimated each woman's average traffic-related air pollution exposure (carbon monoxide, nitric oxides, and particulate matter <2.5 μm) during the first trimester using the California Line Source Dispersion Model, version 4 (CALINE4). By utilizing liquid chromatography-high resolution mass spectrometry, we identified the metabolic profiles of maternal serum for 116 mothers with offspring who later developed ASD and 98 control mothers. Partial least squares discriminant analysis (PLS-DA) was employed to select metabolic features associated with air pollution exposure or autism risk in offspring. We also conducted extensive pathway enrichment analysis to elucidate potential ASD-related changes in the metabolome of pregnant women.

Results: We extracted 4022 and 4945 metabolic features from maternal serum samples in hydrophilic interaction (HILIC) chromatography (positive ion mode) and C18 (negative ion mode) columns, respectively. After controlling for potential confounders, we identified 167 and 222 discriminative features (HILIC and C18, respectively). Pathway enrichment analysis to discriminate metabolic features associated with ASD risk indicated various metabolic pathway perturbations linked to the tricarboxylic acid (TCA) cycle and mitochondrial function, including carnitine shuttle, amino acid metabolism, bile acid metabolism, and vitamin A metabolism.

Conclusion: Using high resolution metabolomics, we identified several metabolic pathways disturbed in mothers with ASD offspring among women experiencing high exposure to traffic-related air pollution during pregnancy that were associated with mitochondrial dysfunction. These findings provide us with a better understanding of metabolic disturbances involved in the development of ASD under adverse environmental conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2021.110823DOI Listing
May 2021

Genetic or Toxicant-Induced Disruption of Vesicular Monoamine Storage and Global Metabolic Profiling in Caenorhabditis elegans.

Toxicol Sci 2021 04;180(2):313-324

Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032, USA.

The proper storage and release of monoamines contributes to a wide range of neuronal activity. Here, we examine the effects of altered vesicular monoamine transport in the nematode Caenorhabditis elegans. The gene cat-1 is responsible for the encoding of the vesicular monoamine transporter (VMAT) in C. elegans and is analogous to the mammalian vesicular monoamine transporter 2 (VMAT2). Our laboratory has previously shown that reduced VMAT2 activity confers vulnerability on catecholamine neurons in mice. The purpose of this article was to determine whether this function is conserved and to determine the impact of reduced VMAT activity in C. elegans. Here we show that deletion of cat-1/VMAT increases sensitivity to the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) as measured by enhanced degeneration of dopamine neurons. Reduced cat-1/VMAT also induces changes in dopamine-mediated behaviors. High-resolution mass spectrometry-based metabolomics in the whole organism reveals changes in amino acid metabolism, including tyrosine metabolism in the cat-1/VMAT mutants. Treatment with MPP+ disrupted tryptophan metabolism. Both conditions altered glycerophospholipid metabolism, suggesting a convergent pathway of neuronal dysfunction. Our results demonstrate the evolutionarily conserved nature of monoamine function in C. elegans and further suggest that high-resolution mass spectrometry-based metabolomics can be used in this model to study environmental and genetic contributors to complex human disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/toxsci/kfab011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041460PMC
April 2021

Correction to: Air Pollution and Adverse Pregnancy and Birth Outcomes: Mediation Analysis Using Metabolomic Profiles.

Curr Environ Health Rep 2020 Dec;7(4):441

Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles (UCLA), 650 Charles E. Young Dr. South, Los Angeles, CA, 90095, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40572-020-00299-wDOI Listing
December 2020

Sampling interstitial fluid from human skin using a microneedle patch.

Sci Transl Med 2020 11;12(571)

School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.

