Grantee Research Project Results
2014 Progress Report: The UCSF Pregnancy Exposures to Environmental Chemicals (PEEC) Children's Center
EPA Grant Number: R835433Center: Center for Integrative Research on Childhood Leukemia and the Environment - 2015
Center Director: Metayer, Catherine
Title: The UCSF Pregnancy Exposures to Environmental Chemicals (PEEC) Children's Center
Investigators: Woodruff, Tracey J.
Institution: University of California - San Francisco
EPA Project Officer: Hahn, Intaek
Project Period: June 1, 2013 through May 31, 2018 (Extended to May 31, 2019)
Project Period Covered by this Report: June 1, 2014 through May 31,2015
Project Amount: $3,312,848
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2012) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
Project 1: The hypothesis of our PEEC Children’s Center is that environmental chemical exposures have harmful effects on human in utero development and on children’s health. Project 1 brings together a team of basic scientists who are investigating the impact of polybrominated diphenyl ether-47 (PBDE-47), a flame retardant, and perfluorooctanoic acid (PFOA), a repellent, on formation of the human placenta. The goal of the project is to map, at high resolution, the effects of these chemicals on the transcriptome (Aim 1), the epigenome (Aim 2) and the functional consequences of the alterations we observe (Aim 3). In Aim 1, we will use our in vitro model of human placentation and an unbiased approach, RNA-seq, to understand the pathways in which PBDE‐47 and/or PFOA are working in terms of effects on trophoblast function. Aim 2 uses the same experimental design to carry out a comprehensive analysis of the effects of these chemicals on histone modifications and DNA methylation. Finally, in Aim 3, we will study the functions of molecules that are targets of the environmental chemicals of interest and which we suspect play important roles in human placental development. These experiments will employ functional and molecular analyses that will allow us to phenotype human trophoblast cells and their defining properties in relation to environmental chemical exposures.
Project 2: Our project tests the hypotheses that 1) PBDEs), perfluorinated chemicals (PFCs), and select environmental organic acids (EOAs) accumulate differently in human fetuses than in pregnant women during the second trimester of pregnancy, and 2) these chemical exposures negatively impact placental development and function, an important outcome that can adversely affect in utero growth, prenatal development, birth weight, and thus, childhood and adult health. Compelling scientific data show that human in utero development is highly susceptible to disruption by exposure to chemicals, in particular endocrine disrupting agents, but a major impediment to understanding these risks is the lack of human data on fetal exposures and on the mechanisms by which chemicals can adversely impact in utero development. Through our work as a Formative Center, we provided some of the first human data characterizing mid-gestation chemical exposures and mechanisms of adverse effects. Specifically, we detected PBDEs, PFCs and EOAs such as bisphenol A (BPA) in 99‐100% of the pregnant women and 95‐100% of fetuses (liver and umbilical cord blood) in our study population. In addition, in vitro experiments that employed our novel human trophoblast progenitor cell (TBPC) model of placental development demonstrated that environmentally relevant doses of PBDE-47 (a PBDE congener) compromised TBPC self-renewal in an undifferentiated state while promoting differentiation (see Project 1, Aim 1). Both effects are hallmarks of poor placental development and have been shown to be risk factors for reduced fetal growth, preterm delivery and preeclampsia. Our project will significantly advance this promising line of research to include a larger sample size, a more diverse set of biological specimens and a wider range of measured chemicals. We also will test the impact of these chemicals on in utero development by assessing the relationship between direct measures of chemical exposure and morphological and molecular markers that enable an assessment of placentation. Accordingly, our specific aims are to:
1) Compare maternal serum, placenta and fetal liver levels of a broad range of chemicals through traditional and novel biomonitoring approaches. We will collect matched biological specimens from 130 pregnant women obtaining elective second trimester pregnancy terminations (excluding cases in which pregnancies are complicated by fetal anomalies or maternal smoking). We will analyze the samples for 17 PBDEs and 12 PFCs. We also will use a novel biomonitoring approach based on liquid chromatography quadrupole time-of-flight/mass spectrometry (LC-QTOF/MS) combined with traditional analytic methods to identify and quantify exposure to the five most frequently detected EOAs in our study population. We will compare measurements of these 34 chemicals in maternal serum to those in the placenta and fetal liver. Thus, at the conclusion of these experiments we will have a much broader understanding of the most significant environmental chemical exposures during pregnancy and the relationships between levels detected in the maternal blood, placenta and fetus.
2) Evaluate the relationship between placental disruption and exposure to PBDEs, PFCs and select EOAs. We will measure known morphological and molecular markers of placental development in the second trimester placentas that are collected in Aim 1. Then, we will evaluate the relationship of these markers to individual and cumulative metrics of PBDE, PFC and EOA exposure measured in the same placental samples. Additionally, the goal of Project 1 is to identify novel PBDE and PFC placental targets (specifically, PBDE-47 and PFOA, respectively). In Aim 3 of that Project, we also will evaluate the relationship between these endpoints, which will be analyzed in the same placental samples, and individual and cumulative metrics of PBDE, PFC and EOA exposure. Thus, at the conclusion of these experiments we will have important new information about the placental effects of endocrine disrupting chemicals (EDCs).
Working with our Community Outreach and Translation Core, we will translate our findings to the clinical and policy communities, providing key inputs for improving public policy approaches to identifying, assessing and preventing human risks from these EDCs.
