Grantee Research Project Results
Final Report: Center for Research on Early Childhood Exposure and Development in Puerto Rico
EPA Grant Number: R836155Center: Center for Research on Early Childhood Exposure and Development in Puerto Rico
Center Director: Alshawabkeh, Akram
Title: Center for Research on Early Childhood Exposure and Development in Puerto Rico
Investigators: Alshawabkeh, Akram , Suh, Helen H. , Cordero, Jose , Manjourides, Justin , Zimmerman, Emily , Gu, April , Meeker, John D.
Institution: Northeastern University
EPA Project Officer: Callan, Richard
Project Period: September 1, 2015 through August 31, 2019 (Extended to August 31, 2022)
Project Amount: $2,099,537
RFA: Children's Environmental Health and Disease Prevention Research Centers (2014) RFA Text | Recipients Lists
Research Category: Human Health , Children's Health
Objective:
Project 1: Project Title: Assessing the Impact of Air Pollution on Adverse Birth Outcomes and Child Development
Our study will provide new evidence of the impacts of air pollution on neonatal and early childhood development for infants and children living in Puerto Rico and of factors that affect susceptibility to air pollution’s harmful impacts. We will do so by leveraging the success of PROTECT, our cohort study of 1800 pregnant women in Puerto Rico for whom a rich dataset of environmental, health, social, demographic, and behavioral factors are being collected. To these data, we will add measurements of air pollution exposures, early childhood development, and non-nutritive suck (NNS), a measure of newborn central nervous system function that has not yet been used to assess neonatal development in environmental epidemiology. We will use these data to achieve three aims: to (1) assess the association of air pollution on adverse birth outcomes; (2) determine the impact of air pollution on child development; and (3) examine effect modification of the air pollution–adverse health relationship by social and personal factors, including socio-economic status, maternal stress, birth outcomes, other pollutant exposures, and housing characteristics.
Project 2: Toxicogenomics-based Mechanistic Multimedia Exposure Assessment and Child Development
Project 2 employs novel in vitro, high throughput screening (HTS) assays to yield new toxicity information needed to reveal the impacts of exposure to complex pollutant mixtures on pathways relevant to neonatal and early childhood development. Significant challenges remain in understanding the complex risks that pollutant mixtures and their metabolites pose for human health. These challenges motivate a new paradigm for toxicity evaluation that is based on an in vitro mechanistic and genetic pathway-based approach that allows combinations of exposures and outcomes to be tested comprehensively yet feasibly. To address this need, we have developed an approach that uses in vitro HTS to measure translational changes in targeted genetic pathways occurring in response to pollutants and pollutant mixtures. Importantly, these pollutants and mixtures are drawn directly from environmental sources, such as water and air, and also from biological matrices like urine. They are then passed through in vitro preparations of human and non-human cells, where we measure biomarkers of oxidative stress, DNA damage and inflammation. These pathways and biomarkers were selected based on their established association with CRECE-relevant neonatal and early childhood health outcomes, and because the biomarkers are found at measurable concentrations in the urine and sera of exposed individuals. Through this approach, we are able to provide pathway- and sample-specific fingerprints of pollutant exposures and their effects that can inform environmental epidemiological studies and even be used themselves as biomarkers of exposure in these studies. Through close collaboration with CRECE’s other two projects, this project will inform epidemiological studies of our cohort of 600 Puerto Rican children. These studies leverage data and infrastructure established under PROTECT, a highly productive NIEHS-funded pregnancy study of a cohort of 1800 pregnant women from Puerto Rico’s northern coast. This project will provide its HTS findings and exposure biomarker measures to Projects 1 and 3, thus allowing those projects to perform health effect analyses for pollutant mixtures identified as toxic by the HTS, and to examine the association of exposure biomarkers with neonatal and early childhood health outcomes.
Grantee Publication (CSS): The spread of antibiotic-resistant bacterial species is a major global health concern and the need for rapid, reliable antimicrobial susceptibility testing (AST) is critical for reducing the use of broad-spectrum antimicrobials while ensuring that patients receive timely and adequate treatment. STAR grantees from the University of Wisconsin–Madison have a recent publication in the journal Lab on a Chip describing a pilot study of a new liquid-phase, open microfluidic system for rapid (less than 4 hours) phenotypic AST that can be used in a clinic or hospital setting.
Title: Under-oil open microfluidic systems for rapid phenotypic antimicrobial susceptibility testing
Abstract: Antimicrobial susceptibility testing (AST) remains the cornerstone of effective antimicrobial selection and optimization in patients. Despite recent advances in rapid pathogen identification and resistance marker detection with molecular diagnostics (e.g., qPCR, MALDI-TOF MS), phenotypic (i.e., microbial culture-based) AST methods – the gold standard in hospitals/clinics – remain relatively unchanged over the last few decades. Microfluidics-based phenotypic AST has been growing fast in recent years, aiming for rapid (i.e., turnaround time <8 h), high-throughput, and automated species identification, resistance detection, and antibiotics screening. In this pilot study, we describe the application of a multi-liquid-phase open microfluidic system, named under-oil open microfluidic systems (UOMS), to achieve a rapid phenotypic AST. UOMS provides an open microfluidics-based solution for rapid phenotypic AST (UOMS-AST) by implementing and recording a pathogen's antimicrobial activity in micro-volume testing units under an oil overlay. UOMS-AST allows free physical access (e.g., by standard pipetting) to the system and label-free, single-cell resolution optical access. UOMS-AST can accurately and rapidly determine antimicrobial activities [including susceptibility/resistance breakpoint and minimum inhibitory concentration (MIC)] from nominal sample/bacterial cells in a system aligned with clinical laboratory standards where open systems and optical microscopy are predominantly adopted. Further, we combine UOMS-AST with a cloud lab data analytic technique for real-time image analysis and report generation to provide a rapid (<4 h) sample-to-report turnaround time, shedding light on its utility as a versatile (e.g., low-resource setting and manual laboratory operation, or high-throughput automated system) phenotypic AST platform for hospital/clinic use.
Grantee Publication (CSS): The spread of antibiotic-resistant bacterial species is a major global health concern and the need for rapid, reliable antimicrobial susceptibility testing (AST) is critical for reducing the use of broad-spectrum antimicrobials while ensuring that patients receive timely and adequate treatment. STAR grantees from the University of Wisconsin–Madison have a recent publication in the journal Lab on a Chip describing a pilot study of a new liquid-phase, open microfluidic system for rapid (less than 4 hours) phenotypic AST that can be used in a clinic or hospital setting.
Title: Under-oil open microfluidic systems for rapid phenotypic antimicrobial susceptibility testing
Abstract: Antimicrobial susceptibility testing (AST) remains the cornerstone of effective antimicrobial selection and optimization in patients. Despite recent advances in rapid pathogen identification and resistance marker detection with molecular diagnostics (e.g., qPCR, MALDI-TOF MS), phenotypic (i.e., microbial culture-based) AST methods – the gold standard in hospitals/clinics – remain relatively unchanged over the last few decades. Microfluidics-based phenotypic AST has been growing fast in recent years, aiming for rapid (i.e., turnaround time <8 h), high-throughput, and automated species identification, resistance detection, and antibiotics screening. In this pilot study, we describe the application of a multi-liquid-phase open microfluidic system, named under-oil open microfluidic systems (UOMS), to achieve a rapid phenotypic AST. UOMS provides an open microfluidics-based solution for rapid phenotypic AST (UOMS-AST) by implementing and recording a pathogen's antimicrobial activity in micro-volume testing units under an oil overlay. UOMS-AST allows free physical access (e.g., by standard pipetting) to the system and label-free, single-cell resolution optical access. UOMS-AST can accurately and rapidly determine antimicrobial activities [including susceptibility/resistance breakpoint and minimum inhibitory concentration (MIC)] from nominal sample/bacterial cells in a system aligned with clinical laboratory standards where open systems and optical microscopy are predominantly adopted. Further, we combine UOMS-AST with a cloud lab data analytic technique for real-time image analysis and report generation to provide a rapid (<4 h) sample-to-report turnaround time, shedding light on its utility as a versatile (e.g., low-resource setting and manual laboratory operation, or high-throughput automated system) phenotypic AST platform for hospital/clinic use.