Tissue interstitial fluid (ISF) surrounds cells and is an underutilized source of biomarkers that complements conventional sources such as blood and urine. However, ISF has received limited attention due largely to lack of simple collection methods. Here, we developed a minimally invasive, microneedle-based method to sample ISF from human skin that was well tolerated by participants. Using a microneedle patch to create an array of micropores in skin coupled with mild suction, we sampled ISF from 21 human participants and identified clinically relevant and sometimes distinct biomarkers in ISF when compared to companion plasma samples based on mass spectrometry analysis. Many biomarkers used in research and current clinical practice were common to ISF and plasma. Because ISF does not clot, these biomarkers could be continuously monitored in ISF similar to current continuous glucose monitors but without requiring an indwelling subcutaneous sensor. Biomarkers distinct to ISF included molecules associated with systemic and dermatological physiology, as well as exogenous compounds from environmental exposures. We also determined that pharmacokinetics of caffeine in healthy adults and pharmacodynamics of glucose in children and young adults with diabetes were similar in ISF and plasma. Overall, these studies provide a minimally invasive method to sample dermal ISF using microneedles and demonstrate human ISF as a source of biomarkers that may enable research and translation for future clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aaw0285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871333PMC
November 2020

Unsupervised dimensionality reduction for exposome research.

Curr Opin Environ Sci Health 2020 Jun 19;15:32-38. Epub 2020 May 19.

Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032.

Understanding the effect of the environment on human health has benefited from progress made in measuring the exposome. High resolution mass spectrometry (HRMS) has made it possible to measure small molecules across a large dynamic range, allowing researchers to study the role of low abundance environmental toxicants in causing human disease. HRMS data have a high dimensional structure (number of predictors >> number of observations), generating information on the abundance of many chemical features (predictors) which may be highly correlated. Unsupervised dimension reduction techniques can allow dimensionality reduction of the various features into components that capture the essence of the variability in the exposome dataset. We illustrate and discuss the relevance of three different unsupervised dimension reduction techniques: principal component analysis, factor analysis, and non-negative matrix factorization. We focus on the utility of each method in understanding the relationship between the exposome and a disease outcome and describe their strengths and limitations. While the utility of these methods is context specific, it remains important to focus on the interpretability of results from each method.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.coesh.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467332PMC
June 2020

Dysregulated lipid and fatty acid metabolism link perfluoroalkyl substances exposure and impaired glucose metabolism in young adults.

Environ Int 2020 12 3;145:106091. Epub 2020 Sep 3.

Division of Environmental Health, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Background: Per- and polyfluoroalkyl substances (PFASs) exposure is ubiquitous among the US population and has been linked to adverse health outcomes including cardiometabolic diseases, immune dysregulation and endocrine disruption. However, the metabolic mechanism underlying the adverse health effect of PFASs exposure is unknown.

Objective: The aim of this project is to investigate the association between PFASs exposure and altered metabolic pathways linked to increased cardiometabolic risk in young adults.

Methods: A total of 102 young adults with 82% overweight or obese participants were enrolled from Southern California between 2014 and 2017. Cardiometabolic outcomes were assessed including oral glucose tolerance test (OGTT) measures, body fat and lipid profiles. High-resolution metabolomics was used to quantify plasma exposure levels of three PFAS congeners and intensity profiles of the untargeted metabolome. Fasting concentrations of 45 targeted metabolites involved in fatty acid and lipid metabolism were used to verify untargeted metabolomics findings. Bayesian Kernel Machine Regression (BKMR) was used to examine the associations between PFAS exposure mixture and cardiometabolic outcomes adjusting for covariates. Mummichog pathway enrichment analysis was used to explore PFAS-associated metabolic pathways. Moreover, the effect of PFAS exposure on the metabolic network, including metabolomic profiles and cardiometabolic outcomes, was investigated.

Results: Higher exposure to perfluorooctanoic acid (PFOA) was associated with higher 30-minute glucose levels and glucose area under the curve (AUC) during the OGTT (p < 0.001). PFAS exposure was also associated with altered lipid pathways, which contributed to the metabolic network connecting PFOA and higher glucose levels following the OGTT. Targeted metabolomics analysis indicated that higher PFOA exposure was associated with higher levels of glycerol (p = 0.006), which itself was associated with higher 30-minute glucose (p = 0.006).