Project 3: This project will examine the hypothesis that prenatal exposures to EDCs affect fetal growth outcomes such as birth weight and small for gestational age (SGA), and whether these adverse effects are magnified by chronic psychosocial stress. We will conduct a prospective study in an economically and ethnically diverse group of pregnant women in order to evaluate two important types of environmental exposures: 1) EDCs (PBDEs and PFCs); and 2) chronic psychosocial stress, using objective and subjective measures of participants’ perceived stress, social standing, physical and social environments, and biomarkers of chronic stress response. We hypothesize that exposure to both EDCs and stress may have synergistic effects on fetal growth. Accordingly, this project has three specific aims:
1) Evaluate the relationship between prenatal PBDE and PFC exposures and birth weight. Hypothesis: Higher levels of PBDEs and PFCs in maternal serum are independently associated with lower birth weight and SGA, and concurrent exposures to these two classes of compounds have cumulative effects on birth weight. We will measure PBDEs and PFCs in serum from pregnant women (N=450) during their second trimester and collect demographic, pregnancy history, and birth outcome data at delivery to analyze the following outcomes: 1) birth weight, 2) low birth weight (less than 2500 grams), and 3) SGA (birth weight less than the 10th percentile for the infant’s gestational age based on growth curves accounting for race/ethnicity and sex).
2) Evaluate the relationship between measures of chronic psychosocial stress in the maternal-fetal unit and birth weight outcomes. Hypothesis: Exposures to chronic stress are associated with lower birth weight and SGA. We will collect three types of chronic stress measurements: 1) metrics based on participants’ perceptions of their social standing and their chronic stress exposures in household, neighborhood, and work environments; 2) geocoded metrics of neighborhood socioeconomic status and civic engagement capacity; and 3) biological markers of chronic stress response in the maternal-fetal unit, including telomere length in umbilical cord leukocytes and corticotropin releasing hormone (CRH) levels in maternal plasma. We will examine whether fetal and maternal biomarkers of stress response mediate the relationship between perceptual and geocoded measures of chronic stress exposure and adverse birth weight effects.
3) Assess whether exposure to chronic psychosocial stress in the maternal-fetal unit modifies the relationship between PBDE and PFC exposures and birth weight outcomes. Hypothesis: The effects of prenatal PBDE and PFC exposures on birth weight are modified by exposure to chronic stress in the maternal-fetal unit. We will evaluate potential interactions between the chemical exposures and chronic stress exposure on birth weight. Our approach to modeling chemical and chronic stress exposures will be informed by our analytical results from Aims 1 and 2. The ethnic and economic diversity of our study population will provide a unique advantage for enhancing scientific understanding about the range of prenatal exposures to persistent and ubiquitous EDCs and their effects on fetal growth.
Community Outreach and Translation Core (COTC)
Aim 1: Communicate the science broadly.
Aim 2: Harness the evolving science to healthcare.
Aim 3: Advance prevention‐based public policy.
Progress Summary:
Project 1: During the second project period, we continued to make progress on Aims 1 and 2. We used human primary cytotrophoblast (CTB) cells, a model system in which we have used more than 20 years to study placentation in normal pregnancy and in pregnancy complications. We chose this primary placental cell model to leverage transcriptomic and epigenomic data generated by our recent participation in the NIH-funded Roadmap Epigenome Mapping Center (Roadmap Epigenomics Consortium, et al., 2015). From these studies, we gained an understanding of the transcriptomic and epigenetic landscape of CTBs and other extraembryonic tissues in vivo under normal physiological conditions. This detailed information provides us a baseline for understanding molecular perturbations that result from exposure to environmental chemicals (e.g., PBDE-47, PFOA), the goal of this project. With regard to Aims 1 and 2, we conducted transcriptomic and methylation analyses of the effects of PBDE-47 exposure in our CTB model system. Based on our experiments dose/time response investigations completed in Year 1, establishing the most relevant timing and dosage parameters, we designed these experiments to include: 1) a sub-cytotoxic concentration of PBDE-47 (1 μM), which was biologically-effective in our model system and relevant to human exposures; and 2) two exposure windows of interest in cultured CTBs, which paralleled significant dynamic changes in cell migratory activity and expression of genes linked to morphogenesis, cell motility, and vascular remodeling pathways. These fundamental cellular and molecular processes are hypothesized to underlie the critical functions of CTBs in vivo, such as uterine invasion, vascular remodeling, and establishing robust physical and physiological connections between the placenta and uterus. We evaluated the effects of PBDE-47 after 24h exposure based on our dose-response investigations in Year 1, and previous reports suggesting PBDEs alter gene/protein expression in trophoblast cell lines at 24h post-exposure (Park, et al., 2014a; 2014b).
