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Research – Environmental Metabolomics Research Group

Research

Our research focuses on health effects associated with air pollution and persistent organic pollutant using advanced exposure assessment and high throughput omics technologies. In particular, we are interested in measuring multi-dimensional exposures and elucidating the molecular mechanisms accounting for the complex health responses to environmental mixtures. These have involved extensive, primary field-based data collection, and laboratory-based analyses. More recently, we have shifted our efforts toward incorporating high-resolution metabolomics and multi-omics into the investigations on the molecular mechanisms and disease etiology associated with environmental exposures and the corresponding health effects.

Using advanced exposure assessment and high-resolution metabolomics (HRM) to investigate the impact of air pollution on the human metabolome and related health outcomes.

A. Traffic Exposure, Maternal Metabolome and Birth Outcomes (TEMMBO) study (supported by NIEHS R21ES032117, PI: Liang)

The Traffic Exposure, Maternal Metabolome and Birth Outcomes (TEMMBO) Study examines associations between prenatal exposures to traffic-related air pollution, longitudinal perturbations in the maternal metabolome, and adverse birth outcomes in a socio-economically diverse, exceptionally phenotyped African American maternal-child cohort. The study approaches include novel exposure assessment through external, traffic emission exposure modeling paired with internal, high-resolution metabolomics data. We expect this work to contribute to the identification of biological pathways and factors mediating associations between traffic-related air pollution exposures and adverse pregnancy and birth outcomes, providing opportunities for targeted interventions to mitigate TRAP-related risk and improve health outcomes, particularly among pregnant women and newborns in the minority population.

Exposures to traffic-related air pollution (TRAP), a primary source of urban air pollution, during pregnancy have been linked to adverse birth outcomes and the development of atopic diseases in childhood. Notably, communities of color and the poor, especially African American (AA) women and children, disproportionately experience both high TRAP exposures and adverse birth and child health outcomes. The mechanisms underlying how maternal TRAP exposures may affect birth outcomes and shape child health disparities are still largely unknown. This is due, in part, to the substantial challenges in accurately characterizing internal dose of exposures and biological responses to TRAP. High-resolution metabolomics (HRM) — a high-throughput analysis method involving the identification and quantification of thousands of metabolic features associated with exogenous exposure and endogenous processes — has emerged as a powerful tool to improve exposure assessment to complex environmental mixtures. In previous work among adults and adolescents, we used HRM to detect metabolic perturbations following exposures to urban air pollution, where we identified and verified several oxidative stress and inflammation-related pathways significantly associated with increased TRAP exposures. These promising initial findings and prior published work on TRAP-mediated response related to birth outcomes and child development have led us to hypothesize that elevated exposure to TRAPs during pregnancy will result in perturbations in specific metabolic pathways, especially those linked to oxidative stress and inflammation, which will increase risk for adverse birth outcomes including preterm birth and small-size-for- gestational age. Our multidisciplinary team of investigators proposes to test this hypothesis in a cohort of 320 AA pregnant women with well-phenotyped birth outcomes and longitudinal high-resolution metabolic profiling. In doing this, we will: 1) generate retrospective estimates of individual-level TRAP exposures using spatiotemporally-resolved source dispersion models (Aim 1); 2) examine whether prenatal exposure to TRAP is longitudinally associated with perturbations in maternal metabolome (Aim 2); and 3) explore whether maternal metabolic pathways that associate with increased TRAP exposures also associate with adverse birth outcomes (i.e. preterm birth and small-size-for-gestational age) under a mediation framework (Exploratory Aim 3). The proposed Traffic Exposure, Maternal Metabolome and Birth Outcomes Study (TEMMBO Study) is highly innovative in being the first longitudinal study to examine links among TRAP exposures, metabolic perturbations and adverse birth outcomes in a socio-economically diverse, exceptionally phenotyped AA maternal-child cohort. This linkage will include novel exposure assessment through external, traffic emission exposure modeling paired with internal, high-resolution metabolomics data. Together, results will contribute towards identifying factors that moderate associations between TRAP exposures and adverse birth outcomes, providing opportunities for interventions to improve outcomes in exposed mothers and children.

  • Use of RLINE dispersion model to generate estimates of personal residential exposures to TRAP (led by Zhenjiang Li)

We are refining the residential TRAP exposure assignment with individual-level estimates using RLINE-source dispersion modelling for near-surface releases to model ambient concentrations of TRAP exposures from mobile sources at a 250 m resolution. Monthly average exposure estimates for each participant-biomonitoring will be assigned based on place of residence (matching 250 m grid cells) and date of biosample collection with fine spatial resolution on TRAP levels.

  • Ambient Air Pollution and Preterm Birth (Led by Yifan Wang and Tszshan Ma)

In this study, we linked ambient PM2.5, NO2, and O3 concentrations at 1-km resolution to 293 participants who delivered between 2014 and 2016. We examined associations between pollutant exposures (during each trimester, entire pregnancy, and 3 years before pregnancy) and preterm birth (PTB) and early-term birth vs. full term birth. The results support targeted interventions to protect pregnant women from air pollution, especially AA populations who have a higher PTB rate.