Conclusions: Increased lipolysis and fatty acid oxidation could contribute to the biological mechanisms linking PFAS exposure and impaired glucose metabolism among young adults. Findings of this study warrants future experimental studies and epidemiological studies with larger sample size to replicate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envint.2020.106091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009052PMC
December 2020

Air Pollution and Adverse Pregnancy and Birth Outcomes: Mediation Analysis Using Metabolomic Profiles.

Curr Environ Health Rep 2020 09;7(3):231-242

Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles (UCLA), 650 Charles E. Young Dr. South, Los Angeles, CA, 90095, USA.

Purpose Of Review: Review how to use metabolomic profiling in causal mediation analysis to assess epidemiological evidence for air pollution impacts on birth outcomes.

Recent Findings: Maternal exposures to air pollutants have been associated with pregnancy complications and adverse pregnancy and birth outcomes. Causal mediation analysis enables us to estimate direct and indirect effects on outcomes (i.e., effect decomposition), elucidating causal mechanisms or effect pathways. Maternal metabolites and metabolic pathways are perturbed by air pollution exposures may lead to adverse pregnancy and birth outcomes, thus they can be considered mediators in the causal pathways. Metabolomic markers have been used to explain the biological mechanisms linking air pollution and respiratory function, and of arsenic exposure and birth weight. However, mediation analysis of metabolomic markers has not been used to assess air pollution effects on adverse birth outcomes. In this article, we describe the assumptions and applications of mediation analysis using metabolomic markers that elucidate the potential mechanisms of the effects of air pollution on adverse pregnancy and birth outcomes. The hypothesis of mediation along specified pathways can be assessed within the structural causal modeling framework. For causal inferences, several assumptions that go beyond the data-including no uncontrolled confounding-need to be made to justify the effect decomposition. Nevertheless, studies that integrate metabolomic information in causal mediation analysis may greatly improve our understanding of the effects of ambient air pollution on adverse pregnancy and birth outcomes as they allow us to suggest and test hypotheses about underlying biological mechanisms in studies of pregnant women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40572-020-00284-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599041PMC
September 2020

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

Environ Int 2020 10 17;143:105957. Epub 2020 Jul 17.

Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envint.2020.105957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708399PMC
October 2020

Untargeted Metabolomics Screen of Mid-pregnancy Maternal Serum and Autism in Offspring.

Autism Res 2020 08 4;13(8):1258-1269. Epub 2020 Jun 4.

Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA.

Discovering pathophysiologic networks in a blood-based approach may help to generate valuable tools for early treatment or preventive measures in autism. To date targeted or untargeted metabolomics approaches to identify metabolic features and pathways affecting fetal neurodevelopment have rarely been applied to pregnancy samples, that is, an early period potentially relevant for the development of autism spectrum disorders (ASD). We conducted a population-based study relying on autism diagnoses retrieved from California Department of Developmental Services record. After linking cases to and sampling controls from birth certificates, we retrieved stored maternal mid-pregnancy serum samples collected as part of the California Prenatal Screening Program from the California Biobank for children born 2004 to 2010 in the central valley of California. We retrieved serum for 52 mothers whose children developed autism and 62 population controls originally selected from all eligible children matched by birth year and child's sex. Also, we required that these mothers were relatively low or unexposed to air pollution and select pesticides during early pregnancy. We identified differences in metabolite levels in several metabolic pathways, including glycosphingolipid biosynthesis and metabolism, N-glycan and pyrimidine metabolism, bile acid pathways and, importantly, C21-steroid hormone biosynthesis and metabolism. Disturbances in these pathways have been shown to be relevant for neurodevelopment in rare genetic syndromes or implicated in previous studies of autism. This study provides new insight into maternal mid-pregnancy metabolic features possibly related to the development of autism and an incentive to explore whether these pathways and metabolites are useful for early diagnosis, treatment, or prevention. LAY SUMMARY: This study found that in mid-pregnancy the blood of mothers who give birth to a child that develops autism has some characteristic features that are different from those of blood samples taken from control mothers. These features are related to biologic mechanisms that can affect fetal brain development. In the future, these insights may help identify biomarkers for early autism diagnosis and treatment or preventive measures. Autism Res 2020, 13: 1258-1269. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/aur.2311DOI Listing
August 2020

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

Anal Chem 2020 07 15;92(13):8836-8844. Epub 2020 Jun 15.

Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, Georgia 30322, United States.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.analchem.0c00338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887762PMC
July 2020

Toxic tall fescue grazing increases susceptibility of the Angus steer fecal microbiota and plasma/urine metabolome to environmental effects.

Sci Rep 2020 02 12;10(1):2497. Epub 2020 Feb 12.

Interdisciplinary Toxicology Program, University of Georgia, Athens, GA, USA.

Impaired thermoregulation and lowered average daily gains (ADG) result when livestock graze toxic endophyte (Epichloë coenophialum)-infected tall fescue (E+) and are hallmark signs of fescue toxicosis (FT), a disease exacerbated by increased temperature and humidity (+temperature-humidity index; +THI). We previously reported FT is associated with metabolic and microbiota perturbations under thermoneutral conditions; here, we assessed the influence of E+ grazing and +THI on the microbiota:metabolome interactions. Using high-resolution metabolomics and 16S rRNA gene sequencing, plasma/urine metabolomes and the fecal microbiota of Angus steers grazing non-toxic or E+ tall fescue were evaluated in the context of +THI. E+ grazing affected the fecal microbiota profile; +THI conditions modulated the microbiota only in E+ steers. E+ also perturbed many metabolic pathways, namely amino acid and inflammation-related metabolism; +THI affected these pathways only in E+ steers. Integrative analyses revealed the E+ microbiota correlated and co-varied with the metabolomes in a THI-dependent manner. Operational taxonomic units in the families Peptococcaceae, Clostridiaceae, and Ruminococcaceae correlated with production parameters (e.g., ADG) and with multiple plasma/urine metabolic features, providing putative FT biomarkers and/or targets for the development of FT therapeutics. Overall, this study suggests that E+ grazing increases Angus steer susceptibility to +THI, and offers possible targets for FT interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-59104-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016188PMC
February 2020

Targeting soluble tumor necrosis factor as a potential intervention to lower risk for late-onset Alzheimer's disease associated with obesity, metabolic syndrome, and type 2 diabetes.

Alzheimers Res Ther 2019 12 31;12(1). Epub 2019 Dec 31.

Department of Physiology, School of Medicine at Emory University, 615 Michael Street, Atlanta, GA, 30322-3110, USA.

Background: Insulin impairment and inflammation are two features common to type 2 diabetes and Alzheimer's disease; however, the molecular and signaling interactions underlying this relationship are not well understood. Mounting evidence point to the associations between the disruption of metabolite processing in insulin impairment and neurodegenerative conditions such as Alzheimer's. Although the brain depends partially on metabolites processed in the periphery, to date, little is known about how soluble tumor necrosis factor signaling (solTNF) impacts integrated peripheral immune and metabolic feedback signals in states of energy overload and insulin insensitivity.

Methods: C57Bl/6J mice were fed a high-fat high-carbohydrate diet (HFHC) for 14 weeks. The brain-permeant biologic XPro1595® was used to block solTNF-dependent pathways. Metabolic and immune alterations were evaluated in the gut, liver, and brain. Behavioral tests were performed. Untargeted metabolomics was carried out in the plasma and liver.

Results: HFHC diet promotes central insulin impairment and dysregulation of immune-modulatory gene expressed in the brain. Alteration of metabolites associated with type 2 diabetes and Alzheimer's such as butanoate, glutamate, biopterin, branched-chain amino acids, purines, and proteoglycan metabolism was observed in HFHC-fed mice. solTNF inhibition ameliorates hepatic metabolic disturbances and hepatic and intestinal lipocalin-2 levels, and decreases insulin impairment in the brain and behavioral deficits associated with HFHC diet.