For these analyses, we collected RNA/DNA samples simultaneously from three independent cultures of second trimester human CTBs, which were exposed to either PBDE-47 (1 μM) or vehicle control (1% DMS; 12 total samples for each analysis). To evaluate gene expression, we used Affymetrix GeneChip Human Gene 2.0 ST Arrays. This platform contains probes for more than 30,000 coding transcripts and includes multiple probes per gene to measure alternative splicing events and transcript variants. Sample processing and hybridization was performed by the UCSF Gladstone Institute. Following data normalization, we applied a fixed effects linear model and ANOVA to determine differentially expressed (DE) genes due to PBDE-47 exposure, culture time, and gestational age. Our previous transcriptomic experiments in (unexposed) cultured CTBs (Robinson, et al., unpublished) and in vivo suggest that culture time and gestational age influences the expression of hundreds of genes important for placental development and function; therefore, we used a statistical approach that controls for these variables. In total, we identified 675 genes significantly differentially expressed (DE; p<0.05, absolute fold-change >1.2) due to PBDE-47 exposure. In general, on a global level, responses to PBDE-47 were independent of the exposure window, i.e., expression changes due to 24h exposure of PBDE-47 were similar despite CTBs being exposed at two different time points (3h vs. 15h post-plating) in culture. Using this subset of DE genes, we performed functional enrichment analysis of Gene Ontology (GO) Biological Processes and KEGG Pathways. We observed significant overrepresentation of GO Biological Processes, including Inflammation, Cholesterol/Steroid Metabolism, and Neuron Differentiation related pathways. Interestingly, targets within these pathways have been previously proposed to be altered by PBDEs in other models (Park, et al., 2014b; Slotkin, et al., 2013; Wang, et al., 2011). Using qRT-PCR, we currently are interrogating the dose-dependent effects of PBDE-47 of specific DE targets relevant for placental development in independent CTB samples. To date, we have confirmed significant dose-dependent upregulation of GREM1 and MMP1 following PBDE-47 exposure. The role of GREM1 in the placenta is relatively unknown, but it likely functions in villus morphogenesis (O'Connell, et al., 2013). Alterations in MMP1 expression have been associated with impairment of CTB invasion and pregnancy complications with links to faulty placentation (e.g., preeclampsia; Lian, et al., 2010). For our initial epigenomic analyses, we measured global methylation using Illumina Infinium HumanMethylation450 BeadChip arrays. This approach enabled us to investigate methylation levels for ~99% of genes and ~96% of CpG islands in the human genome. All data were processed using a state-of-the-art pipeline developed in Dr. Costello's laboratory, which includes methylumi background correction and normalization operations. We currently are summarizing our transcriptomic data analyses to be able to pinpoint specific targets in which we will conduct a focused analysis of methylation levels between PBDE-47 and vehicle control exposure groups. These initial -omic studies will provide us information regarding our experimental design and provide clues to prepare for more resource-intensive investigations (RNA-seq, methylation/histone regulation) that will be initiated in the near future. To increase the utility of our CTB model for environmental investigations, we also are developing high-throughput functional tests to evaluate migratory activity in our culture system. Using a semi-automated protocol, which includes nuclear staining (Hoescht), multiple image capture (Leica), and image content analysis (Volocity), we are able to measure the distance between hundreds of thousands of cells across multiple time points in vitro. In unexposed cultures, we have shown that significant migratory activity occurs within the first 39h of culture, suggesting that the invasive/migratory programming that these cells undergo in vivo is conserved in culture. We currently are testing the effects of PBDE-47 on these cellular processes.
Our initial experiments with PBDE-47 (5 μM) suggest a reduction in migratory activity in CTBs (n=1). This assay will potentially enable us to link mechanistic relationships between environmental exposures and morphological phenotypic behaviors relevant to the in vivo condition. Furthermore, these endpoints will be combined with the other morphological (time-lapse imaging) and molecular (immunolocalization, immunoblot, qRT-PCR) assessments that we have used to characterize environmental (i.e., PBDE-47 and PFOA) effects in CTBs. We also have extended our initial analyses of the transcriptome and epigenome in purified CTBs and tissues of the extraembryonic compartment from the Roadmap Epigenome Mapping Center, which was completed with support from this grant. In the initial experiments, as discussed at length previously in our Year 1 progress report, we analyzed the transcriptome and epigenome of purified CTBs, chorionic villi, chorionic membranes and basal plate. The analysis includes gene expression levels measured by RNA-seq, DNA methylation, Chip-seq targeting specific histone modifications and mIR expression. PCA analysis of the global methylation pattern showed that these extraembryonic cells/tissues form a distinct cluster as compared to human embryonic stem cells (hESCs), fetal brain and all other samples that the Roadmap has analyzed. Interestingly, BMP-treated hESCs, purported to be an in vitro model of human trophoblasts, cluster with untreated hESCs, indicating that they are unlike authentic CTBs in terms of their epigenome. Analysis of the DNA methylation and histone modification patterns of primary CTBs (the model used in our environmental studies) revealed that these extraembryonic cells are globally hypomethylated in comparison to hESCs and other fetal and adult tissues analyzed. Differentially methylated regions (DMEs) included key gene regulatory regions and transposable elements that are typically highly methylated in other cell types. Furthermore, many of these epigenetically regulated components in CTBs display changes related to developmental stage (second trimester vs. term), suggesting gestational age dependent differential sensitivity to environmental compounds that may act through epigenetic mechanisms. Due to these startling findings, we validated these initial comparisons by adding eight new CTB samples to our analyses (n=4 for each gestational period; second trimester vs. term). These new data highly correlate with our previous findings. Continued identification of the epigenetic landscape of CTBs and other extraembryonic tissues gives us important baseline information for understanding, in detail, the effects of exposing these cells to PBDEs and PFOA. It allows us to conduct targeted analyses in addition to our global exploration of the epigenetic changes induced by exposures. Aim 3 experiments are designed to analyze the functions of molecules that are targets of the environmental chemicals of interest and which we suspect play important roles in human placental development. The deep understanding we are developing of the normal transcriptomic and epigenomic landscape of CTBs will help put the data we generate in the exposure experiments in the proper context and inform future targeted analyses.
This project continues to provide significant professional development opportunities for a postdoctoral fellow in the laboratory, Dr. Joshua Robinson. He has been working on this project, which examines the effects of PBDEs on placental-derived cells, in combination with his K99 Pathways to Independence project entitled, “Polybrominated Diphenyl Ether Effects on Human Neuronal Development.” His growing expertise in using in vitro model systems for studying the developmental effects (in humans) of gestational exposures to environmental chemicals is the direct result of participation in these projects.
Project 2: We began recruitment and enrollment in August 2014 in the Women’s Options Center at San Francisco General Hospital. To date there are 168 participants enrolled in this study (see Table 1). We have collected more than 500 samples total; 112 are matched sets (maternal serum, fetal placenta and fetal liver). We continue with study enrollment, sample collection and processing. We hired a new Clinical Research Coordinator (Erin DeMicco) in March 2015 to replace Janet Pan. Erin will oversee all aspects of study coordination, including monitoring recruitment and enrollment and data quality.
We continue to collaborate with San Francisco General Hospital (SFGH) Women’s Option Center (WOC), and we continue to use the joint consent form and IRB for several of our ongoing research projects at the WOC, including the current project. All study personnel have undergone required trainings for Human Subjects Research and Biosafety as well as Blood‐borne Pathogens trainings. We are maintaining institutional approvals for our project, including IRB/Human Subjects Approval, Biological Use Authorization, and SFGH research approvals.