Project 2: Toxicogenomics-based Mechanistic Multimedia Exposure Assessment and Child Development
Project 2 employs novel in vitro, high throughput screening (HTS) assays to yield new toxicity information needed to reveal the impacts of exposure to complex pollutant mixtures on pathways relevant to neonatal and early childhood development. Significant challenges remain in understanding the complex risks that pollutant mixtures and their metabolites pose for human health. These challenges motivate a new paradigm for toxicity evaluation that is based on an in vitro mechanistic and genetic pathway-based approach that allows combinations of exposures and outcomes to be tested comprehensively yet feasibly. To address this need, we have developed an approach that uses in vitro HTS to measure translational changes in targeted genetic pathways occurring in response to pollutants and pollutant mixtures. Importantly, these pollutants and mixtures are drawn directly from environmental sources, such as water and air, and also from biological matrices like urine. They are then passed through in vitro preparations of human and non-human cells, where we measure biomarkers of oxidative stress, DNA damage and inflammation. These pathways and biomarkers were selected based on their established association with CRECE-relevant neonatal and early childhood health outcomes, and because the biomarkers are found at measurable concentrations in the urine and sera of exposed individuals. Through this approach, we are able to provide pathway- and sample-specific fingerprints of pollutant exposures and their effects that can inform environmental epidemiological studies and even be used themselves as biomarkers of exposure in these studies. Through close collaboration with CRECE’s other two projects, this project will inform epidemiological studies of our cohort of 600 Puerto Rican children. These studies leverage data and infrastructure established under PROTECT, a highly productive NIEHS-funded pregnancy study of a cohort of 1800 pregnant women from Puerto Rico’s northern coast. This project will provide its HTS findings and exposure biomarker measures to Projects 1 and 3, thus allowing those projects to perform health effect analyses for pollutant mixtures identified as toxic by the HTS, and to examine the association of exposure biomarkers with neonatal and early childhood health outcomes.
Project 3: Biomarker Epidemiology of In Utero Environmental Exposures and Child Development
It has been documented that there are particularly high rates for a number of developmental conditions, as well as elevated exposure to environmental contaminants, in Puerto Rico. Most human studies to date on environmental exposures and child health have focused on metals or persistent organic pollutants, but there is a great need for more data on emerging chemicals of concern, such as those currently used in a wide array of industrial and consumer applications. Chemicals such as phenols and parabens disrupt endocrine function, induce oxidative stress, and cause other alterations that may result in reduced fetal or child growth, preterm birth, neurodevelopmental delays, reproductive tract anomalies, obesity, allergies/asthma, and others. While near-ubiquitous exposures to these chemicals have been documented among pregnant women, well-designed human studies are greatly needed to determine whether developmental impacts are related to early life in utero exposure. In addition, few studies have addressed the real life situation of considering multiple exposures and susceptibility factors. To fill these gaps, we will use state-of-the-art epidemiologic approaches among an underserved and potentially highly exposed population. We will leverage an ongoing NIH-funded pregnancy cohort study in Puerto Rico (P42ES017198) that is building a rich dataset on environmental, clinical, social, demographic, behavioral, dietary and other factors among 1800 pregnant women on the island’s Northern coast. The study will follow 600 children born into the cohort through the age of 4 years. This project will link with Project 1 to test the impacts of exposure to multi-pollutant mixtures, and Project 2 to exchange information about mechanisms and test mixtures for our biomarker epidemiology study and their toxicity screening study.
Summary/Accomplishments (Outputs/Outcomes):
Project 1: To measure fine particle (PM2.5 ) concentrations, the Project 1 team installed three stationary ambient monitoring (SAM) sites in the study area along the north coast of Puerto Rico. Sites were selected based on their (1) proximity to participant homes and distance from major PM2.5 sources; (2) site characteristics such as the lack of trees, at least 10-20 meters of open space, and the presence of a nearby electricity source; and (3) monitor placement, including whether we could place monitors in a secure area with inlets at least 4 feet off the ground and no taller than a 4 story building. Based on these criteria, sites were identified in the municipalities of Morovis, Manatí, and Arecibo. Field technicians from Northeastern University provided installation and training to staff from the University of Puerto Rico, and all sites were operational by November 2016.
Two hurricanes affected sampling in September 2017. For Hurricane Irma, we suspended sampling on September 5 and resumed sampling on September 12 at all three sites. Hurricane Maria’s impact on sampling was substantial. We suspended sampling on September 18 at all three sites. Hurricane Maria completely destroyed our Arecibo monitoring site, partially destroyed our Morovis site, and damaged our Manatí site. The Manatí and Morovis sites were repaired and restored in December 2017 and January 2018, respectively. A new site in Arecibo was identified and the SAM was installed in 2019.
Air filters were analyzed for PM2.5 concentrations and Black Carbon (BC). Field technicians in Boston analyzed filters first for PM2.5 concentrations and then for BC by reflectance to preserve sample integrity. Once analyzed, the samples were stored in individual Petri dishes in a temperature-controlled balance room. XRF analyses were performed on a subset of our collected PM2.5 samples.
Project 2: Toxicity of Pollutant mixtures in Puerto Rican Drinking Water
Project 2 adopted a tea-bag equilibrium extraction method developed under PROTECT, after preliminary testing showed improved recovery rate and reproducibility as compared to a conventional solid phase extraction (SPE) method. A total of 18 tap water samples were collected from a subset of CRECE cohort participants. In order to identify potential toxicity nature and levels, and to reveal the potential causal agents, we conducted parallel toxicity assessment and chemical analysis. For toxicity evaluation, we performed cytotoxicity and HTS pathway-specific toxicogenomics assays that target various stress response pathways. For chemical characterization of the water samples, in collaboration with other participants, we conducted un-targeted analysis, metals analysis (13 different metals) and targeted analysis of volatile DBPs and DEHP.
Initial results demonstrated that the high throughput screening in vitro quantitative toxicogenomics assay is effective for evaluating and revealing the water toxicity level and profile changes among different drinking water sources. The results also demonstrated that the assay allows investigation of the background toxicity level and profiles in PR drinking water sources including groundwater, well water, and tap water. The quantitative measures of pathway-specific and chemical-specific biomarkers of exposure to water contaminants, including CECs, metals, and associated toxicity fingerprints, were obtained for each water sample using HTS assays for oxidative stress, DNA damage, protein stress, chemical stress and inflammation. Comparison and correlation analysis of the quantitative toxicity profiling index (PELIs) with results from un-targeted organics analysis, as well as metals analysis, revealed potential association or casual relationships. n September 2017, Hurricane Maria made landfall in Puerto Rico as a category 4 storm. 88% of the island was still without electricity (about 3 million people) one month after the storm, and 29% of the island had no access to clean water (about 1 million people). To study the impact of Hurricane Maria on tap water quality, 9 sampling sites around the entire island were chosen for tap water sample collection starting Dec. 2017. In the initial round of sampling, we completed and analyzed two sets of tap water samples collected at each site in Dec. 2017 and Feb. 2018. The results show that for most of the sampling sites (8 out of 9 sites), the total PELI values decreased over time, which may indicate the water quality improvement of drinking water sources in PR from the impact of Hurricane Maria. However, higher general and DNA stress response were induced upon exposure to tap water samples collected at Guayanilla site in Feb. than that in Dec., probably revealing a possible change of either drinking water source quality or water treatment process. More mechanistic insights will be obtained after receiving chemical analysis data and geography information. This preliminary test demonstrated the capability and sensitivity of our in vitro toxicogenomics assay to assist in water quality monitoring after natural or anthropic events and accidents.