Conclusions: Our novel findings suggest that HFHC diet impacts central insulin signaling and immune-metabolic interactions in a solTNF-dependent manner to increase the risk for neurodegenerative conditions. Our novel findings indicate that selective solTNF neutralization can ameliorate peripheral and central diet-induced insulin impairment and identify lipocalin-2 as a potential target for therapeutic intervention to target inflammation and insulin disturbances in obesogenic environments. Collectively, our findings identify solTNF as a potential target for therapeutic intervention in inflammatory states and insulin disturbances in obesogenic environments to lower risk for AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13195-019-0546-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937979PMC
December 2019

Discovery of metabolic alterations in the serum of patients infected with Plasmodium spp. by high-resolution metabolomics.

Metabolomics 2019 12 23;16(1). Epub 2019 Dec 23.

College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong, 30019, Republic of Korea.

Introduction: Despite the advances in diagnosis and treatment, malaria has still not been eradicated. Metabolic interactions between the host and Plasmodium may present novel targets for malaria control, but such interactions are yet to be deciphered. An exploration of metabolic interactions between humans and two Plasmodium species by high-resolution metabolomics may provide fundamental insights that can aid the development of a new strategy for the control of malaria.

Objectives: This study aimed at exploring the metabolic changes in the sera of patients infected with Plasmodium falciparum and Plasmodium vivax.

Methods: Uni- and multivariate metabolomic analyses were performed on the sera of four groups of patients, namely normal control (N, n = 100), P. falciparum-infected patients (PF, n = 21), P. vivax-infected patients (PV, n = 74), and non-malarial pyretic patients (Pyr, n = 25).

Results: Univariate and multivariate analyses of N, PF, and PV groups showed differential metabolic phenotypes and subsequent comparisons in pairs revealed significant features. Pathway enrichment test with significant features showed the affected pathways, namely glycolysis/gluconeogenesis for PF and retinol metabolism for PV. The metabolites belonging to the affected pathways included significantly low 2,3-diphosphoglycerate and glyceraldehyde-3-phosphate in the sera of PF. The sera of PV had significantly low levels of retinol but high levels of retinoic acid.

Conclusion: Our study reveals metabolic alterations induced by Plasmodium spp. in human serum and would serve as a milestone in the development of novel anti-malarial strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11306-019-1630-2DOI Listing
December 2019

High-resolution metabolomic profiling of Alzheimer's disease in plasma.

Ann Clin Transl Neurol 2020 01 11;7(1):36-45. Epub 2019 Dec 11.

Department of Neurology, Emory University, Atlanta, Georgia.

Background: Alzheimer's disease (AD) is a complex neurological disorder with contributions from genetic and environmental factors. High-resolution metabolomics (HRM) has the potential to identify novel endogenous and environmental factors involved in AD. Previous metabolomics studies have identified circulating metabolites linked to AD, but lack of replication and inconsistent diagnostic algorithms have hindered the generalizability of these findings. Here we applied HRM to identify plasma metabolic and environmental factors associated with AD in two study samples, with cerebrospinal fluid (CSF) biomarkers of AD incorporated to achieve high diagnostic accuracy.

Methods: Liquid chromatography-mass spectrometry (LC-MS)-based HRM was used to identify plasma and CSF metabolites associated with AD diagnosis and CSF AD biomarkers in two studies of prevalent AD (Study 1: 43 AD cases, 45 mild cognitive impairment [MCI] cases, 41 controls; Study 2: 50 AD cases, 18 controls). AD-associated metabolites were identified using a metabolome-wide association study (MWAS) framework.

Results: An MWAS meta-analysis identified three non-medication AD-associated metabolites in plasma, including elevated levels of glutamine and an unknown halogenated compound and lower levels of piperine, a dietary alkaloid. The non-medication metabolites were correlated with CSF AD biomarkers, and glutamine and the unknown halogenated compound were also detected in CSF. Furthermore, in Study 1, the unknown compound and piperine were altered in MCI patients in the same direction as AD dementia.