Association between prenatal exposures to ambient air pollutants and preterm birth in the Atlanta African American Mother-Child Cohort. (Manuscript in preparation)

  • Use of high-resolution metabolomics to assess the impact of prenatal TRAP exposures on maternal metabolome and preterm birth outcomes (led by Zhenjiang Li)

We will examine associations between prenatal exposure to TRAP and longitudinal perturbations in maternal metabolome at the first and third trimesters using an untargeted HRM workflow by integrating existing advanced algorithms in metabolic feature extraction, pathway enrichment, and metabolite annotation. We will also explore whether maternal metabolic pathways that associate with increased TRAP exposures also associate with adverse birth outcomes (i.e. preterm birth and small-size-for-gestational age) under a mediation framework. We will explore mediation with a “meet in the middle” framework and we will also conduct a formal mediation analysis.

Include but not limited to the following research topics:

    • Assess the impact of prenatal exposures to TRAP on preterm birth outcomes
    • Assess the associations between prenatal exposures to TRAP and pregnancy complications
    • Investigate how oxidative stress and inflammatory metabolites mediate the associations between TRAP exposures and adverse pregnancy and birth outcomes
    • Examine the aggregate impact of TRAP exposures on birth outcomes and maternal metabolome using mixture analysis

B. Dorm Room Inhalation to Vehicle Emissions (DRIVE) Study (supported by Health Effect Institute, PI: Sarnat)

The Dorm Room Inhalation to Vehicle Emissions (DRIVE) study was conducted to measure traditional single- and novel multipollutant traffic indicators along a complete emissions-to-dose exposure pathway. The overarching goal of DRIVE was to evaluate the suitability of these indicators for use as primary traffic exposure metrics in the small cohort and panel-based epidemiological studies. A detailed description of the DRIVE study design, as well as the sampling methods, can be found here.

Briefly, intensive field sampling was conducted on the campus of the Georgia Institute of Technology (GIT) between September 2014 and January 2015 at 8 monitoring sites (2 indoor and 6 outdoor) ranging from 0.005 to 2.3 km away from the busiest and most congested highway artery in Atlanta. The pollutants measured were selected to provide information concerning the heterogeneous particulate and gaseous composition of primary traffic emissions, including the measurement of traditional traffic-related species [e.g., carbon monoxide (CO), nitrogen dioxide (NO2), nitric oxide (NO), fine particulate matter (PM2.5) and black carbon (BC)], and secondary species [e.g., ozone (O3) and sulfate, as well as organic carbon (OC) which is both primary and secondary due to traffic as well as other sources]. Along with these pollutants, we measured two multipollutant traffic indicators: Integrated Mobile Source Indicators (IMSIs) and Fine Particulate Matter Oxidative Potential (FPMOP). A limited assessment of low-cost sensors was added to the study to supplement the four original DRIVE aims. In addition, 54 GIT students living in one of two dormitories either near (20 m) or far (1.4 km) from the highway were recruited to conduct personal exposure sampling and weekly biomonitoring. High-resolution metabolomics profiling was conducted on four (monthly) venous blood and twelve (weekly) saliva samples collected from each of the 54 participants. In total, 175 plasma samples (average of 3.2 repeated samples per participant) and 621 2-ml vials of saliva (average of 11.5 repeated samples per participant) were collected.

  • The Oxidative Potential of Fine Particulate Matter and Biological Perturbations in Human Plasma and Saliva Metabolome.—Tang, Z., Sarnat, J.A., Weber, R.J., Russell, A.G., Zhang, X., Li, Z., Yu, T., Jones, D.P., and Liang, D. Under review.
  • Saliva Metabolome in Assessing Internal Exposures to Traffic-Related Air Pollution.—Li, Z., Sarnat, J.A., Liu, K., Chang, CJ., Ly, V., Greenwald, R., Chang, H.C., Russell, A.G., Jones, D.P., and Liang, D. Manuscript in preparation.

Include but not limited to the following research topics:

  • Develop and evaluate R-LINE dispersion models to characterize the spatial and temporal patterns of TRAP exposures
  • Develop and evaluate personal exposure metrics to TRAP using spatiotemporal resolved measurements and models along with GPS data
  • Characterize the impact of different factors on personal exposures to TRAP
  • Use personal exposure assessment and high-resolution metabolomics to investigate the impact of TRAP exposures on plasma and saliva metabolome

C. Metabolomics Wide Association Study on Ambient Air Pollution Exposure in the Cancer Prevention Study-II Nutrition Cohort (CPSII-MWAS-AIR) (supported by the NIEHS HERCULES Exposome Center pilot awards, PI: Liang)

We will work with metabolomics profiling data from the Cancer Prevention Study II Nutrition Cohort, a large prospective cohort that have enrolled adults from various racial and ethnic backgrounds from across the United States, and extends follow-up over long periods of time to identify the causes of cancer and other adverse health outcomes. The CPSII-MWAS-AIR study will be built on existing CPS resources, using metabolomics data previously analyzed from 1,438 non-current smoking postmenopausal women within this cohort, and the spatiotemporally resolved retrospective assessment on the individual levels of air pollution. We anticipate that findings from this study will contribute to a better understanding of the underlying molecular mechanisms of air pollution toxicity and, potentially, cancer disease etiology.