We continue to purchase lab supplies and biospecimen collection material necessary for carrying out study activities. All biospecimen collection materials are sent to our collaborators to test for possible contamination of chemicals of interest (PBDEs and PFCs). Methods for PBDE analysis in serum and liver have been developed by our collaborators at California Department of Toxic Substances (DTSC), Drs. Myrto Petreas and June-Soo Park. Methods development for PBDE analysis in placenta has been finalized; results were presented during an EPA site visit. Methods for PFCs analysis in serum, liver, and placenta are in their final stages of development by Dr. Roy Gerona at UCSF Department of OB/Gyn and Reproductive Sciences. Dr. Roy Gerona has completed methods for non‐targeted analysis of EOAs in serum using LC‐QTOF/MS, and has submitted a manuscript for publication.
Project 3: Year 2 was spent recruiting participants at San Francisco General Hospital (SFGH), Moffitt‐Long Hospital (MLH) and the new Betty Irene Moore Women’s Health Hospital at Mission Bay (MB). In January 2015, women’s health services, including the prenatal clinic and labor & delivery, moved from MLH to MB. We initiated participant recruitment efforts at SFGH in the first week of March 2014, expanded to MLH in May 2014 and MB in January 2015. Currently, recruitment takes place at the prenatal clinics at SFGH and MB, although we do some second trimester participant visits at MLH. We anticipate this will phase out over the course of Year 3 and all study activities will take place at SFGH and MB only.
We have enrolled 141 participants so far. We average two enrollments per week. Our enrollment rate is lower than anticipated due to the hospital move and personnel changes. We should enroll at a faster rate in Year 3 because research operations at the new hospital (MB) have become more efficient and a replacement clinical research coordinator has been hired. Also, we have modified our recruitment protocol, improved staffing configurations, and leveraged assistance with nursing staff to increase enrollment rates and improve the efficiency of data collection activities (conducting interviews and blood draws). All study personnel have undergone required trainings for Human Subjects Research, APeX, Biosafety and Blood‐borne Pathogens.
We maintain institutional approvals for our project, including IRB/Human Subjects Approval, Biological Use Authorization, SFGH and MLH research approvals. PBDE methods development in serum by our collaborators at California Department of Toxic Substances, Drs. Myrto Petreas and June‐Soo Park, is complete. Dr. Roy Gerona at UCSF Department of OB/Gyn and Reproductive Sciences is finalizing methods for PFCs analysis in serum. Methods for CRH analysis were completed by the Fisher lab and telomere analysis will begin at the end of Year 3 by the Blackburn Lab. We plan to begin preliminary analysis of chemical compounds at the end of Year 3.
We continue to purchase lab supplies and biospecimen collection material necessary for carrying out study activities. All biospecimen collection materials are sent to our collaborators to test for possible contamination by chemicals of interest (PBDEs and PFCs).
Core A: Community Outreach and Research Translation:
Aim 1: Communicate the Science Broadly: Distributed 5,363 electronic and hard copies of our All That Matters series of patient‐centered brochures; were quoted in 11 print or online media outlets; had 11,204 unique visitors to the website; made a total of 52 presentations to clinical and policy audiences and to the public on reproductive environmental health science (N= 37) and on our Navigation Guide systematic review methodology (N= 15); used Facebook and Twitter to communicate the science five times per week; held 1 month-long tweet campaign that sent out multiple daily tweets covering the information in Toxic Matters, for a total of 113 tweets; developed a partnership with a health educator/product developer (SafetyNEST) who is integrating the content of Toxic Matters into a mobile app; FASTEP partner UCLA Women's Health Education & Resource Center adapted Toxic Matters to a wallet-sized card; updated Toxic Matters to include tips on how to avoid flame retardants in collaboration with the UCSF Sustainability Committee, which also provided funding to print more than 10,000 copies of the new brochure; held a FASTEP webinar to address the evidence for communicating information about toxic chemicals to women and men of reproductive age; and served on the planning committee, co-sponsored, and attended the UCLA Reproductive Health and the Environment: Best Practices for Los Angeles County on March 17, 2015.
Aim 2: Harness the Evolving Science to Healthcare: A critical outcome of our efforts was organizing the collaboration between our COTC and health professional societies to write an Opinion by the International Federation of Gynecology and Obstetrics (FIGO) on Reproductive Health Impacts of Exposure to Toxic Environmental Chemicals. FIGO is the leading voice of reproductive health professionals around the world and its actions have global resonance. FIGO's member organizations include 125 countries/territories. The FIGO Opinion, based in part on the scientific evidence produced by the Children’s Centers, and which was adopted by FIGO in May, concludes that “Based on accumulating robust evidence of exposures and adverse health impacts related to toxic environmental chemicals, FIGO joins other leading reproductive health professional societies in calling for timely action to prevent harm. FIGO recommends that reproductive and other health professionals advocate for policies to prevent exposure to toxic environmental chemicals, work to ensure a healthy food system for all, make environmental health part of health care, and champion environmental justice.” We also worked with Student Health Professionals for Social Responsibility, which engages more than 20 students across the UCSF School of Medicine, Pharmacology, Dentistry, and Nursing, to organize an elective course on environmental health including health care institutional sustainability issues. Drs. Gould and Woodruff also served as elective course faculty; attended six meetings of the UCSF Sustainability Committee and were instrumental in UCSF adopting an antibiotic free meat and poultry purchasing policy in May 2014; and submitted written comments to the Institute of Medicine recommending the collection of occupation on electronic medical records.