Conclusions: In plasma, AD was reproducibly associated with elevated levels of glutamine and a halogen-containing compound and reduced levels of piperine. These findings provide further evidence that exposures and behavior may modify AD risks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.50956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952314PMC
January 2020

The metabolome: A key measure for exposome research in epidemiology.

Curr Epidemiol Rep 2019 26;6:93-103. Epub 2019 Apr 26.

Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University School of Medicine, Atlanta, GA.

Purpose Of Review: Application of omics to study human health has created a new era of opportunities for epidemiology research. However, approaches to characterize exogenous health triggers have largely not leveraged advances in analytical platforms and big data. In this review, we highlight the exposome, which is defined as the cumulative measure of exposure and biological responses across a lifetime as a cornerstone for new epidemiology approaches to study complex and preventable human diseases.

Recent Findings: While no universal approach exists to measure the entirety of the exposome, use of high-resolution mass spectrometry methods provide distinct advantages over traditional biomonitoring and have provided key advances necessary for exposome research. Application to different study designs and recommendations for combining exposome data with novel data analytic frameworks to study complex interactions of multiple stressors are also discussed.

Summary: Even though challenges still need to be addressed, advances in methods to characterize the exposome provide exciting new opportunities for epidemiology to support fundamental discoveries to improve public health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905435PMC
April 2019

Benzo[a]pyrene Perturbs Mitochondrial and Amino Acid Metabolism in Lung Epithelial Cells and Has Similar Correlations With Metabolic Changes in Human Serum.

J Occup Environ Med 2019 12;61 Suppl 12:S73-S81

Clinical Biomarkers Laboratory, Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia (Dr Smith, Dr Walker, Dr Uppal, Dr Go, Dr Jones); Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York (Dr Utell); Division of Pulmonary Medicine, Department of Medicine, University of Rochester Medical Center, Rochester, NY (Dr Utell); Department of Public Health Sciences, Division of Pulmonary Medicine, University of Rochester Medical Center, Rochester, New York (Dr Hopke); Department of Preventive Medicine & Biostatistics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland (Dr Mallon, Dr Krahl); Armed Forces Health Surveillance Center, Silver Springs, Maryland (Dr Rohrbeck).

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JOM.0000000000001687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897313PMC
December 2019

Integrative Network Analysis Linking Clinical Outcomes With Environmental Exposures and Molecular Variations in Service Personnel Deployed to Balad and Bagram.

J Occup Environ Med 2019 12;61 Suppl 12:S65-S72

Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, Georgia (Dr Smith, Dr Walker, Dr Go, Dr Jones, Dr Uppal); Department of Microbiology & Immunology and Department of Biostatistics & computational Biology (Dr Thakar); Department of Environmental Medicine (Dr Thakar, Dr Utell); Department of Medicine, Pulmonary Division (Dr Thatcher, Dr Woeller, Dr Utell); Department of Public Health Sciences (Dr Hopke), University of Rochester Medical Center, Rochester, New York; Department of Preventive Medicine & Biostatistics, Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Bethesda (Dr Mallon, Dr Krahl); Armed Forces Health Surveillance Center, Silver Spring (Ms Rohrbeck), Maryland.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JOM.0000000000001710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897323PMC
December 2019

Analysis of Postdeployment Serum Samples Identifies Potential Biomarkers of Exposure to Burn Pits and Other Environmental Hazards.

J Occup Environ Med 2019 12;61 Suppl 12:S45-S54

Department of Medicine, University of Rochester Medical Center, Rochester, New York (Dr Thatcher, Dr Sime, Dr Phipps, and Dr Utell); Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York (Dr Woeller, Dr Sime, Dr Phipps, and Dr Utell); Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York (Dr Thakar, Dr Khan, Dr Sime, and Dr Phipps); Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York (Dr Thakar and Dr Khan); Department of Public Health Sciences, University of Rochester Medical Center, Rochester, New York (Dr Hopke); Center for Air Resources Engineering and Science, Clarkson University, Potsdam, New York (Dr Hopke); Clinical Biomarkers Laboratory, Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia (Dr Smith, Dr Uppal, Dr Walker, Dr Go, and Dr Jones); Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York (Dr Walker); Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland (Dr Krahl and Dr Mallon); Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia (Dr Thatcher and Dr Sime).