The study is ongoing with close collaboration with Dr. Ying Wang and the Population Science team at the American Cancer Society. The Emory team includes Dr. Donghai Liang, Dr. Jeremy Sarnat, Ziyin Tang, Sabrina Chen, Sitong Chen, and Youran Tan.

Metabolomics Wide Association Study on Ambient Air Pollution Exposure in the Cancer Prevention Study-II Nutrition Cohort (Manuscript in preparation)

There are multiple potential rotation/thesis/dissertation opportunities and please reach out to Dr. Liang if you are interested in learning more about these.

D. Saliva Metabolome in Traffic-related Health (SMITH) pilot study (supported by Emory RSPH Dean’s Pilot Award, PI: Liang)

The SMITH study will examine the suitability and feasibility of using saliva as an alternative biological matrix for use in high-resolution metabolomics (HRM) application and biomarker discovery. This study builds on the DRIVE study by leveraging the saliva and plasma samples collected from a panel of voluntary undergraduates who lived in the dormitories close to a busy highway.  We will perform a comprehensive comparison of the overlapping features and unique features detected in both biospecimens and evaluated saliva’s potential for discovering novel biomarkers and biological pathways associated with the exposure to traffic-related air pollution compared to plasma.

  • Saliva Metabolome in Assessing Internal Exposures to Traffic-Related Air Pollution. (Led by Zhenjiang Li)
    Li, Z., Sarnat, J.A., Liu, K., Chang, CJ., Ly, V., Greenwald, R., Chang, H.C., Russell, A.G., Jones, D.P., and Liang, D. Manuscript in preparation.

Include but not limited to the following research topics:

  • Use R-LINE dispersion models and GPS data to generate longitudinal personal exposures to TRAP
  • Use high-resolution metabolomics to investigate the longitudinal impact of TRAP exposures on saliva metabolome

E. Atlanta Commuter Exposure (ACE/ACE-2) Study (supported by CDC and U.S. EPA, PI: Sarnat)

ACE was a longitudinal panel study of 60 participants for a targeted examination of oxidative stress and inflammation for a suite of cardiovascular and respiratory outcomes associated with on-road traffic exposures during morning rush hour car commutes in Atlanta, GA. We focused on in-vehicle air pollution concentrations including PM2.5 mass, black carbon (BC), particle-bound polycyclic aromatic hydrocarbons (pbPAHs), particle number concentration (PNC), and noise (dB), and examined the targeted inflammatory biomarker levels and metabolomic profiles to trace potential metabolic perturbations associated with on-road traffic exposures.

ACE-2 was a randomized, crossover panel study of 60 young adults with or without asthma in Atlanta, GA. In the first part of this study, we measured in-vehicle environmental exposures and corresponding changes in acute pulmonary and inflammatory response through endogenous biomarkers using epidemiologic analysis to examine the hypothesis that in-vehicle exposures during a highway commute differ from exposures during a surface street commute and indoor clinic exposure sessions, leading to transient inflammatory and acute cardiorespiratory response. In the second part of this study, we identified the molecular pathways perturbed following traffic pollution exposures on people with asthma using an untargeted MWAS framework. We also examined how asthma status modifies these perturbations to explore potential molecular mechanisms of traffic-related air pollutants (TRAP)  toxicity on people with asthma. We view this work as a critical step in the development of targeted interventions aimed at reducing the health burden associated with this pollutant source, particularly in individuals with asthma.

  • Exposure assessment on on-roadway and in-cabin TRAP exposures

Greenwald, R., Bergin, M.H., Yip, F., Boehmer, T., Kewada, P., Shafer, M.M., Schauer, J.J. and Sarnat, J.A., 2014. On-roadway In-cabin exposure to particulate matter: measurement results using both continuous and time-integrated sampling approaches. Aerosol Science and Technology, 48(6), pp.664-675.

Vreeland, H., Weber, R., Bergin, M., Greenwald, R., Golan, R., Russell, A.G., Verma, V. and Sarnat, J.A., 2017. Oxidative potential of PM2. 5 during Atlanta rush hour: Measurements of in-vehicle dithiothreitol (DTT) activity. Atmospheric Environment, 165, pp.169-178.

  • Characterizing the impact of TRAP exposures on acute pulmonary and inflammatory responses

Sarnat, J.A., Golan, R., Greenwald, R., Raysoni, A.U., Kewada, P., Winquist, A., Sarnat, S.E., Flanders, W.D., Mirabelli, M.C., Zora, J.E. and Bergin, M.H., 2014. Exposure to traffic pollution, acute inflammation and autonomic response in a panel of car commuters. Environmental research, 133, pp.66-76.