Aim 3: Advance Prevention‐Based Public Policy: We advanced uptake of the Navigation Guide systematic review methods through 15 meetings and briefings with decision‐makers in key federal and state agencies, including with key governmental and clinical organizational leaders. We also held four Navigation Guide Work Group Webinars; submitted written comments to the National Toxicology Program on its Draft Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration; completed our third case study on applying the Navigation Guide methodology; and secured funding to conduct two additional case studies. Two reports by the National Academy of Sciences cited the Navigation Guide methodology as illustrative of the type of methodology that should be adopted by the USEPA’s IRIS program for conducting evidence integration; and we formally became part of an international collaboration on the use of systematic reviews for evidence integration of animal studies (the CAMARADES—Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies collaboration).
Future Activities:
Project I: Modeling the Effects of EDCs on Early Stages of Human Placental Development. At the beginning of the Year 3, we will continue with the analyses of the data that we have obtained so far on the transcriptome and epigenome in PBDE-47 exposed and control CTBs. In independent cultures, we will confirm and interrogate differentially expressed targets due to PBDE-47 exposure on RNA, epigenome and protein levels in a dose-dependent manner. We will summarize these findings and use this information to inform the design of the next stage of experiments to investigate the dose-dependent effects of PBDE-47 or PFOA on the transcriptome and epigenome (including histone regulation). As we coalesce these datasets, we will choose the targets on which the functional analyses will concentrate for Aim 3.
Project 2: Mid-Gestation Exposure to EDCs and Effects on Placental Development. In the next reporting period, we will continue with recruitment and collection of biospecimens at SFGH. Target enrollment is 185 women in their second trimester and we anticipate recruiting the remaining ~20 study participants in the next reporting period. We also will begin to measure PBDE and PFC levels in matched samples of maternal serum, fetal liver and placenta, conduct non-targeted analysis of EOAs in matched samples, and continue morphological and molecular assessment of placenta samples.
Project 3: Effects of EDCs and Chronic Psychosocial Stress of Fetal Growth. We will continue to enroll participants each week from each study site (SFGH and MB), and finish enrollment by the middle of Year 4. We are continuing with method development for PFCs in Year 3, and will start chemical analysis for both PBDEs and PFCs by the end of Year 3. We also will begin stress biomarker analysis during Year 3.
Core A: Community Outreach and Translation Core (COTC). Continued advancement of our aims, including at the October 2015 FIGO World Congress at which time FIGO will release its Opinion on Toxic Environmental Chemicals, we will hold a day-long “Summit on Shaping Our Planetary,” which will set an agenda for moving the Opinion’s recommendations forward, and we will organize feature presentations by key scientific and thought leaders in the field to educate reproductive health professionals worldwide on this topic. These events will bring huge international attention to bear on environmental health and justice among the 8,000 meeting attendees and the press.
References:
Park HR, Loch-Caruso R. Protective effect of nuclear factor E2-related factor 2 on inflammatory cytokine response to brominated diphenyl ether-47 in the HTR-8/SVneo human first trimester extravillous trophoblast cell line. Toxicol Appl Pharmacol. 2014 Oct 11;281(1):67-77. doi: 10.1016/j.taap.2014.09.015. [Epub ahead of print] PubMed PMID: 25305463; PubMed Central PMCID: PMC4393751.
Park HR, Kamau PW, Loch-Caruso R. Involvement of reactive oxygen species in brominated diphenyl ether-47-induced inflammatory cytokine release from human extravillous trophoblasts in vitro. Toxicol Appl Pharmacol. 2014 Jan 15;274(2):283-92. doi: 10.1016/j.taap.2013.11.015. Epub 2013 Dec 1. PubMed PMID: 24296301; PubMed Central PMCID: PMC3931445.
Slotkin TA, Card J, Infante A, Seidler FJ. BDE99 (2,2',4,4',5-pentabromodiphenyl ether) suppresses differentiation into neurotransmitter phenotypes in PC12 cells. Neurotoxicol Teratol. 2013 May-Jun;37:13-7. doi: 10.1016/j.ntt.2013.02.001. Epub 2013 Feb 16. PubMed PMID:23422510; PubMed Central PMCID: PMC3669237.
Wang KL, Hsia SM, Mao IF, Chen ML, Wang SW, Wang PS. Effects of polybrominated diphenyl ethers on steroidogenesis in rat Leydig cells. Hum Reprod. 2011 Aug;26(8):2209-17. doi:10.1093/humrep/der165. Epub 2011 Jun 3. PubMed PMID: 21642635.
O'Connell BA, Moritz KM, Walker DW, Dickinson H. Synthetic glucocorticoid dexamethasone inhibits branching morphogenesis in the spiny mouse placenta. Biol Reprod. 2013 Jan 31;88(1):26. doi:10.1095/biolreprod.112.100644. Print 2013 Jan. PubMed PMID: 23242523.
Lian IA, Toft JH, Olsen GD, Langaas M, Bjørge L, Eide IP, Børdahl PE, Austgulen R. Matrix metalloproteinase 1 in pre-eclampsia and fetal growth restriction: reduced gene expression in decidual tissue and protein expression in extravillous trophoblasts. Placenta. 2010 Jul;31(7):615-20. doi:10.1016/j.placenta.2010.04.003. Epub 2010 May 8. PubMed PMID: 20452670.