Objective: The potential health risks of deployment to sites with open burn pits remain poorly understood, in part, because personal exposure monitoring was not performed. Here, we investigated whether postdeployment serum samples contain biomarkers associated with exposure to burn pits.

Methods: A total of 237 biomarkers were measured in 800 serum samples from deployed and never-deployed subjects. We used a regression model and a supervised vector machine to identify serum biomarkers with significant associations with exposures and deployment.

Results: We identified 101 serum biomarkers associated with polycyclic aromatic hydrocarbons, dioxins or furans, and 54 biomarkers associated with deployment. Twenty-six of these biomarkers were shared in common by the exposure and deployment groups.

Conclusions: We identify a potential signature of exposure to open burn pits, and provide a framework for using postexposure sera to identify exposures when contemporaneous monitoring was inadequate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JOM.0000000000001715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901100PMC
December 2019

Associations of Benzo(ghi)perylene and Heptachlorodibenzo-p-dioxin in Serum of Service Personnel Deployed to Balad, Iraq, and Bagram, Afghanistan Correlates With Perturbed Amino Acid Metabolism in Human Lung Fibroblasts.

J Occup Environ Med 2019 12;61 Suppl 12:S35-S44

Clinical Biomarkers Laboratory, Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia (Dr Smith, Dr Uppal, Dr Walker, Dr Go, Dr Jones); Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York (Dr Woeller, Dr Utell); Division of Pulmonary Medicine, Department of Medicine, University of Rochester Medical Center, Rochester, NY (Dr Thatcher, Dr Utell); Department of Public Health Sciences, Division of Pulmonary Medicine, University of Rochester Medical Center, Rochester, New York (Dr Hopke); Armed Forces Health Surveillance Center, Silver Springs, Maryland (Dr Rohrbeck); Department of Preventive Medicine & Biostatistics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland (Dr Mallon, Dr Krahl).

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JOM.0000000000001669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861127PMC
December 2019

Metabolome-Wide Association Study of Deployment to Balad, Iraq or Bagram, Afghanistan.

J Occup Environ Med 2019 12;61 Suppl 12:S25-S34

Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, and Critical Care Medicine, Emory School of Medicine, Atlanta, Georgia (Drs Go, Smith, Walker, Uppal, Jones); Armed Forces Health Surveillance Center, Silver Spring (Dr Rohrbeck); Occupational and Environmental Medicine Residency Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University, Bethesda (Dr Krahl, Dr Mallon), Maryland; Center for Air Resources Engineering and Science, Clarkston University, Potsdam, New York (Dr Hopke, Dr Utell).

Objective: To use high-resolution metabolomics (HRM) to identify metabolic changes in military personnel associated with deployment to Balad, Iraq, or Bagram, Afghanistan.

Methods: Pre- and post-deployment samples were obtained from the Department of Defense Serum Repository (DoDSR). HRM and bioinformatics were used to identify metabolic differences associated with deployment.

Results: Differences at baseline (pre-deployment) between personnel deployed to Bagram compared with Balad or Controls included sex hormone and keratan sulfate metabolism. Deployment to Balad was associated with alterations to amino acid and lipid metabolism, consistent with inflammation and oxidative stress, and pathways linked to metabolic adaptation and repair. Difference associated with deployment to Bagram included lipid pathways linked to cell signaling and inflammation.

Conclusions: Metabolic variations in pre- and post-deployment are consistent with deployment-associated responses to air pollution and other environmental stressors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JOM.0000000000001665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901093PMC
December 2019

Environmental Chemicals Altered in Association With Deployment for High Risk Areas.