Mirabelli, M.C., Golan, R., Greenwald, R., Raysoni, A.U., Holguin, F., Kewada, P., Winquist, A., Flanders, W.D. and Sarnat, J.A., 2015. Modification of traffic-related respiratory response by asthma control in a population of car commuters. Epidemiology (Cambridge, Mass.), 26(4), p.546.

Krall, J.R., Ladva, C.N., Russell, A.G., Golan, R., Peng, X., Shi, G., Greenwald, R., Raysoni, A.U., Waller, L.A. and Sarnat, J.A., 2018. Source-specific pollution exposure and associations with pulmonary response in the Atlanta Commuters Exposure Studies. Journal of exposure science & environmental epidemiology, 28(4), pp.337-347.

Golan, R., Ladva, C., Greenwald, R., Krall, J.R., Raysoni, A.U., Kewada, P., Winquist, A., Flanders, W.D., Liang, D. and Sarnat, J.A., 2018. Acute pulmonary and inflammatory response in young adults following a scripted car commute. Air Quality, Atmosphere & Health, 11(2), pp.123-136.

  • Use of high-resolution metabolomics to assess the impact of TRAP exposures on human metabolome among the study participants with and without asthma

Liang, D., Ladva, C.N., Golan, R., Yu, T., Walker, D.I., Sarnat, S.E., Greenwald, R., Uppal, K., Tran, V., Jones, D.P. and Russell, A.G., 2019. Perturbations of the arginine metabolome following exposures to traffic-related air pollution in a panel of commuters with and without asthma. Environment international, 127, pp.503-513.

Ladva, C.N., Golan, R., Liang, D., Greenwald, R., Walker, D.I., Uppal, K., Raysoni, A.U., Tran, V., Yu, T., Flanders, W.D. and Miller, G.W., 2018. Particulate metal exposures induce plasma metabolome changes in a commuter panel study. PloS one, 13(9), p.e0203468.

  • Comparison between biometrics for use in environmental metabolomics to characterize internal exposures to TRAP

Ladva, C.N., Golan, R., Greenwald, R., Yu, T., Sarnat, S.E., Flanders, W.D., Uppal, K., Walker, D.I., Tran, V., Liang, D. and Jones, D.P., 2017. Metabolomic profiles of plasma, exhaled breath condensate, and saliva are correlated with potential for air toxics detection. Journal of breath research, 12(1), p.016008.

 

Include but not limited to the following research topics:

  • Use GPS data and recorded image to characterize on-road and in-cabin TRAP exposures
  • Use semi-targeted metabolomics to investigate the impact of TRAP exposures on acute inflammatory responses and perturbations in the plasma metabolome
  • Investigate how the asthmatic status modify the perturbations in the acute inflammatory biomarkers and perturbations in the NO-Arginine metabolism

F. Center for Health Discovery and Well-Being (CHDWB) Study (supported by Emory RSPH Dean’s Pilot Award, PI: Ebelt)

The CHDWB cohort was initiated in May 2008 and randomly recruited employees affiliated with Emory University from 2008 to 2012. In this study, we examined metabolic perturbations associated with short-term exposures to traffic-related air pollutants (TRAP), including carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), fine particulate matter (PM2.5), organic carbon (OC), and elemental carbon (EC) among 180 participants of CHDWB cohort. Metabolic perturbations were assessed following an untargeted HRM workflow and used the feature-specific Tobit regression models.

In collaboration with Dr. Stefanie Ebelt from the Rollins School of Public Health. The related publication includes:

Li, Z., Liang, D., Ye, D., Chang, H.H., Ziegler, T.R., Jones, D.P. and Ebelt, S.T., 2021. Application of high-resolution metabolomics to identify biological pathways perturbed by traffic-related air pollution. Environmental Research, 193, p.110506.

G. Environment and Reproductive Health (EARTH) Study (supported by NIEHS and U.S. EPA, PI: Gaskins)

The EARTH study is a prospective cohort aimed at evaluating environmental and nutritional determinants of fertility among couples undergoing fertility evaluation at the Massachusetts General Hospital (MGH) Fertility Center. This project included 200 women undergoing a fresh assisted reproductive technology (ART) cycle at Massachusetts General Hospital Fertility Center (2005-2015). A serum sample was collected during stimulation, and untargeted metabolic profiling was conducted using liquid chromatography with ultra-high-resolution mass spectrometry. Exposure to nitrogen dioxide (NO2), ozone (O3), fine particulate matter <2.5 µm (PM2.5), and black carbon (BC) was estimated using validated spatiotemporal models. Multivariable linear regression models were used to evaluate the associations between the air pollutants, live birth, and metabolic feature intensities. A meet in the middle approach was used to identify overlapping features and metabolic pathways.

In collaboration with Dr. Audrey J. Gaskins from the Rollins School of Public Health. Related publication and ongoing projects include:

Gaskins, A.J., Tang, Z., Hood, R.B., Ford, J., Schwartz, J.D., Jones, D.P., Laden, F., Liang, D. and EARTH Study Team, 2021. Periconception air pollution, metabolomic biomarkers, and fertility among women undergoing assisted reproduction. Environment International, 155, p.106666.

