Grantee Research Project Results
2019 Progress 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 F. , Manjourides, Justin , Zimmerman, Emily , Gu, April Z , Meeker, John D.
Current 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 Period Covered by this Report: September 1, 2018 through August 31,2019
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: 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 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 lifein uteroexposure. 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.
Progress Summary:
Project 1: Assessing the Impact of Air Pollution on Adverse Birth Outcomes and Child Development
Our major activities this reporting period focused on measurements and analysis of fine particle (PM2.5) and PM2.5-associated black carbon (BC) and metal concentrations, analyzing historical birth outcome data from the Puerto Rico Department of Health Vital Statistics for 1999–2013, analyzing birth outcome data from PROTECT (Aim 1 of CRECE), and analyzing air pollution and non-nutritive suck (NNS) data from CRECE. In addition, we worked to obtain permission to re- establish an air pollution monitoring site in Arecibo, as the original site was ruined during Hurricane Maria. We also started a pilot study to measure PM2.5 and ultra-fine particle levels using Purple Air sensors at a rotating series of monitoring sites within the North Shore of Puerto Rico. This work supported each of our three aims.
Exposure Measures: Air Pollution Monitoring Sites
We performed several activities needed to begin to measure PM2.5concentrations on a weekly basis at each of three stationary ambient monitoring (SAM) sites on the north coast of Puerto Rico.
PM2.5sampling.We prepared filters for sampling and measured PM2.5concentrations at three monitoring sites. Once sampling was complete, we reviewed sampling data for quality control, and field technicians use flow meters to record the flow before and after each filter is sampled. Sampled filters with flow rate change beyond 10% are marked void. Filters are also marked void in the case of damage or disrupted sampling time caused by city power outages. We analyzed collected filters for PM2.5, BC and metal concentrations.
During this reporting period, 151 air samples were collected at three sites. 47 were collected at Arecibo, 52 at Manatí, and 52 at Morovis. Two filters were blanks and one was disqualified due to flow rate changes greater than 10%, caused by a faulty flowmeter, which was subsequently repaired. Monitoring at Arecibo, which had been suspended in September 2017 due to hurricane damage, was restarted in August 2018 in a location within one mile of the previous location. To date, we have collected a total of 239 PM2.5 samples, with 236 valid samples (2 blank samples and 1 damaged filter).
Laboratory Analysis of Collected PM2.5Filters.Laboratory analysis of weekly fine particle concentrations (PM2.5) and Black Carbon (BC) is conducted monthly. Field technicians in Boston analyze filters first for PM2.5concentrations and then for BC by reflectance to preserve sample integrity. Once analyzed, the samples are stored in individual Petri dishes in a temperature-controlled balance room. XRF analyses were performed on
94 of our collected PM2.5 samples. During the reporting period, we analyzed 151 filters for PM2.5 and BC and 34 filters for elemental components of PM2.5.
Health Measures
Child Development.To date, 278 infants have completed the ASQ-3 and 203 have completed the BDI. Data collection and analyses are ongoing.
Non-nutritive suck (NNS) and communication.Preliminary data from 147 full-term infants (72 males, 75 females) show that higher prenatal phthalate exposure results in slower NNS frequency and increases in NNS amplitudes. The increase in amplitude could be a compensatory mechanism used in response to altered temporal suck pattern. Overall,in uterophthalate exposure was associated with frequency and amplitude of non-nutritive suck (NNS) in infants at 4-6 weeks. These findings show a link between infant sucking and prenatal exposures, which needs to be explored in more detail with a larger sample size. Data collection and analyses are ongoing. Further, emerging trends show a relation between Neonatal NNS Frequency and ASQ-3 Communication Scores at 6-months in 33 full-term infants. More data is needed to explore these trends in more detail.
Epidemiological Analyses
Exposure Assessment. We characterized pre-natal PM2.5 exposures for PROTECT babies and pre-natal PM2.5, BC, and metal exposures for CRECE babies. For both, we did so using available monitoring station data and imputation methods.
PM2.5and Low Birth Weight.We assessed the association between birthweight and trimester-specific maternal exposure to fine particulate matter (PM2.5) in Puerto Rico for live births between 1999-2013. We did so using data 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. Results from this analysis were published in:
· Kirwa K, Manjourides J, Suh HH. Low birth weight and PM2.5in Puerto Rico.Environmental Epidemiologyin press.
PM2.5 Exposures and Pre-Term Birth in PROTECT babies.We estimated PM2.5 exposures for each PROTECT baby and have conducted preliminary analyses of the association of PM2.5 exposures and pre-term birth.
These analyses show consistent associations of PM2.5 exposures and increased pre-term birth. We are finishing these analyses and plan to submit for publication to Environmental Health Perspectivesor a similarly ranked peer-reviewed journal.
PM2.5, Metals, and Non-nutritive Suck. We estimated PM2.5 exposures for CRECE babies that have NNS data. We have compiled that database, run summary statistics, and run variable diagnostics and have begun to preliminary analyses of the association of PM2.5 exposures and NNS. We plan to finish our analyses by Winter/Spring 2020, after which we will write and submit for publication toEnvironmental Health Perspectivesor a similarly ranked peer-reviewed journal.
Project 2:Toxicogenomics-based Mechanistic Multimedia Exposure Assessment and Child Development Toxicogenomics-based Mechanistic Multimedia Exposure Assessment and Child Development
Toxicity of Pollutant Mixtures in Puerto Rican Drinking Water: We have analyzed 36 tap water samples collected according to the two sampling schemes: (1) Eighteen samples were collected from the households of recruited pregnant women in Northern Puerto Rico (PR) from April 2016 to February 2018 within the cohort; (2) another eighteen tap water samples were collected from nine locations across PR (including collaborating university laboratories and hotels) at two time points (December 2017 and February 2018). 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,17 of which were wastewater-derived (including pharmaceutical and personal care products [PPCP], plasticizers, perfluorochemicals, sweeteners, etc.) and 10 of which 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).