Organic compounds from all 36 tap water samples were enriched via porous extraction paddle (PEP) immediately after sample collection in collaborating laboratories at the University of Puerto Rico (UPR) and subjected to both chemical analysis and toxicity assays. The 21 acidified water samples were analyzed for 18 trace elements on ICP-MS at NU, while all 36 organic extracts eluted from PEP were subjected to targeted and suspect screening for 234 organic micropollutants including PR human exposure-relevant chemicals on high-resolution LC-MS at Cornell University. In parallel, a HTS quantitative toxicogenomics assay with GFP-fused yeast reporters library (74 biomarkers) targeting genotoxicity, oxidative, protein, chemical, and general stress, and a RT-qPCR assay with human A549 cells targeting inflammation, genotoxicity, oxidative stress, endocrine disruption (ED), aryl hydrocarbon receptor (AHR) and apoptosis effects, were employed for toxicity assessment. Based on the initial assay sensitivity and reproducibility test for tap water analysis, the relative enrichment factor (REF) for all tap water samples was selected to be 200 times.
The results of chemical analysis showed that all 18 trace elements were detected in tap water samples with detection frequencies ranging from 19 to 100 percent. Seven trace elements, including As, Ba, Cr, Cu, Fe, Pb, and Rb, were detected in all 21 samples. The top 3 metals with highest concentrations averaged over all samples were Sr (160 µg/L), Cu (43 µg/L), and Ba (31 µg/L). For spatial distribution, higher cumulative contamination levels for trace elements were observed in the 18 samples collected in northern PR where 8 active National Priorities List (NPL) sites were located. For temporal analysis, we used the date when Hurricane Maria (HM) made landfall in PR as a cutoff timeline (Sept. 20, 2017) since this event was shown to adversely impact surface and groundwater quality according to other groups’ preliminary studies. Average concentrations of 14 out of 18 metals increased after HM with Mn, Ni, As, and Cu exhibiting highest fold changes of 14.2, 3.5, 1.8 and 1.6 times, respectively. According to t-test, contamination level of As in the tap water samples collected after HM was significantly higher than those before HM (p = 0.01036).
For organic screening, a total of 27 micropollutants were detected in at least one of the 36 samples, of which 17 were wastewater-derived (including pharmaceutical and personal care products (PPCP), plasticizers, perfluorochemicals, sweeteners, etc.) and 10 were agricultural-derived (pesticides) based on their primary uses. The top 5 organic micropollutants showing the highest occurrence in at least 20 samples were DEET
(insect repellent), diethyl phthalate (DEP, plasticizer), benzophenone (PPCP), sucralose (sweetener), and perfluorooctanoic acid (PFOA, perfluorochemical). Meanwhile, all 27 micropollutants were measured within the concentration range of 0.5 – 850 ng/L, which is well below the human-health benchmark levels, when available. Compared with pre-hurricane samples, 20 out of the 27 micropollutants showed elevated average concentrations after HM with sucralose, atrazine-2-hydroxy, PFOA, and 2,4-D exhibiting highest fold changes of 7.47, 3.64, 3.35, and 2.05, respectively. Specifically for pesticides and their degradation products, the 3 most frequently detected ones were DEET, 2,4-D, and atrazine-2-hydroxy in 100%, 47.2%, and 27.8% of all samples, respectively. Similar to trace elements, cumulative concentrations of organic micropollutants showed clear spatial distribution that were higher in the tap water samples collected at northern PR.
The toxicity screening results from the yeast toxicogenomics-based assay revealed pathway-specific molecular toxicity levels and distinct toxicity profiles among different sampling locations at different time points, demonstrating the sensitivity of the assay to detect and differentiate the potential toxicity levels of different environmental samples, even at sub-cytotoxic doses. Except for two biomarkers (PDR3 in chemical stress and SOD1 in oxidative stress), 97% of the biomarkers showed differential up-regulation levels (PELI > 1.5) in exposure to at least 3 of the 36 tap water samples at REF = 200. Biomarkers involved in chemical, protein and oxidative stresses were significantly up-regulated (p < 0.05) in exposure to the 16 pre-hurricane samples, while the post-hurricane samples mainly induced protein expression changes in genotoxicity and general stress
(osmotic stress, trehalose biosynthesis, signal transduction, and apoptosis). Meanwhile, results from the RT-qPCR assay demonstrated that eight stress genes representing six cellular stress response pathways showed differential expression (fold difference > 2 or < 0.5) relative to untreated control in at least one of the 34 samples tested, with CYP1A1 and CYP1B1 in AHR pathway showing highest average fold changes (I). Exposure to post-hurricane extracts induced significantly higher expression levels (p < 0.05) of ESR2 and TNF-α genes involved in ED and inflammation pathways, respectively, than pre-hurricane samples; while Rad51 gene, assisting in DNA double-strand break repair (DSBR) mainly via homologous recombination (HR), was shown to be significantly up-regulated in exposure to pre-hurricane samples. For spatial distribution, higher molecular toxicity levels were detected in exposure to tap water extracts at REF=200 collected in northern PR as revealed by the two toxicity assays.
Correlation analysis between bioassay responses and organic micropollutants indicated that PFOA and benzophenone in tap water extracts at REF = 200 showed significant correlation (p < 0.05) with chemical and oxidative stress in yeast cells, while the herbicide 2,4-D was significantly correlated (p < 0.01) with oxidative stress (HO1), apoptosis (Casp3), and DNA damage (KU70) in human cells. Based on the hazard quotient (HQ) calculation using drinking water MCL levels from US EPA as “permitted dose”, arsenic is the top one prioritized contaminant in all samples (HQ 0.17-0.99).
To further investigate the lasting impact of Hurricane Maria on drinking water quality in Puerto Rico, 60 more tap water samples were collected from Mar. 2018 to Jan. 2019 during the second round of sampling events following the same protocol, and analyzed for inorganic and organic trace pollutants and molecular-level toxicity effects. According to the chemical analyses, a total of 18 trace elements and 38 organic micropollutants were detected in at least one of the 60 water samples measured, with the concentrations all below the corresponding health-based benchmark levels (MCLs or HBSLs if available). For inorganic trace elements specifically, the top three elements with the highest average concentrations were Sr (322 μg/L), Cu (73 μg/L), and Ba (25 μg/L). The average contamination levels of trace elements decreased from February to May 2018 after HM, slightly increased from June to August when entering the wet season featuring heavier storms and rainfalls, and finally approached equal or below the average pre-HM levels (except for Cr, Ni, Sr, U, and Zn) in early 2019. A similar temporal trend has been observed for most organic micropollutants, while all reduced to the pre-HM contamination levels in early 2019. Collectively, these temporal trends indicate the sweeping and lasting impact of HM on the drinking water quality in PR that would take almost one year to recover to the pre-hurricane background levels. It should be recognized that other impacting factors such as storm seasons and background spatial changes in water sources may also complexify the recovery process of the water quality. In addition, compared to the post-HM samples collected from December 2017 to February 2018, 15 new organic micropollutants were detected in at least one of the 60 water samples during the 2nd round of sampling; among which 26.7% were biocides, 40% were pharmaceutical residues, and another 26.7% were degradation products or metabolites of pesticides or drugs. Therefore, more concerns may need to put on these persistent pollutants during the follow-up monitoring and remediation actions due to their potential for long-range transport, persistence in the environment, ability to bio-magnify and bio-accumulate in ecosystems, as well as their significant negative effects on human health and the environment. According to the yeast toxicogenomics-based assay targeting oxidative and DNA stress response pathways, exposure to tap water samples collected in April 2018 induced overall higher oxidative stress at the relative enrichment factor of 400 compared to later sampling months from May to October; whereas for DNA stress, no obvious temporal trend was observed, with the highest PELI value induced by the PS5-CY sample collected in August 2018 at Cayey, PR. The pathway perturbations were complicated by the cocktails of different chemical contaminants for different sampling sites and time points; thus more efforts are currently undergoing on statistical data analysis to explore potential connections between trace pollutants and molecular toxicity effects.