Journal Articles: 48 Displayed | Download in RIS Format
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Abrahamsson D, Park J, Singh R, Sirota M, Woodruff T. Applications of Machine Learning to In Silico Quantification o Chemicals without Analytical Standards. Journal of Chemical Information and Modeling 2020;60(6):2718-2727. |
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Abrahamsson D, Siddharth A, Young T, Sirota M, Park J, Martin J, Woodruff T. In Silico Structure Predictions for Non-targeted Analysis: From Physicochemical Properties to Molecular Structures. JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMOTY 2022;33(7):1134-1147 |
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Abrahamsson D, Brueck C, Prasse C, Lambropoulou D, Koronaiou L, Wang M, Park J, Woodruff T. Extracting Structural Information from Physicochemical Property Measurements Using Machine Learning-A New Approach for Structure Elucidation in Non-targeted Analysis. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023;27(40):14827-14838 |
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Bland G, Abrahamsson D, Wang M, Zlatnik M, Morello-Frosch R, Park J, Sirota M, Woodruff T. Exploring applications of non-targeted analysis in the characterization of the prenatal exposome. SCIENCE OF THE TOTAL ENVRIONMENT 2023;912(169458) |
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Casey JA, Karasek D, Ogburn, EL, Goin DE, Dang K, Braveman PA, Morello-Frosch R. Coal and oil power plant retirements in California:association with reduced preterm birth among populations nearby. American Journal of Epidemiology 2018;187(8):1586-1594. |
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Casey JA, Gemmill A, Karasek D, Ogburn, EL, Goin DE, Morello-Frosch R. Increase in fertility following coal and oil power plant retirements in California. Environmental Health 2018;17(1):44 (10 pp.). |
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Di Renzo GC, Conry JA, Blake J, DeFrancesco MS, DeNicola N, Martin Jr. JN, McCue KA, Richmond D, Shah A, Sutton P, Woodruff TJ, van der Poel SZ, Giudice LC. International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals. International Journal of Gynaecology and Obstetrics 2015;131(3):219-225. |
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Gerona RR, Pan J, Zota AR, Schwartz JM, Friesen M, Taylor JA, Hunt PA, Woodruff TJ. Direct measurement of bisphenol A (BPA), BPA glucuronide and BPA sulfate in a diverse and low-income population of pregnant women reveals high exposure, with potential implications for previous exposure estimates: a cross-sectional study. Environmental Health 2016;15:50 (14 pp.). |
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Gerona RR, Schwartz JM, Pan J, Friesen MM, Lin T, Woodruff TJ. Suspect screening of maternal serum to identify new environmental chemical biomonitoring targets using liquid chromatography-quadrupole time-of-flight mass spectrometry. Journal of Exposure Science & Environmental Epidemiology 2018;28(2):101-108. |
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Goin D, Abrahamsson D, Wang M, Jiang T, Park J, Sirota M, Morello-Frosch R, DeMicco E, Zlatnik M, Woodruff T. Disparities in chemical exposures among pregnant women and neonates by socioeconomic and demographic characteristics:A nontargeted approach. ENVIRONMENTAL RESEARCH 2022;215(1):114158. |
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Goin D, Abrhamsson D, Wang M, Park J, Sirota M, Morello-Frosch R, DeMicco E, Trowbridge J, Augt L, O'Connell S, Ladella S, Zlatnik M, Woodruff T. Investigating geographic differences in environmental chemical exposures in maternal and cord sera using non-targeted screening and silicone wristbands in California. JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY 2022;. |
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Huang H, Wang A, Morello-Frosch R, Lam J, Sirota M, Padula A, Woodruff TJ. Cumulative risk and impact modeling on environmental chemical and social stressors. Current Environmental Health Reports 2018;5(1):88-99. |
R835433 (2017) R835433 (Final) |
Exit |
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Johnson PI, Sutton P, Atchley DS, Koustas E, Lam J, Sen S, Robinson KA, Axelrad DA, Woodruff TJ. The Navigation Guide—evidence-based medicine meets environmental health: systematic review of human evidence for PFOA effects on fetal growth. Environmental Health Perspectives 2014;122(10):1028-1039. |
R835433 (2014) R835433 (Final) |
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Johnson PI, Koustas E, Vesterinen HM, Sutton P, Atchley DS, Kim AN, Campbell M, Donald JM, Sen S, Bero L, Zeise L, Woodruff TJ. Application of the Navigation Guide systematic review methodology to the evidence for developmental and reproductive toxicity of triclosan. Environment International 2016;92-93:716-728. |
R835433 (2015) R835433 (2016) R835433 (Final) |
Exit Exit Exit |
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Koustas E, Lam J, Sutton P, Johnson PI, Atchley DS, Sen S, Robinson KA, Axelrad DA, Woodruff TJ. The Navigation Guide—evidence-based medicine meets environmental health:systematic review of nonhuman evidence for PFOA effects on fetal growth. Environmental Health Perspectives 2014;122(10):1015-1027. |
R835433 (2014) R835433 (Final) |
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Lam J, Koustas E, Sutton P, Johnson PI, Atchley DS, Sen S, Robinson KA, Axelrad DA, Woodruff TJ. The Navigation Guide—evidence-based medicine meets environmental health:integration of animal and human evidence for PFOA effects on fetal growth. Environmental Health Perspectives 2014;122(10):1040-1051. |
R835433 (2014) R835433 (Final) |