Toxicity of Puerto Rican Air Pollutant Mixtures:
To investigate the toxicity of Puerto Rican ambient air pollutant mixtures, PM2.5 sampling was conducted in the northern coast of Puerto Rico from Jul 2016 to Jun 2017 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 RT-qPCR assay. 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 up- regulation 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.
Toxicity of Chemicals and Metabolites Found in Urine:
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 from March 2017 to May 2018. 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.
Thirteen urine samples have been analyzed. More urine samples will be collected until summer 2020. 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. Currently, we are waiting for more samples to be collected and more data analysis will be conducted for correlations with metabolites concentrations and preterm variables or gestational age after all the postpartum information are collected.
Project 3:Biomarker Epidemiology of In Utero Environmental Exposures and Child Development
This year, we have been utilizing the infrastructure we spent the initial project years building for child follow-up and data collection with the research support core and the other projects. Recruitment into the study continues to go well despite significant challenges, including the devastating hurricanes in 2017. To date, we have collected data on 437 children in CRECE, and recruitment and follow-up are ongoing.
Thus far we have had samples analyzed by the CDC National Laboratory in Atlanta for phenols and parabens from more than 900 mothers across all three trimesters of pregnancy. In last year’s progress report we described our submitted paper on phenols/parabens in relation to hormones among the moms in CRECE during pregnancy, as well as preliminary data on predictors of phenols/parabens and the associations between phenols/parabens and birth outcomes. The paper on phenols/parabens and hormones is now published (Aker et al. 2019;Environ Health, 18(1):28; PMID 30940137).
This past year we have published our final data analysis on demographic and product use predictors of phenol/parabens in the cohort, and on the associations between phenols/parabens and pregnancy outcomes. In the paper on predictors of phenol/paraben concentrations (Ashrap et al. 2018;Environ Int, 121(Pt 1):990- 1002; PMID 30316544), we reported very high concentrations of triclocarban (TCC) in our cohort, with levels more than 30-times greater than those found among women in the general U.S. population. Additionally, 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.
In our analysis of the association between phenols/parabens and gestational age and birth weight (Aker et al. 2018;Environ Res, 169:41-51; PMID 30412856), we found that BP-3, MPB and PPB were associated with an increase in gestational age, while 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 decrease in gestational age among females. BPS was associated with an increase in the odds of small for gestation age (SGA) at visit 3, and a suggestive increase in the odds of large for gestation age at visit 1.
Finally, we are beginning to focus our attention on the interaction between phenol/paraben exposure and social determinants of health on these pregnancy outcomes. In an analysis that has been accepted for publication and is currently in press atScience of the Total Environment, 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; we will continue investigating these interactions as we explore associations between phenol/paraben exposures and child developmental measures.
Future Activities:
Project 1: Assessing the Impact of Air Pollution on Adverse Birth Outcomes and Child Development
During the no-cost extension, we plan to continue to collect air pollution and child health data, as described in our original proposal. Specifically, we plan to:
- Continue our pilot study using Purple Air sensors to measure PM2.5 and ultra-fine particle levels at a rotating series of monitoring sites along the northern coast region
- Continue analysis of NNS data along with other child development outcomes
- Continue assessment of child development, using all measures including NNS, survey and other measures, with the goal of increasing sample sizes for further analysis
- Finalize analysis on PM2.5 exposures and pre-term birth using birth outcome and maternal characteristics data from the PROTECT birth co-hort
Project 2:Toxicogenomics-based Mechanistic Multimedia Exposure Assessment and Child Development Toxicogenomics-based Mechanistic Multimedia Exposure Assessment and Child Development
The team has been granted a no cost extension until August 2020. For the final report, we will obtain and finish the experimental and data analysis for all the scopes in the proposal. For the coming year, the main efforts will be finalizing the data analysis and generating manuscripts for publication. The team will also attend various conferences and workshops to disseminate the results from this project.
Project 3:Biomarker Epidemiology of In Utero Environmental Exposures and Child Development
We will continue to work with the Human Subjects Core and other projects on ensuring effective participant recruitment and efficient collection of quality data and samples. We will continue working with the various laboratories to obtain state-of-the-art data on environmental exposure, hormone levels, oxidative stress, and inflammation. We plan to continue investigating measures of maternal stress and how it relates to exposure and intermediate outcome measures. Finally, we will also begin examining relationships betweenin uterophenol and paraben exposure and child outcome measures including size/growth, non- nutritive suck (NNS), and anogenital distance (AGD).
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. |
R836155 (2019) R836155 (2020) |
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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. |
R836155 (2019) R836155 (2020) |
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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. |
R836155 (2019) R836155 (2020) |
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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). |
R836155 (2020) |
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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. |
R836155 (2020) |
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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. |
R836155 (2021) |
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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.. |
R836155 (2021) |
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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. |
R836155 (Final) |
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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. |
R836155 (2019) R836155 (2020) |
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Supplemental Keywords:
air pollution, metals, neurodevelopment, adverse birth outcomes, toxicogenomics, environmental exposure, biomarkers, pathway-specific effects, biomarkers, phenols, parabens, endocrine disruptersRelevant Websites:
Center for Research on Early Childhood Exposure and Development in Puerto Rico (CRECE) 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
- Final Report
- 2021 Progress Report
- 2020 Progress Report
- 2018 Progress Report
- 2017 Progress Report
- 2016 Progress Report
- Original Abstract
47 journal articles for this center