Toxicity of Puerto Rican Air Pollutant Mixtures
Project 2 collaborated with Project 1 to assess toxicity of air pollution in Puerto Rico. In collaboration with Professor Dan Li (FuDan University, China), the team refined the protocols and air sample pre-treatment methods for toxicity analysis of air pollutants. We explored the toxicity of emissions produced by the combustion of four typical petrol and diesel fuels widely used, including 93 octane petrol, 97 octane petrol, light
diesel oil, and heavy diesel oil.
We conducted toxicity evaluation of organic extractions of fuels combustion samples with and without rat S9 (liver microsomes) metabolic activation at the concentration of 50 mg/L. The sample-specific impacts of organic components were assessed using yeast HTS assays for oxidative stress, DNA damage, protein stress, chemical stress and general stress, with results reported as quantitative pathway- and chemical-specific biomarker measures and toxicity fingerprints.
To investigate the toxicity of Puerto Rican ambient air pollutant mixtures, PM2.5 sampling was conducted in the northern coast of Puerto Rico by Prof. Helen Suh’s group (Project 1) at Tufts University. After sampling, metal mixtures were extracted by hot acid (5.55% HNO3/16.75% HCl) from Teflon filters and neutralized to pH7 before subject to the toxicity evaluation of a yeast HTS toxicogenomics assay and a human A549 cell RTqPCRassay. To achieve the minimum sample weight requirement for the toxicogenomics assay, air pollutant mixtures collected through 5-6 weeks were combined together as 1 sample. A total of 8 combined samples were analyzed.
The sample-specific impacts of air sample extracts were assessed using the yeast HTS toxicogenomics-based assay (76 biomarkers) for the evaluation of oxidative stress, DNA damage, protein stress, chemical stress and general stress, with results reported as quantitative pathway-specific biomarker measures and toxicity fingerprints. Dose-response relationships were established through four concentrations (0.2, 1, 5, 25 mg/L). The values of overall toxicity endpoint 1/EC-PELI1.5 generated from dose-response curves ranged from 0.06 to 0.85 for all eight air samples, with samples collected in winter displaying higher toxicity compared to other seasons through the sampling year. Similar trends with toxicity fingerprints at the concentration of 25 mg/L
showed that the toxicity of air samples collected in Dec 2016 was the highest. The toxicity screening results revealed the distinct pathway-specific toxicity profiles of PR air samples at different time points. Higher upregulation of biomarkers that represent chemical and protein stresses were detected in most of the samples, while enhanced oxidative and DNA stresses were observed in samples collected around Dec 2016.
Correspondence analysis was conducted to investigate the patterns of the toxicity profiles of the PR air samples, showing that at the concentration of 25 mg/L, samples in Dec 2016 were separated more by DNA stress on X-axis, and that chemical and protein stresses separated most samples on Y-axis. Meanwhile, transcription levels of 13 genes representing oxidative, inflammation, DNA stresses and apoptosis were investigated in response to air sample extracts (25 mg/L) in human A549 cells using a RT-qPCR assay. All biomarkers showed differential expression (fold change>2 or <0.5) relative to untreated control in at least one of the eight samples, with GPX in oxidative pathway and NFKB2 in inflammation pathway showing the highest
average fold change (I). Similar to yeast assay results, samples collected from Oct 2016 to Jan 2017 induced more expression of stress-response genes, especially genes related to inflammation and oxidative stress. The results demonstrate that the high throughput screening in vitro quantitative toxicogenomics assay is effective for evaluating and revealing the potential health impact of fuel combustion emissions, and the toxicity
profiles differs among different fuels. The results show that, without S9 metabolic activation, the combustion sample from 97# octane petrol induced the least stress response with almost no gene show up-regulation among all the 77 ORF tested. Combustion samples from 93# octane petrol show similar toxicity profiles with that from light diesel oil; both induced high response on protein and chemical stress. However, the toxicity profiles of four combustion samples with S9 metabolic activation differ with those without S9 activation. All of the four combustion samples show raised toxicity after S9 metabolic activation, which may indicate potential composition changes and metabolic activity of the samples. Previous studies showed the metabolic activity of
PAHs, which are the major components of fuel combustion emission.
Toxicity of Chemicals and Metabolites Found in Urine
The tea-bag equilibrium extraction method from PROTECT was again used to assess toxicity of chemicals in urine. Initial testing showed that the assay is sensitive enough to reveal the potential toxicity of a urine sample at original concentration 1X. We conducted correlations analysis between the urine sample profiling results from our assay with metabolites concentrations and preterm variables or gestational age after all the postpartum information collected within the CRECE center from other teams. In order to investigate the potential relationships between the pregnancy exposome and adverse pregnancy outcomes, urine samples of accumulated first morning voids were collected from the households of recruited pregnant women in Northern Puerto Rico. The chemicals and metabolites from urine samples were enriched via a Porous Extraction Paddle (PEP) device immediately after sample collection in collaborating laboratories at the University of Puerto Rico (UPR), and then were subject to the evaluation of a pathway-specific toxicogenomics assay that targets five stress response pathways (i.e. oxidative stress, DNA damage, protein stress, chemical stress and general stress). Since urine volume and solute concentrations vary widely based upon water consumption and other physiological and pathophysiological factors, urine concentration normalization is critical. Samples were normalized according to their specific gravities measured by a refractometer. β-glucuronidase/sulfatase was added to urine samples before conducting the toxicogenomics assay to deconjugate metabolites. Based on the initial assay sensibility and reproducibility test, the relative enrichment factor for all urine samples was selected to be 1X (the original concentration). Quantitative pathway-specific toxicity endpoints and toxicity fingerprints were obtained for 76 biomarkers within the five stress-response pathways. All biomarkers showed differential up-regulation levels (PELI>1.5) in exposure to at least 3 out of the 13 urine samples. Integrated up-regulated responses of all five stress-response pathways were shown in all 13 samples. DNA damage or chemical stress showed the highest up-regulation levels compared to other stress-response pathways among 11 out of 13 urine samples; general stress showed the highest up-regulation levels in the other 2 samples. The toxicity screening results from the yeast toxicogenomics-based assay revealed the distinct toxicity profiles among urine samples of different individuals.
Project 3:
To address the project aims, CRECE recruited a cohort of pregnant women and their children and conducted follow-up appointments from birth through age 4. To aid in recruitment and follow-up, CRECE rented a clinic space in Manatí, Puerto Rico, across the street from the Manatí Medical Center where many participants gave birth and had pre- and post-natal medical appointments. The CRECE clinic provided a venue for completing questionnaires, child behavioral and developmental assessments, and maternal urine and blood sample collection. Child assessments included measurement of infant Non-Nutritive Suck (NNS) to assess infant neurodevelopment. Maternal blood and urine samples were collected in all three trimesters and analyzed by the CDC for hormones and exposures to chemicals and metals.