Duration of PM2. 5 exposure and alterations in the serum metabolome. Hood, R.B., Liang, D., Tang, Z., Kloog, I., Schwartz, J., Laden, F., Jones, D. and Gaskins, A.J., 2021, (Under Review)

H. Air Pollution Metabolome-Wide Association Study (MWAS) Systematic Review

We are working on a systematic review to summarize recent research of air pollution studies utilizing untargeted metabolomics and identify gaps in the peer-reviewed literature and opportunities for further understanding the mechanistic basis of air pollution toxicity. Using PRISMA guidelines, we screened articles published within MEDLINE and Web of Science between 1/1/05 and 06/30/21. Two reviewers independently screened a total of 1,074 abstracts, with discrepancies resolved by a third reviewer. 22 studies fulfilled eligibility criteria and were included in this review. Over 300 metabolic features were associated with at least one or more air pollutants, with 52 features validated using authentic reference standards. Hypoxanthine, arginine, and histidine were among 12 metabolites consistently exhibiting associations with fine particulate matter and nitrogen dioxide exposure in at least three independent studies. Oxidative stress and inflammation-related pathways, including glutathione, leukotriene, and vitamin E metabolism, were the most commonly perturbed pathways reported in over 55% of studies. Challenges and gaps exist in metabolite annotation; over 80% of the reported features were not chemically annotated, limiting the interpretability and generalizability of the findings. Numerous investigations have demonstrated the feasibility of using untargeted metabolomics as a platform linking exposure to internal dose and biological response. Metabolic perturbations in oxidative stress and acute inflammation pathway were associated with both short- and long-term air pollution exposure. Future directions should focus on the validation of these findings via hypothesis-driven protocols and technical advances in metabolic annotation and quantification.

In collaboration with Dr. Jelle Vlaanderen and Dr. Roel Vermeulen from the Utrecht University.

Systematic Review on Untargeted Metabolomics Application in Air Pollution Health Research: Current Progress, Analytical Challenges, and Future Direction. Liang, D., Li, Z., Vlaanderen, J., Tang, Z., Vermeulen, R. and Sarnat, J.A., (Manuscript in preparation)

I. Air Pollutants and the Gut Microbiota and Metabolome During Early Life: Implications for Childhood (supported by the Health Effect Institute, PI: Tanya Alderete)

In this study, our overarching hypothesis is that increased exposure to air pollutants during pregnancy and early life will result in altered gut microbial profiles and fecal metabolites in infants, which will increase the risk for childhood obesity through changes in infant growth trajectories during the first two years of life.

In collaboration with Dr. Tanya Alderete from University of Colorado Boulder. We are currently conducting high-resolution metabolic profiling on the longitudinal biosamples. There are several potential research opportunities and please reach out to Dr. Liang if you are interested in learning more about this study.

Our multidisciplinary team of investigators propose to test this hypothesis in a longitudinal cohort of Hispanic mother-infant pairs with existing validated clinical assessments of infant growth trajectories. In addition, gut microbial profiling and high-resolution fecal metabolomics profiles will advance our understanding of the mechanisms underlying the obesogenic effects of air pollutants in early life. Our specific aims are to determine the extent to which prenatal and/or early life exposure to ambient and/or near-roadway air pollution (NRAP) is: 1) cross-sectionally associated with the infant gut microbiota and fecal metabolites from 5 a priori-selected metabolic pathways (i.e., short-chain fatty acid, lipid, amino acid, bile acid, and tryptophan metabolism) at 1, 6, 12, 18, and 24-months of age (Aim 1), 2) longitudinally associated with alterations to the infant gut microbiota and the same suite of a priori selected pathways (Aim 2), and 3) to determine whether infant gut bacteria and/or fecal metabolic pathways associated with increased ambient (PM2.5, NO2, O3) and/or NRAP exposures are also associated with infant growth trajectories under a mediation framework (Aim 3). To address these aims, the proposed research includes experts in environmental epidemiology, exposure assessment, microbiology, metabolomics, early life obesity, and biostatistics. As such, this project is in line with HEI’s strategic mission, which is focused on producing timely and credible science needed to inform air quality. Lastly, obesity is a global health issue; thus, this study is innovative and offers a unique opportunity to advance our understanding of the early life environmental contributions to obesity and to open new global avenues for childhood obesity prevention.

Using targeted exposure assessment and advanced high-resolution omics technologies to investigate the impact of various ubiquitous environmental toxicants on maternal and child health.

A. Per- and poly-fluoroalkyl substances (PFAS) Exposures and Child Health (PEACH) Study (supported by NIEHS Environmental influences on Child Health Outcomes Opportunities and Infrastructure Fund (ECHO OIF), PI: Liang)

The overarching goal of the PEACH study is to apply an advanced untargeted metabolomics workflow to investigate associations between PFAS levels, perturbations in maternal and newborn metabolome and adverse birth outcomes. PEACH will draw from repeated metabolic profiling on a subset of 320 AA pregnant women within the Atlanta African American Maternal-Child ECHO cohort and will propose to conduct, in Human Health Exposure Analysis Resource (HHEAR) lab hubs, repeated advanced targeted chemical analysis and untargeted metabolomics to generate comprehensive longitudinal exosomes profiling of PFAS levels and responses on both AA mother and newborns.