J Occup Environ Med 2019 12;61 Suppl 12:S15-S24

Clinical Biomarkers Laboratory, Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia (Dr Smith, Dr Uppal, Dr Walker, Dr Go, Dr Jones); Department of Environmental Medicine (Dr Utell); Pulmonary Division, Department of Medicine (Dr Utell); Department of Public Health Sciences (Dr Hopke), University of Rochester Medical Center, Rochester, New York ; Uniformed Services University of the Health Sciences, Department of Preventive Medicine & Biostatistics, F. Edward Hébert School of Medicine, Bethesda (Dr Mallon, Dr Krahl); Armed Forces Health Surveillance Center, Silver Spring (Ms Rohrbeck), Maryland.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JOM.0000000000001647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299071PMC
December 2019

Advances in Comprehensive Exposure Assessment: Opportunities for the US Military.

J Occup Environ Med 2019 12;61 Suppl 12:S5-S14

Department of Preventive Medicine and Biostatistics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland (Dr Krahl, Dr Benchoff, Dr Mallon); Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia (Dr Go, Dr Jones, Dr Smith, Dr Walker, Dr Uppal); Department of Environmental Medicine (Dr Woeller, Dr Phipps, Dr Utell); Department of Medicine (Dr Thatcher, Dr Utell); Microbiology and Immunology (Dr Thakar, Dr Phipps); Department of Public Health Sciences (Dr Hopke), University of Rochester Medical Center, Rochester; Center for Air Resources Engineering and Science, Clarkson University, Potsdam (Dr Hopke), New York.

Objective: Review advances in exposure assessment offered by the exposome concept and new -omics and sensor technologies.

Methods: Narrative review of advances, including current efforts and potential future applications by the US military.

Results: Exposure assessment methods from both bottom-up and top-down exposomics approaches are advancing at a rapid pace, and the US military is engaged in developing both approaches. Top-down approaches employ various -omics technologies to identify biomarkers of internal exposure and biological effect. Bottom-up approaches use new sensor technology to better measure external dose. Key challenges of both approaches are largely centered around how to integrate, analyze, and interpret large datasets that are multidimensional and disparate.

Conclusions: Advances in -omics and sensor technologies may dramatically enhance exposure assessment and improve our ability to characterize health risks related to occupational and environmental exposures, including for the US military.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JOM.0000000000001677DOI Listing
December 2019

Use of Biomarkers to Assess Environmental Exposures and Health Outcomes in Deployed Troops.

J Occup Environ Med 2019 12;61 Suppl 12:S1-S4

Department of Preventive Medicine and Biostatistics, Uniformed Services University, Bethesda (Dr Mallon, Dr Krahl); Department of Environmental Medicine (Dr Woeller, Dr Hopke, Dr Utell); Pulmonary Division, Department of Medicine (Dr Thatcher, Dr Thakar, Dr Utell); Microbiology and Immunology (Dr Woeller); Department of Public Health Sciences (Dr Walker, Dr Smith, Dr Uppal, Dr Go, Dr Jones), Emory University, Atlanta, Georgia US Army Public Health Center, Edgewood (Dr Gaydos), Maryland; Medical Counter-CBRN and Environmental Health, Office of the Joint Staff Surgeon, The Pentagon, Washington DC (Mr Haines).

Objective: This paper provides an overview of our Military Biomarkers Research Study (MBRS) designed to assess whether biomarkers can be used to retrospectively assess deployment exposures and health impacts related to deployment environmental exposures.

Methods: The MBRS consists of four phases. Phase I was a feasibility study of stored sera. Phase II looks at associations between exposures and biomarkers. Phase III examines relationships of biomarkers and health outcomes, and Phase IV investigates in vitro biomarker changes associated with exposures to chemicals of interest. This paper briefly summarizes work already published and introduces the new reports contained in this supplement.

Results: Novel biomarkers were identified. These were associated with deployment exposures.

Conclusions: Significant associations were noted between deployment exposures, microRNA biomarkers and metabolomic biomarkers, and deployment health outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JOM.0000000000001752DOI Listing
December 2019
-->