Recruitment for this study began in 2016. At the end of the study in 2022, a total of 858 mother and child pairs were recruited into the study. Throughout the study, Project 3 worked closely with the Human Subjects Core at the University of Puerto Rico on study procedures, data collection, and samples shipping and processing.
Conclusions:
Project 1: Air pollution impacts on birth outcomes
To assess the impact of air pollution on birth outcomes, CRECE researchers obtained historical data and air filters. Historical PM2.5 filters were obtained from the Department of Public Health in Puerto Rico and analyzed for elemental concentrations using XRF. Historical data came from EPA air quality data, comparing PM2.5 daily mean concentrations across the island (EPA monitor locations included Guaynabo, Guayama, Ponce, Mayagüez, and Adjuntas). We also downloaded and processed data for SO2, NO2, ozone, and lead, and compared concentrations at locations across the island to characterize local air pollution.
We used these data to examine the association of air pollution concentrations and adverse birth outcomes using administrative birth records data for Puerto Rico from 1999 through 2014. The birth records data came from the Puerto Rico Department of Health Vital Statistics which included data on gender, race, birth date, estimated gestation period, birth weight, and maternal age, and maternal behaviors for each infant born between 1999–2014 in Puerto Rico. We defined low birth weight (LBW) as less than 2,500 grams and very low birth weight (VLBW) as less than 1,500 grams. We assessed prenatal PM2.5 exposure for each infant based on the nearest central regulatory air pollution monitor. Results showed a median PM2.5 concentration of 7.0 μg/m3, with 10.5% of infants having low birth rates. Risk ratios associated with an interquartile range difference in mean PM2.5 concentrations were 1.00 (95% CI 0.98, 1.02), 1.02 (1.00, 1.04), and 1.00 (0.98, 1.03) for trimesters 1, 2, and 3, respectively. Our preliminary findings indicate that second trimester exposures to PM2.5 had the strongest association with low birth weight.
Additionally, we leveraged birth outcome data from the PROTECT cohort to examine the association of fine particulate (PM2.5) exposures and preterm birth (PTB) and the modification of these associations by prenatal phthalate exposure levels and sociodemographic factors, such as maternal age and infant gender. We assessed prenatal PM2.5 exposures for each infant based on the nearest US Environmental Protection Agency monitor. We estimated prenatal phthalate exposures as the geometric mean of urinary measurements obtained during pregnancy. We then examined the association between PM2.5 and PTB using modified Poisson regression and assessed modification by including interaction terms in our statistical models. In our cohort, we found 9.1% of 1092 singleton births were born preterm. 92.9% of mothers had at least a high school education, and nearly all women were Hispanic white, black, or mixed race. Median (range) prenatal PM2.5 concentrations were 6.0 (3.1-19.8) μ g/m3. Among our ethnic minority cohort, prenatal PM2.5 exposure is associated with a small but significant increase in risk of preterm birth, with an interquartile range (IQR) increase in PM2.5 associated with a 1.2% (95% CI 0.4, 2.1%) higher risk of PTB. There was little difference in PTB risk in strata of infant sex, mother's age, family income, history of adverse birth outcome, parity, and pre-pregnancy body mass index. Pregnancy urinary phthalate metabolite levels did not modify the PM2.5-PTB association.
Air pollution impacts on child development
To measure infant neurodevelopment, CRECE researcher Dr. Emily Zimmerman developed a custom Non-nutritive suck (NNS) device to collect information on infant non-nutritive suck patterns. Neurodevelopment through age four was assessed via the Batelle Developmental Inventory 2nd Edition (BDI-2), Ages & Stages Questionnaire 3 (ASQ-3), Child Behavior Checklist (CBCL), Modified Checklist for Autism in Toddlers (MCHAT), and others. CRECE rented and developed a clinic space in Manatí, across from the Manatí Medical Center, for conducting follow-up visits and assessments.
We examined the association of air pollution exposures and non-nutritive suck (NNS) using data from 2017-2019 for 198 infants aged 0-3 months enrolled in CRECE. We measured NNS using a pacifier attached to a pressure transducer, allowing for real-time visualization of NNS amplitude, frequency, duration, cycles/burst, cycles/min and bursts/min. These data were linked to 9-month average prenatal concentrations of PM2.5 and its components, measured at three community monitoring sites. We used linear regression to examine the PM2.5-NNS association in single pollutant models, controlling for household smoke exposure, maternal age, residential location, infant sex, age at testing, NNS duration, and gestational age. We found the average NNS amplitude and burst duration to equal 17.1 cmH2O and 6.13 seconds, respectively. Decreased NNS amplitude was consistently and significantly associated with 9-month average exposure to sulfur (-1.03 ± 0.51), zinc (-1.09 ± 0.50), copper (−1.10 ± 0.54) vanadium (-1.16 ± 0.54), and nickel (-1.53 ± 0.50). Decrements in NNS frequency were associated with sulfur exposure (0.036 ± 0.02), but not other examined PM components. These findings provide new evidence that prenatal maternal exposure to specific PM components are associated with impaired neurodevelopment in Puerto Rican infants soon after birth.
Project 2:
Project 3: Chemical Exposures and Birth Outcomes
In the CRECE cohort, triclocarban (TCC) was associated with a suggestive decrease in gestational age. Urinary biomarker concentrations at the earliest time point, 16-20 weeks gestation, may be a susceptible window of exposure. The association between TCS and gestational age differed by infant sex, wherein TCS was associated with an increase in gestational age among males, and a suggestive decrease in gestational age among females. The potential inverse association between triclocarban (TCC) and gestational age at delivery is of particular interest given the much higher levels (30x) of TCC in this cohort compared to women from NHANES. Project 3 also completed analysis of demographic and product use predictors of phenol/paraben exposure in the cohort. We found a significant decreasing temporal trend for urine concentrations of BPA during the study period, while the BPA substitute, BPS, showed an increasing temporal trend. We found significant positive associations between biomarker concentrations with self-reported use of bar soap (TCC), liquid soap (TCS), sunscreen (BP-3), lotion (BP-3, TCS, and parabens), perfume (B-PB), nail polish (B-PB) and cosmetics (BP-3 and parabens). There was an increasing trend of TCC urinary concentrations with increased concentrations of TCC listed as the active ingredient in the bar soap products that were reported being used by study participants. A similar trend was also observed for TCS urinary concentration across different liquid soap products in which TCS was listed as the active ingredient. To our knowledge, this is the largest and most comprehensive study to date reporting concentrations, temporal variability, and predictors of phenol and paraben biomarkers among a cohort of pregnant women. Our results suggest several potentially important exposure sources to phenols and parabens in this population and can inform targeted approaches to reduce exposure to these chemicals or their precursors.
Project 3 also investigated the interaction between phenol/paraben exposure and social determinants of health on these pregnancy outcomes. We found that associations between triclocarban, bisphenol-S, methyl- and propylparaben in relation to gestational length were stronger among women with negative Total scores on the Life Experiences Survey (LES). Among women with negative Total LES scores, bisphenol-S and triclocarban were associated with a 3-5 day decrease in gestational length [(-3.15; 95% CI:-6.06, -0.24); (-4.68; 95% CI: -8.47, -0.89)], whereas methylparaben and propylparaben were associated with a 2-3 day increase in gestational length [(2.21; 95% CI: 0.02, 4.40); (2.92; 95% CI: 0.58, 5.26)]. Significant interactions were driven by negative life events, but the association with triclocarban was driven by fewer positive life events. In summary, associations between exposure biomarkers and gestational length were stronger in the presence of negative life events. This provides evidence supporting the hypothesis that stress makes the body more vulnerable to chemical exposure.