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Lam J, Lanphear BP, Bellinger D, Axelrad DA, McPartland J, Sutton P, Davidson L, Daniels N, Sen S, Woodruff TJ. Developmental PBDE exposure and IQ/ADHD in childhood: a systematic review and meta-analysis. Environmental Health Perspectives 2017;125(8):086001 (20 pp.). |
R835433 (2016) R835433 (2017) R835433 (Final) |
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Lam J, Kotas E, Sutton P, Padula A, Cabana M, Vesterinen H, Griffiths C, Dickie M, Daniels N, Whitaker E, Woodruff T. Exposure to formaldehyde and asthma outcomes:A systematic review, meta-analysis, and economic assessment. PLOS ONE 2021;16(3):e0248258. |
R835433 (Final) |
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Lam J, Sutton P, Kalkbrenner A, Windham G, Halladay A, Koustas E, Lawler C, Davidson L, Daniels N, Newschaffer C, Woodruff T. A Systematic Review and Meta-Analysis of Multiple Airborne Pollutants and Autism Spectrum Disorder. PLoS One. 2016 Sep 21;11(9):e0161851. doi:10.1371/journal.pone.0161851. PubMed PMID:27653281; PubMed Central PMCID:PMC5031428. |
R835433 (2016) R835433 (Final) |
Exit Exit |
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McHale CM, Osborne G, Morello-Frosch R, Salmon AG, Sandy MS, Solomon G, Zhang L, Smith MT, Zeise L. Assessing health risks from multiple environmental stressors: moving from G×E to I×E. Mutation Research 2018;775:11-20. |
R835433 (2017) R835433 (Final) |
Exit Exit Exit |
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Morello-Frosch R, Cushing LJ, Jesdale BM, Schwartz JM, Guo W, Guo T, Wang M, Harwani S, Petropoulou SE, Duong W, Park J-S, Petreas M, Gajek R, Alvaran J, She J, Dobraca D, Das R, Woodruff TJ. Environmental chemicals in an urban population of pregnant women and their newborns from San Francisco. Environmental Science & Technology 2016;50(22):12464-12472. |
R835433 (2015) R835433 (2017) R835433 (Final) |
Exit Exit Exit |
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Morgan RL, Thayer KA, Bero L, Bruce N, Falck-Ytter Y, Ghersi D, Guyatt G, Hooijmans C, Langendam M, Mandrioli D, Mustafa RA, Rehfuess EA, Rooney AA, Shea B, Silbergeld EK, Sutton P, Wolfe MS, Woodruff TJ, Verbeek JH, Holloway AC, Santesso N, Schunemann HJ. GRADE: assessing the quality of evidence in environmental and occupational health. Environment International 2016;92-93:611-616. |
R835433 (2015) R835433 (2016) R835433 (Final) |
Exit Exit Exit |
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Parry E, Zota AR, Park J-S, Woodruff TJ. Polybrominated diphenyl ethers (PBDEs) and hydroxylated PBDE metabolites (OH-PBDEs): a six-year temporal trend in Northern California pregnant women. Chemosphere 2018;195-777-783. |
R835433 (2017) R835433 (Final) |
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Pelch K, Reade A, Kwiatkowski C, Merced-Nieves F, Cavalier H, Schultz K, Wolffe T, Varshavsky J. The PFAS-Tox Database:A systematic evidence map of health studies on 29 per-and polyfluoroalkyl substances. ENVIRONMENTAL INTERNATIONAL 2022;167(107408). |
R835433 (Final) |
Exit Exit |
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Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller MJ, Amin V, Whitaker JW, Schultz MD, Ward LD, Sarkar A, Quon G, Sandstrom RS, Eaton ML, Wu YC, Pfenning AR, Wang X, Claussnitzer M, Liu Y, Coarfa C, Harris RA, Shoresh N, Epstein CB, Gjoneska E, Leung D, Xie W, Hawkins RD, Lister R, Hong C, Gascard P, Mungall AJ, Moore R, Chuah E, Tam A, Canfield TK, Hansen RS, Kaul R, Sabo PJ, Bansal MS, Carles A, Dixon JR, Farh KH, Feizi X, Karlic R, Kim AR, Kulkarni A, Li D, Lowdon R, Elliott G, Mercer TR, Naph SJ, Onuchic V, Polak P, Rajagopal N, Ray P, Sallari RC, Siebenthall KT, Sinnott-Armstrong NA, Stevens M, Thurman RE, Wu J, Zhang B, Zhou X, Beaudet AE, Boyer LA, De Jager PL, Farnham PJ, Fisher SJ, Haussler D, Jones SJ, Li W, Marra MA, McManus MT, Sunyaev S, Thomson JA, Tlsty TD, Tsai LH, Wang W, Waterland RA, Zhang MQ, Chadwick LH, Bernstein BE, Costello JF, Ecker JR, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos JA, Wang T, Kellis M. Integrative analysis of 111 reference human epigenomes. Nature 2015;518(7539):317-330. |
R835433 (2014) R835433 (Final) |
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Robinson JF, Kapidzic M, Gormley M, Ona K, Dent T, Seifikar H, Hamilton EG, Fisher SJ. Transcriptional dynamics of cultured human villous cytotrophoblasts. Endocrinology 2017;158(6):1581-1594. |
R835433 (2016) R835433 (2017) R835433 (Final) |
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Robinson J, Hamilton E, Lam J, Chen H, Woodruff T. Differences in cytochrome p450 enzyme expression and activity in fetal and adult tissues. PLACENTA 2020;100:35-44. |
R835433 (Final) R834678 (Final) |
Exit Exit |
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Solomon GM, Morello-Frosch R, Zeise L, Faust JB. Cumulative environmental impacts: science and policy to protect communities. Annual Review of Public Health 2016;37:83-96. |
R835433 (2015) R835433 (2017) R835433 (Final) |
Exit Exit |
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Stotland NE, Sutton P, Trowbridge J, Atchley DS, Conry J, Trasande L, Gerbert B, Charlesworth A, Woodruff TJ. Counseling patients on preventing prenatal environmental exposures--a mixed-methods study of obstetricians. PLoS ONE 2014;9(6):e98771 (7 pp.). |
R835433 (2014) R835433 (Final) |
Exit Exit Exit |
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Sutton PM, Giudice LC, Woodruff TJ. Moving from awareness to action on preventing patient exposure to toxic environmental chemicals. American Journal of Obstetrics and Gynecology 2016;214(5):555-558. |
R835433 (2015) R835433 (Final) |
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Sutton, P, Woodruff, TJ, Conry, J, Giudice, LC. Exposure to toxic chemicals:reproductive health professionals speak about the first 1,000 days. San Francisco Medicine 2014;87(9):12-13. |
R835433 (2014) R835433 (Final) |