The “Per- and poly-fluoroalkyl substances Exposures And Child Health (PEACH) Study” aims to apply an advanced untargeted metabolomics workflow to investigate associations between PFAS levels, perturbations in maternal and newborn metabolome and adverse birth outcomes.  The Emory ECHO team has established a socio-economically diverse, exceptionally phenotyped AA maternal-child cohort that enrolls pregnant women in the early prenatal period and extends dyad follow-up through age five to investigate the impacts of the prenatal microbiome, metabolome, epigenome, environmental toxicants, and stress on preterm birth, infant and child neurodevelopment. PEACH will draw from repeated metabolic profiling on a subset of 320 AA pregnant women within the Atlanta ECHO cohort and will propose to conduct, in HHEAR lab hubs, targeted analysis to assess PFAS levels on exposed mothers and newborns, and global metabolomics on newborns. This objective will be addressed via three Specific Aims:

Specific Aim 1: We will examine whether prenatal serum PFAS levels are longitudinally associated with perturbations in the maternal metabolome. Hypothesis 1: Serum PFAS level during pregnancy will be longitudinally associated with perturbations in the maternal metabolome, particularly among pathways related to endocrine disruption and oxidative stress.

Specific Aim 2: We will examine whether fetal PFAS levels, measured in newborn dried blood spots, are associated with perturbations in the metabolome, and whether they are similar with what we observe in Aim 1. Hypothesis 2: Fetal PFAS levels will be associated with perturbations in the newborn metabolome, where the perturbed pathways will be similar to those observed in maternal metabolome.

Specific Aim 3: We will explore whether perturbed metabolic pathways associate with increased PFAS levels are also associated with adverse birth outcomes under a mediation framework. Hypothesis 3: Serum PFAS levels during pregnancy will be associated with perturbations in metabolic pathways linked to endocrine disruption and oxidative stress, which will increase risk for adverse birth outcomes.

We see this study as a highly novel opportunity for investigating molecular mechanisms of PFAS toxicity on adverse birth outcomes. We further expect this work to contribute to the identification of novel biological factors and metabolic biomarkers of at-risk individuals, which will benefit other ECHO-wide consortium studies to identify factors that moderate associations between PFAS levels and adverse child health outcomes. Ultimately, these findings should inform targeted interventions to mitigate PFAS-related risk and provide opportunities for solutions-oriented research to improve health outcomes in exposed mothers and children.

  • Investigating biological pathways and intermediate biomarkers in newborn metabolome underlying the association between maternal serum PFAS and fetal growth outcomes using high-resolution metabolomics. (Led by Kaitlin Taibl)

This prospective cohort study included 267 African American pregnant people who gave birth to a singleton in Atlanta, Georgia between 2016 and 2020. Maternal PFAS concentrations were measured in serum samples obtained between 6–17 gestational weeks. Linear and logistic regression was used to assess associations between PFAS concentrations and gestational weeks at birth or PTB and ETB compared to full-term birth, respectively. Molecular signatures of the exposure-outcome relationships were phenotyped in newborn DBS samples with untargeted metabolomics.

Newborn Metabolomic Signatures of Maternal Serum Per- and Polyfluoroalkyl Substance Levels and Reduced Length of Gestation: A Prospective Analysis in the Atlanta African American Maternal-Child Cohort (Tabil et al., under review)

  • Examining variability of longitudinal PFAS concentrations during pregnancy and maternal-fetal transfer rate of PFAS among African Americans in the PEACH study. (Led by Youran Tan)

We quantified serum concentrations of twelve PFAS among pregnant women during early (8-14 weeks) and late (24-30 weeks) gestation, as well as levels of four PFAS in dried blood spots (DBS) from paired newborns in the Atlanta AA Maternal-Child cohort (2014-2018). We characterized the variability of PFAS levels across gestation using intraclass correlation coefficients (ICC) and transfer rate. Multivariable linear regression models were fit to assess how maternal early or late PFAS levels predict newborn PFAS levels.

Variability of per- and polyfluoroalkyl substances concentrations among pregnant African American women and newborns (Tan et al., manuscript in preparation)

  • Examining PFAS levels and hemodynamics during pregnancy (Taibl and Eick et al.,)

Include but not limited to the following research topics:

    • Investigate changes in PFAS levels during early and late pregnancy and the corresponding perturbations in maternal and newborn metabolome
    • Examine predictors of longitudinal PFAS levels in maternal serum and newborn dried blood spots
    • Use mixture analysis to examine the joint effects of PFAS levels on maternal and newborn metabolome

B. Maintenance and Enhancement of the Atlanta African American Maternal-Child Cohort (Supported through NIEHS R24 PI: Dunlop and Jones)

Environmental exposures during the critical prenatal and early childhood periods can result in lifelong health consequences. Mechanisms underlying these exposure-health relationships are complex, with exogenous exposures (such as chemical toxicants) affecting endogenous processes (such as gene regulation and metabolism), which perturb metabolic pathways that lead to adverse health outcomes. Both adverse exposures and their health consequences disproportionately impact African American (AA) women and children, highlighting that health disparities begin in utero and are amplified postnatally. Through this work, we expect to advance environmental health science around the assessment of chemical mixtures and their adverse preclinical (metabolic and epigenetic) health effects in our own high disparity population of pregnant women and newborns and to support other cohorts and cross-cohort collaborations involving the use of high-dimensional multi-omic data.