Another significant finding is Project 3’s analysis of the commonly used herbicide glyphosate and adverse pregnancy outcomes in our cohort (Silver et al. 2021). There have been surprisingly few human studies on the potential reproductive and developmental effects of glyphosate given how much is used every year in the U.S. and globally. In our study we measured glyphosate (GLY) and its environmental metabolite aminomethylphosphonic acid (AMPA) in urine samples from pregnant women at our study visits #1 and #3 within a nested case-control analysis looking at preterm birth. We found that detection rates were 77.4% and 77.5% for GLY and 52.8% and 47.7% for AMPA, and geometric means (geometric standard deviations) were 0.44 (2.50) and 0.41 (2.56) μg/L for GLY and 0.25 (3.06) and 0.20 (2.87) μg/L for AMPA, for Visits 1 and 3, respectively. Preterm birth was significantly associated with specific gravity-corrected urinary GLY and AMPA at Visit 3, whereas associations with levels at Visit 1 and the Visits 1-3 average were largely null or inconsistent. Adjusted odds ratios (ORs) for an interquartile range increase in exposure at Visit 3 were 1.35 (95% CI: 0.99, 1.83) and 1.67 (95% CI: 1.26, 2.20) for GLY and AMPA, respectively. This paper appeared with a supporting commentary in Environmental Health Perspectives, and received some media attention. It was also recognized as an NIEHS extramural paper of the month for July 2021.
Project 3 also explored various biological pathways involved in developmental effects related to chemical exposures by exploring targeted and untargeted lipidomics/metabolomics, and other relevant markers of inflammation and oxidative stress. One of these to highlight is our analysis of matrix metalloproteinases (MMPs) in relation to metals exposure (Kim et al. 2022). MMPs are important regulators of uterine remodeling, a critical process for healthy pregnancies, and studies have revealed a link between an imbalance in MMPs and adverse birth outcomes. Toxicological studies have indicated that exposure to heavy metals can alter the levels of inflammatory cytokines, including MMPs. Despite growing evidence, the clear association between heavy metal exposure and MMPs has yet to be explored extensively in human populations. To have a better understanding of the association, in this study, we assessed associations between maternal blood metal levels with MMPs among 617 pregnant women in our Puerto Rico cohort. We observed significant associations between cesium, manganese, and zinc with all three MMPs that were measured (MMP1, MMP2, and MMP9). We also observed differences in metal-MMPs associations by fetal sex. Cobalt was positively associated with MMP1 only in women with male fetuses, and cesium was negatively associated with MMP1 only in women with female fetuses. MMP2 had significant associations with maternal metal concentrations only in women with female fetuses. This study highlighted significant metal-MMPs associations that may inform research on new avenues for understanding heavy metal-induced adverse birth outcomes and the development of diagnostic tools.
Another exploratory analysis looked at lipidomic profiles in relation to phthalate exposure (Ashrap et al. 2022). Phthalate metabolites were measured in urine and lipidomic profiles were identified from plasma samples by liquid chromatography-mass spectrometry-based shotgun lipidomics. After controlling for multiple comparisons, 33 phthalate-lipid associations were identified (False discovery rate adjusted p value < 0.05), and diacylglycerol 40:7 and plasmenyl-phosphatidylcholine 35:1 were the most strongly associated with multiple phthalate metabolites. Metabolites of di-2-ethylhexyl phthalate, bis(2-ethylhexyl) phthalate, dibutyl phthalates, and diisobutyl phthalate were associated with increased ceramides, lysophosphatidylcholines, lysophosphatidylethanolamines, and triacylglycerols, particularly those containing saturated and mono-unsaturated fatty acid chains. Polymerized glycerides are important for energy production and regulated through hormone signaling, while plasmenyl-phosphatidylcholines have been implicated in membrane dynamics and important for cell-to-cell signaling. Characterization of these mechanisms are relevant for informing the etiology of maternal and children's health outcomes.
Chemical Exposures and Child Developmental Outcomes
Project 3 also completed analysis on chemical exposures in pregnancy in relation to non-nutritive suck (NNS) parameters. Urinary phthalate metabolite levels were measured in women at up to three time points in pregnancy as a measure of in utero exposure to the child. Infants had their NNS sampled using our custom research pacifier between 4-6 (± 2 weeks) weeks of age, yielding the following NNS dependent measures: cycles/burst, frequency, amplitude, bursts/min, and cycles/min. We used multiple linear regression to assess associations between individual phthalate metabolites and NNS measurements, adjusting for infant sex, birthweight, and urinary specific gravity. An interquartile range (IQR) increase in mono carboxyisononyl phthalate across pregnancy was associated with 3.5% (95%CI: -6.2, -0.8%) lower NNS frequency and 8.9% (0.6, 17.3%) higher NNS amplitude. Similarly, an IQR increase in mono-2-ethylhexyl phthalate was also associated with 3.4% (-6.5, -0.2%) lower NNS frequency, while an IQR increase in di-2-ethylhexyl terephthalate metabolites was associated with 11.2% (2.9, 19.5%) higher NNS amplitude. Gestational exposure to phthalates may alter NNS amplitude and frequency in full-term infants. These findings indicate that the infants may be increasing their NNS amplitude to compensate for their slower NNS frequency. These preliminary findings could have important clinical implications for earlier detection of exposure-related deficits in neurofunction as well as implications for subsequent neurodevelopment and related interventions.
Journal Articles: 47 Displayed | Download in RIS Format
Other center views: | All 68 publications | 47 publications in selected types | All 47 journal articles |
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Aker AM, Watkins DJ, Johns LE, Ferguson KK, Soldin OP, Anzalota Del Toro LV, Alshawabkeh AN, Cordero JF, Meeker JD. Phenols and parabens in relation to reproductive and thyroid hormones in pregnant women. Environmental Research 2016;151:30-37. |
R836155 (2017) R836155 (2020) R836155C003 (2017) |
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Aker AM, Johns L, McElrath TF, Cantonwine DE, Mukherjee B, Meeker JD. Associations between maternal phenol and paraben urinary biomarkers and maternal hormones during pregnancy: a repeated measures study. Environment International 2018;113:341-349. |
R836155 (2018) R836155 (2019) R836155 (2020) |
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Aker AM, Ferguson KK, Rosario ZY, Mukherjee B, Alshawabkeh AN, Cordero JF, Meeker JD. The associations between prenatal exposure to triclocarban, phenols and parabens with gestational age and birth weight in northern Puerto Rico. Environmental Research 2019;169:41-51. |
R836155 (2019) R836155 (2020) |
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Aung MT, Johns LE, Ferguson KK, Mukherjee B, McElrath TF, Meeker JD. Thyroid hormone parameters during pregnancy in relation to urinary bisphenol A concentrations: a repeated measures study. Environment International 2017;104:33-40. |
R836155 (2018) R836155 (2019) R836155 (2020) |
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Aung MT, Ferguson KK, Cantonwine DE, McElrath TF, Meeker JD. Preterm birth in relation to the bisphenol A replacement, bisphenol S, and other phenols and parabens. Environmental Research 2019;169:131-138. |
R836155 (2019) R836155 (2020) |
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Bedrosian LD, Ferguson KK, Cantonwine DE, McElrath TF, Meeker JD. Urinary phthalate metabolite concentrations in relation to levels of circulating matrix metalloproteinases in pregnant women. Science of the Total Environment 2018;613-614:1349-1352. |
R836155 (2018) R836155 (2019) R836155 (2020) |
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Cantonwine DE, Ferguson KK, Mukherjee B, McElrath TF, Meeker JD. Urinary bisphenol A levels during pregnancy and risk of preterm birth. Environmental Health Perspectives 2015;123(9):895-901. |
R836155 (2020) R836155C003 (2017) |
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Cathey A, Ferguson KK, McElrath TF, Cantonwine DE, Pace G, Alshawabkeh A, Cordero JF, Meeker JD. Distribution and predictors of urinary polycyclic aromatic hydrocarbon metabolites in two pregnancy cohort studies. Environmental Pollution 2018;232:556-562. |
R836155 (2018) R836155 (2019) R836155 (2020) |
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Ferguson KK, Cantonwine DE, McElrath TF, Mukherjee B, Meeker JD. Repeated measures analysis of associations between urinary bisphenol-A concentrations and biomarkers of inflammation and oxidative stress in pregnancy. Reproductive Toxicology 2016;66:93-98. |
R836155 (2017) R836155 (2020) R836155C003 (2017) |
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Ferguson KK, Meeker JD, Cantonwine DE, Chen Y-H, Mukherjee B, McElrath TF. Urinary phthalate metabolite and bisphenol A associations with ultrasound and delivery indices of fetal growth. Environment International 2016;94:531-537. |
R836155 (2017) R836155 (2020) R836155C003 (2017) R834513 (Final) R835436 (2016) R835436 (2017) |
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Ferguson KK, McElrath TF, Pace GG, Weller D, Zeng L, Pennathur S, Cantonwine DE, Meeker JD. Urinary polycyclic aromatic hydrocarbon metabolite associations with biomarkers of inflammation, angiogenesis, and oxidative stress in pregnant women. Environmental Science & Technology 2017;51(8):4652-4660. |
R836155 (2018) R836155 (2019) R836155 (2020) |
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Johns LE, Ferguson KK, Meeker JD. Relationships between urinary phthalate metabolite and bisphenol A concentrations and vitamin D levels in U.S. adults: National Health and Nutrition Examination Survey (NHANES), 2005-2010. Journal of Clinical Endocrinology and Metabolism 2016;101(11):4062-4069. |
R836155 (2017) R836155 (2020) R836155C003 (2017) |
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Lan J, Gou N, Rahman SM, Gao C, He M, Gu AZ. A quantitative toxicogenomics assay for high-throughput and mechanistic genotoxicity assessment and screening of environmental pollutants. Environmental Science & Technology 2016;50(6):3202-3214. |
R836155 (2020) R836155C002 (2016) |
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Lewis RC, Johns LE, Meeker JD. Serum biomarkers of exposure to perfluoroalkyl substances in relation to serum testosterone and measures of thyroid function among adults and adolescents from NHANES 2011-2012. International Journal of Environmental Research and Public Health 2015;12(6):6098-6114. |
R836155 (2020) R836155C003 (2017) R835436 (2014) R835436 (2015) R835436 (2017) |
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Watkins DJ, Fortenberry GZ, Sanchez BN, Barr DB, Panuwet P, Schnaas L, Osorio-Valencia E, Solano-Gonzalez M, Ettinger AS, Hernandez-Avila M, Hu H, Tellez-Rojo MM, Meeker JD. Urinary 3-phenoxybenzoic acid (3-PBA) levels among pregnant women in Mexico City: distribution and relationships with child neurodevelopment. Environmental Research 2016;147:307-313. |
R836155 (2017) R836155 (2020) R836155C003 (2017) R835436 (2015) R835436 (2016) R835436 (2017) |
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Yuan Y, Meeker JD, Ferguson KK. Serum polybrominated diphenyl ether (PBDE) concentrations in relation to biomarkers of oxidative stress and inflammation: the National Health and Nutrition Examination Survey 2003-2004. Science of the Total Environment 2017;575:400-405. |
R836155 (2017) R836155 (2018) R836155 (2020) R836155C003 (2017) |
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Watkins DJ, Ferguson KK, Anzalota Del Toro LV, Alshawabkeh AN, Cordero JF, Meeker JD. Associations between urinary phenol and paraben concentrations and markers of oxidative stress and inflammation among pregnant women in Puerto Rico. International Journal of Hygiene and Environmental Health 2015;218(2):212-219. |
R836155 (2020) R836155C003 (2017) |
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Ashrap P, Watkins DJ, Calafat AM, Ye X, Rosario Z, Brown P, Velez-Vega CM, Alshawabkeh A, Cordero JF, Meeker JD. Elevated concentrations of urinary triclocarban, phenol and paraben among pregnant women in northern Puerto Rico:predictors and trends. Environment International 2018;121:990-1002. |
R836155 (2019) R836155 (2020) |
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Ferguson KK, Meeker JD, Cantonwine DE, Mukherjee B, Pace GG, Weller D, McElrath TF. Environmental phenol associations with ultrasound and delivery measures of fetal growth. Environment International 2018;112:243-250. |
R836155 (2019) R836155 (2020) |
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Lan J, Rahman SM, Gou N, Jiang T, Plewa MJ, Alshawabkeh A, Gu AZ. Genotoxicity assessment of drinking water disinfection byproducts by DNA damage and repair pathway profiling analysis. Environmental Science & Technology 2018;52(11):6565-6675. |
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Zhang Y, Gu AZ, Xie S, Li X, Cen T, Li D, Chen J. Nano-metal oxides induce antimicrobial resistance via radical-mediated mutagenesis. Environment International 2018;121:1162-1171. |
R836155 (2019) R836155 (2020) |
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Aker AM, Ferguson KK, Rosario ZY, Mukherjee B, Alshawabkeh AN, Calafat AM, Cordero JF, Meeker JD. A repeated measures study of phenol, paraben and Triclocarban urinary biomarkers and circulating maternal hormones during gestation in the Puerto Rico PROTECT cohort. Environmental Health 2019;18(1):28. |
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Li D, Gu AZ. Antimicrobial resistance:a new threat from disinfection byproducts and disinfection of drinking water?. Current Opinion in Environmental Science & Health 2019;7:83-91. |
R836155 (2019) R836155 (2020) |
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Aung MT, Ferguson KK, Cantonwine DE, Bakulski KM, Mukherjee B, Loch-Caruso R, McElrath TF, Meeker JD. Associations between maternal plasma measurements of inflammatory markers and urinary levels of phenols and parabens during pregnancy:a repeated measures study. Science of The Total Environment 2019;650:1131-1140. |