A series of studies have close collaboration with Dr. Anne L. Dunlop and Dr. Dean Jones from Emory School of Medicine.

  • Phthalates Exposures and Maternal Metabolic Perturbations Study

In this project, we measured eight urinary phthalate metabolites in early and late pregnancy, including Monoethyl phthalate (MEP), Mono-n-butyl phthalate (MBP), Mono(2-ethlyhexyl) phthalate (MEHP), and Mono (2-ethyl-5-hydroxyhexyl phthalate (MEHHP) to assess maternal exposures to phthalates among pregnant AA women. Metabolite and metabolic pathway perturbation were evaluated using an untargeted HRM workflow.

Zhang X, Barr DB, Dunlop AL, Panuwet P, Sarnat JA, Lee GE, Tan Y, Corwin EJ, Jones DP, Ryan PB, Liang D. Assessment of metabolic perturbations associated with exposure to phthalates among pregnant African American women. Science of The Total Environment. 2022 Apr 20;818:151689.

  • Tobacco Smoke Exposures, Maternal Metabolic Perturbations, and Adverse Birth Outcomes Study

In this project, we measured collected early and late pregnancy urine samples for cotinine measurement and serum samples for high-resolution metabolomics (HRM) profiling from 105 pregnant women from the Atlanta African American Maternal-Child cohort (2014–2016). Maternal metabolome perturbations mediating prenatal tobacco smoke exposure and adverse birth outcomes were assessed by an untargeted HRM workflow using generalized linear models, followed by pathway enrichment analysis and chemical annotation, with a meet-in-the-middle approach.

Tan Y, Barr DB, Ryan PB, Fedirko V, Sarnat JA, Gaskins AJ, Chang CJ, Tang Z, Marsit CJ, Corwin EJ, Jones DP. High-resolution metabolomics of exposure to tobacco smoke during pregnancy and adverse birth outcomes in the Atlanta African American maternal-child cohort. Environmental Pollution. 2022 Jan 1;292:118361.

  • PFAS Exposures, Maternal Metabolic Perturbations, and Adverse Birth Outcomes Study

In this project, serum perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) measurements and untargeted serum metabolomics profiling were conducted in 313 pregnant African American women at 8–14 weeks gestation. Multiple linear regression models were applied to assess the associations of PFAS with birth weight and small-for-gestational age (SGA) birth. A high-resolution metabolomics workflow including metabolome-wide association study, pathway enrichment analysis, and chemical annotation and confirmation with a meet-in-the-middle approach was performed to characterize the biological pathways and intermediate biomarkers of the PFAS-fetal growth relationship.

Chang CJ, Barr DB, Ryan PB, Panuwet P, Smarr MM, Liu K, Kannan K, Yakimavets V, Tan Y, Ly V, Marsit CJ. Per-and polyfluoroalkyl substance (PFAS) exposure, maternal metabolomic perturbation, and fetal growth in African American women: a meet-in-the-middle approach. Environment international. 2022 Jan 1;158:106964.

  • Bisphenol A and Bisphenol F Exposures and Maternal Metabolic Perturbations Study (Led by Rachel Tchen and Youran Tan)

From a subset of the 230 study participants in the Atlanta AA Maternal-Child cohort, we collected urine samples during the early pregnancy period for targeted exposure assessment on BPA and BPF. Serum samples were collected at the same time for HRM profiling. Using an established untargeted HRM workflow, we investigated the metabolic perturbations associated with exposure to BPA and BPF.

Use of high-resolution metabolomics to assess the biological perturbations associated with maternal exposure to Bisphenol A and Bisphenol F among pregnant African American women (Tchen and Tan et al., under review)

  • Preterm birth and Maternal Metabolomics (Led by Donghai Liang and Youran Tan)

The rates of preterm birth prior to 34 weeks’ gestation are significantly higher among AA women compared to other racial groups and the etiology of spontaneous preterm birth (sPTB) remains imperfectly understood. Many studies showed inconsistency in perturbed maternal metabolome associated with sPTB so we plan to perform an MWAS using untargeted HRM to identify potential metabolic biomarkers associated with preterm birth, specifically, sPTB among pregnant women within the Atlanta AA Maternal-Child Cohort.