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Eick SM, Meeker JD, Brown P, Swartzendruber A, Rios-McConnell R, Shen Y, Milne GL, Vega CV, Rosario Z, Alshawabkeh A, Cordero JF. Associations between socioeconomic status, psychosocial stress, and urinary levels of 8-iso-prostaglandin-F2α during pregnancy in Puerto Rico. Free Radical Biology and Medicine 2019;143:95-100. |
R836155 (2020) |
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Cathey AL, Watkins D, Rosario ZY, Vélez C, Alshawabkeh AN, Cordero JF, Meeker JD. Associations of phthalates and phthalate replacements with CRH and other hormones among pregnant women in puerto rico. Journal of the Endocrine Society 2019;3(6):1127-49. |
R836155 (2020) |
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Ferguson KK, Rosario Z, McElrath TF, Vélez Vega C, Cordero JF, Alshawabkeh A, Meeker JD. Demographic risk factors for adverse birth outcomes in Puerto Rico in the PROTECT cohort. PloS one 2019;14(6):e0217770.. |
R836155 (2020) |
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Ferguson KK, Rosen EM, Rosario Z, Feric Z, Calafat AM, McElrath TF, Vega CV, Cordero JF, Alshawabkeh A, Meeker JD. Environmental phthalate exposure and preterm birth in the PROTECT birth cohort. Environment international 2019;132:105099. |
R836155 (2020) |
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Boss J, Mukherjee B, Ferguson KK, Aker A, Alshawabkeh AN, Cordero JF, Meeker JD, Kim S. Estimating outcome-exposure associations when exposure biomarker detection limits vary across batches. Epidemiology 2019;30(5):746-55. |
R836155 (2020) |
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Kirwa K, McConnell-Rios R, Manjourides J, Cordero J, Alshawabekeh A, Suh HH. Low birth weight and PM2. 5 in Puerto Rico. Environmental epidemiology 2019;3(4). |
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Aung MT, Yu Y, Ferguson KK, Cantonwine DE, Zeng L, McElrath TF, Pennathur S, Mukherjee B, Meeker JD. Prediction and associations of preterm birth and its subtypes with eicosanoid enzymatic pathways and inflammatory markers. Scientific reports 2019;9(1):1-7. |
R836155 (2020) |
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Xie S, Gu AZ, Cen T, Li D, Chen J. The effect and mechanism of urban fine particulate matter (PM2. 5) on horizontal transfer of plasmid-mediated antimicrobial resistance genes. Science of the Total Environment 2019;683:116-23. |
R836155 (2020) |
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Ingle ME, Watkins D, Rosario Z, VélezVega CM, Calafat AM, Ospina M, Ferguson KK, Cordero JF, Alshawabkeh A, Meeker JD. An exploratory analysis of urinary organophosphate ester metabolites and oxidative stress among pregnant women in Puerto Rico. Science of the Total Environment 2020;703:134798. |
R836155 (2020) |
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Manjourides J, Zimmerman E, Watkins DJ, Carpenito T, Vélez-Vega CM, Huerta-Montañez G, Rosario Z, Ayala I, Vergara C, Feric Z, Ondras M. Cohort profile:Center for Research on Early Childhood Exposure and Development in Puerto Rico. BMJ open 2020;10(7):e036389. |
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Lin Y, Sevillano-Rivera M, Jiang T, Li G, Cotto I, Vosloo S, Carpenter CM, Larese-Casanova P, Giese RW, Helbling DE, Padilla IY. Impact of Hurricane Maria on Drinking Water Quality in Puerto Rico. Environmental Science & Technology 2020;54(15):9495-509. |
R836155 (2020) |
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Welton M, Vega CM, Murphy CB, Rosario Z, Torres H, Russell E, Brown P, Huerta-Montanez G, Watkins D, Meeker JD, Alshawabkeh A. Impact of Hurricanes Irma and Maria on Puerto Rico Maternal and Child Health Research Programs. Maternal and child health journal 2020;24(1):22-9. |
R836155 (2020) |
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Aker A, McConnell RE, Loch-Caruso R, Park SK, Mukherjee B, Rosario ZY, Vélez-Vega CM, Huerta-Montanez G, Alshawabkeh AN, Cordero JF, Meeker JD. Interactions between chemicals and non-chemical stressors:the modifying effect of life events on the association between triclocarban, phenols and parabens with gestational length in a Puerto Rican cohort. Science of The Total Environment 2020;708:134719. |
R836155 (2019) R836155 (2020) |
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Eick SM, Ferguson KK, Milne GL, Rios-McConnell R, Vélez-Vega C, Rosario Z, Alshawabkeh A, Cordero JF, Meeker JD. Repeated measures of urinary oxidative stress biomarkers and preterm birth in Puerto Rico. Free Radical Biology and Medicine 2020;146:299-305. |
R836155 (2020) |
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Zimmerman E, Watkins DJ, Huerta-Montanez G, Pabon ZR, Feric Z, Manjourides J, Velez-Vega CM, Figueroa A, Hines M, Martens A, Cordero J. Associations of gestational phthalate exposure and non-nutritive suck among infants from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) birth cohort study. Environment international 2021;152:106480. |
R836155 (2021) |
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Jiang T, Lin Y, Amadei CA, Gou N, Rahman SM, Lan J, Vecitis CD, Gu AZ. Comparative and mechanistic toxicity assessment of structure-dependent toxicity of carbon-based nanomaterials. Journal of Hazardous Materials 2021;418:126282. |
R836155 (2021) |
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Aung MT, Ashrap P, Watkins DJ, Mukherjee B, Rosario Z, Vélez-Vega CM, Alshawabkeh AN, Cordero JF, Meeker JD. Maternal lipidomic signatures in relation to spontaneous preterm birth and large-for-gestational age neonates. Scientific reports 2021;11(1):1-1. |
R836155 (2021) |
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Morton S, Honda T, Zimmerman E, Kirwa K, Huerta-Montanez G, Martens A, Hines M, Ondras M, Eum KD, Cordero JF, Alshawabekeh A. Non-nutritive suck and airborne metal exposures among Puerto Rican infants. Science of The Total Environment 2021;789:148008. |
R836155 (2021) |
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Silver MK, Fernandez J, Tang J, McDade A, Sabino J, Rosario Z, Vélez Vega C, Alshawabkeh A, Cordero JF, Meeker JD. Prenatal exposure to glyphosate and its environmental degradate, aminomethylphosphonic acid (AMPA), and preterm birth:a nested case–control study in the PROTECT cohort (Puerto Rico). Environmental health perspectives 2021;129(5):057011. |
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Kirwa K, Feric Z, Manjourides J, Alshawabekeh A, Vega CM, Cordero JF, Meeker JD, Suh HH. Preterm birth and PM2. 5 in Puerto Rico:evidence from the PROTECT birth cohort. Environmental Health 2021;20(1):1-1.. |
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Ashrap P, Aker A, Watkins DJ, Mukherjee B, Rosario-Pabón Z, Vélez-Vega CM, Alshawabkeh A, Cordero JF, Meeker JD. Psychosocial status modifies the effect of maternal blood metal and metalloid concentrations on birth outcomes. Environment International 2021;149:106418. |
R836155 (2021) |
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Park S, Zimmerman E, Huerta-Montañez G, Rosario-Pabón Z, Vélez-Vega CM, Cordero JF, Alshwabekah A, Meeker JD, Watkins DJ. Gestational exposure to phthalates and phthalate replacements in relation to neurodevelopmental delays in early childhood. Toxics 2023;11(1):65. |
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Muenter MM, Aiken A, Akanji JO, Baig S, Bellou S, Carlson A, Conway C, Cowell CM, DeLateur NA, Hester A, Joshi C. The response of Escherichia coli to the alkylating agents chloroacetaldehyde and styrene oxide. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 2019;840:1-10. |
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Supplemental Keywords:
air pollution, metals, neurodevelopment, adverse birth outcomes, biomarkers, environmental exposure, phenols, parabens, endocrine disrupters, toxicogenomics, environmental exposure, biomarkers, pathway-specific effectsRelevant Websites:
Northeastern University Research Exit
Progress and Final Reports:
Original Abstract Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R836155C001 Air Pollution Impacts on Neonatal and Early Childhood Development
R836155C002 Toxicogenomics-based Mechanistic Multimedia Exposure Assessment and Child Development
R836155C003 Biomarker Epidemiology of In Utero Environmental Exposures and Child Development
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- 2021 Progress Report
- 2020 Progress Report
- 2019 Progress Report
- 2018 Progress Report
- 2017 Progress Report
- 2016 Progress Report
- Original Abstract
47 journal articles for this center