  • Race and Metabolomics (Led by Donghai Liang and Anne Dunlop)

We plan to use Krieger Scales (KEOD) and Jackson-Hogue scales (JHP) to evaluate the discrimination and contextualized stress level among pregnant AA women within the Atlanta AA Maternal-Child Cohort. We will explore if the different discrimination and stress levels would have an impact on maternal metabolome, in order to potentially reduce the health burden and health disparities in this minority population.

  • Infant Gender and Maternal Metabolomics (Led by Donghai Liang and Youran Tan)

We will leverage the longitudinal metabolic profiling on AA pregnant women that had healthy full-term babies born from Atlanta AA Maternal-Child Cohort to explore the role of infant gender on maternal metabolome, with a focus on the changes in sex hormone related pathways and metabolites.

  • Integration of multi-omics to investigate the molecular connection between maternal exposures to ubiquitous environmental pollutants and adverse birth outcomes (Led by Donghai Liang)

Advances in omics technologies, such as epigenomics, metabolomics, and microbiomics, permit the collection of high-dimensional molecular data from individuals and offer the potential to characterize the biological mechanisms. Moreover, the integration analysis of the multi-omics data provides a more comprehensive understanding of disease mechanisms. This study will integrate and simultaneously analyze longitudinal multi-omics data (epigenome, metabolome, and microbiome) to investigate and elucidate the molecular connection between maternal exposures to ubiquitous environmental pollutants and adverse birth outcomes in a unique, socio-economically diverse, exceptionally phenotyped African American maternal-child cohort. The study approaches will include novel longitudinal exposomics profiling through external, targeted exposure assessment and modeling paired with internal, high-resolution multi-omics profiling on 500 African American pregnant women within this maternal-child cohort.

There are multiple potential rotation/thesis/dissertation opportunities, ranging from examining the impact of persistent organic pollutants (POPs, including PFAS, PBDEs, PCBs, OCPs), non-POPs (e.g., phthalates, bisphenol), and air pollutants on maternal and child health outcomes, to investigating the underlying mechanisms using single- and multi-omics technologies (e.g., metabolomics, epigenomics, lipidomics, and microbiomics, etc.,). Please reach out to Dr. Liang if you are interested in learning more about these.

C. Study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE, PI: Barr)

Metabolome-Wide Association Study of the Relationship Between Insecticide Exposure and First Trimester Serum Metabolite Levels in Pregnant Thai Farmworkers (Led by Donghai Liang and Jonathan Batross)

In collaboration with Dr. Dana Barr from the Rollins School of Public Health.  Learn more about her RSPH’s Laboratory for Exposure Assessment and Development in Environmental Research.

Organophosphate (OP) insecticides are a common group of neurotoxic insecticides whose main biological target is acetylcholinesterase, an enzyme that catabolizes the neurotransmitter acetylcholine. While OP insecticides are made to mitigate insects, they can also affect humans. Thailand is an agro-centric country with a high use of OP insecticides. Farmworkers, many of whom are pregnant, are exposed to OP insecticides during their routine jobs that will result in fetal exposure to these insecticides and may ultimately result in child neurodevelopmental deficits. The Study of Asian Women and their Offspring’s Development and Environmental Exposures (SAWASDEE) followed 322 mother-child dyads from pregnancy until three years old obtaining time-resolved prenatal and postnatal exposure measures along with extensive neurodevelopmental analyses. We used liquid chromatography-high resolution mass spectrometry to conduct metabolic profiling on first trimester serum samples collected from 50 of these participants to evaluate metabolic perturbations in relation to OP insecticide exposure. To assess the levels of OP insecticide exposure, we measured the selective metabolite of chlorpyrifos and chlorpyrifos- methyl-3,5,6-trichloro-2-pyridinol (TCPY)-in first trimester urine samples. Following an untargeted metabolome-wide association study workflow, we used generalized linear models, pathway enrichment analyses, and chemical annotation to identify significant metabolites and pathways associated with urinary OP levels.

D. The Michigan PBB Cohort: A Unique, Highly Exposed Community Followed for 45 Years and Three Generations (PI: Marcus)

Metabolic changes associated with polybrominated biphenyls and polychlorinated biphenyls in the Michigan PBB registry (Led by Susan Hoffman)

In collaboration with Dr. Michele Marcus from the Rollins School of Public Health.

Polybrominated Biphenyl (PBB) and Polychlorinated Biphenyl (PCB) are endocrine-disrupting chemicals (EDCs).  In Michigan, people were exposed to PBB during a time-limited contamination event in the 1970s and are continuously exposed to PCBs.  Using high-resolution metabolomics (HRM), this study aimed to identify biological mechanisms underlying human health effects of PBB and PCB exposure. HRM profiling was conducted on serum samples from the Michigan PBB Registry collected from a subset of 500 individuals representing both F0 (directly exposed to PBB) and F1 (exposed through parents) generations from 2011 to 2014.  This study measured PBB-153 stratified by generation and ƩPCB (PCB-118, PCB-138, PCB-153, and PCB-180) in the total combined subset (as all experienced direct PCB exposure).  Metabolite and metabolic pathway perturbation were evaluated using an untargeted HRM workflow.