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Uyghurturk D, Goin D, Martinez-MierEA, Woodruff T, DenBesten P. Maternal and fetal exposures to fluoride during mid-gestation among pregnant women in northern California. ENVIRONMENTAL HEALTH 2020;19(1):38. |
R835433 (Final) |
Exit Exit |
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Vandenberg LN, Ågerstrand M, Beronius A, Beausoleil C, Bergman A, Bero LA, Bornehag CG, Boyer CS, Cooper GS, Cotgreave I, Gee D, Grandjean P, Guyton KZ, Hass U, Heindel JJ, Jobling S, Kidd KA, Kortenkamp A, Macleod MR, Martin OV, Norinder U, Scheringer M, Thayer KA, Toppari J, Whaley P, Woodruff TJ, Ruden C. A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals. Environmental Health 2016;15(1):74. |
R835433 (2015) R835433 (Final) |
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Vandenberg LN, Gerona RR, Kannan K, Taylor JA, van Breemen RB, Dickenson CA, Liao C, Yuan Y, Newbold RR, Padmanabhan V, Vom Saal FS, Woodruff TJ. Erratum to: A round robin approach to the analysis of bisphenol A (BPA) in human blood samples. Environmental Health 2016;15:43. |
R835433 (2017) R835433 (Final) |
Exit Exit |
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Varshavsky J, Zota A, Woodruff T. A Novel Method for Calculating Potency-Weighted Cumulative Phthalates Exposure with Implications for Identifying Racial/Ethnic Disparities among Reproductive-Aged Women in NHANES 2001-2012. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2016;5(19):10616-10624. |
R835433 (Final) |
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Varshavsky J, Morello-Frosch R, Woodruff T, Zota A. Dietary sources of cumulative phthalates exposure among the general population in NHANES 2005-2014. ENVIRONMENT INTERNATIONAL 2018;115:417-429. |
R835433 (Final) |
Exit Exit |
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Varshavsky J, Morello-Frosch R, Harwani S, Snider M, Petropoulou S, Park J, Petras M, Reynolda P, Nguyen T, Quach T. A Pilot Biomonitoring Study of Cumulative Phthalates Exposure among Vietnamese American Nail Salon Workers. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020;17(1). |
R835433 (Final) |
Exit Exit |
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Varshavsky J, Smith A, Wang A, Hom E, Izano M, Huang H, Padula A, Woodruff T. Heightened susceptibility:A review of how pregnancy and chemical exposures influence maternal health. Reproductive Toxicology 2020;92(SI):14-56. |
R835433 (Final) R835643 (Final) |
Exit Exit |
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Vesterinen HM, Johnson PI, Koustas E, Lam J, Sutton P, Woodruff TJ. In support of EHP's proposal to adopt the ARRIVE guidelines. Environmental Health Perspectives 2013;121(11‐12):A325. |
R835433 (2013) R835433 (2014) R835433 (Final) |
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Vesterinen HM, Morello-Frosch R, Sen S, Zeise L, Woodruff TJ. Cumulative effects of prenatal-exposure to exogenous chemicals and psychosocial stress on fetal growth: systematic-review of the human and animal evidence. PLoS One 2017;12(7):e0176331 (29 pp.). |
R835433 (2017) R835433 (Final) |
Exit Exit |
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Wang A, Padula A, Sirota M, Woodruff TJ. Environmental influences on reproductive health: the importance of chemical exposures. Fertility and Sterility 2016;106(4):905-929. |
R835433 (2016) R835433 (2017) R835433 (Final) R835643 (2016) R835643 (2017) |
Exit Exit |
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Wang A, Gerona RR, Schwartz JM, Lin T, Sirota M, Morello-Frosch R, Woodruff TJ. A suspect screening method for characterizing multiple chemical exposures among a demographically diverse population of pregnant women in San Francisco. Environmental Health Perspectives 2018;126(7):077009 (13 pp.). |
R835433 (2017) R835433 (Final) |
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Woodruff TJ, Sutton P. The Navigation Guide systematic review methodology: a rigorous and transparent method for translating environmental health science into better health outcomes. Environmental Health Perspectives 2014;122(10):1007-1014. |
R835433 (2014) R835433 (Final) |
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Zota AR, Linderholm L, Park JS, Petreas M, Guo T, Privalsky ML, Zoeller RT, Woodruff TJ. Temporal comparison of PBDEs, OH-PBDEs, PCBs, and OH-PCBs in the serum of second trimester pregnant women recruited from San Francisco General Hospital, California. Environmental Science & Technology 2013;47(20):11776-11784. |
R835433 (2017) R835433 (Final) |
Exit Exit Exit |
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Zota AR, Mitro SD, Robinson JF, Hamilton EG, Park JS, Parry E, Zoeller RT, Woodruff TJ. Polybrominated diphenyl ether (PBDEs) and hydroxylated PBDE metabolites (OH-PBDEs) in maternal and fetal tissues, and associations with fetal cytochrome P450 gene expression. Environment International 2018;112:269-278. |
R835433 (2017) R835433 (Final) |
Exit Exit Exit |
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Zota A, Mitro S, Robinson J, Hamilton E, Park J, Parry E, Zoeller R, Woodruff J. Polybrominated diphenyl ethers PBDEs and hydroxylated PBDE metabolites OH-PBDEs in maternal and fetal tissues, and associations with fetal cytochrome P450 gene expression. ENVIRONMENT INTERNATIONAL 2018;112:269-278. |
R835433 (Final) |
Exit Exit |
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Morello-Frosch R, Cushing LJ, Jesdale BM, Schwartz JM, Guo W, Guo T, Wang M, Harwani S, Syrago-Petropoulou SSE, Duong W, Park J-S, Petreas M, Gajek R, Alvaran J, She J, Dobraca D, Das R, Woodruff TJ (2016) Environmental Chemicals in an Urban Population of Pregnant Women and their Newborns from San Francisco. Environ Sci and Technol DOI:10.1021/acs.est.6b03492. |
R835433 (2016) |
Exit Exit Exit |
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Johnson PI, Sutton P, Koustas E, Vesterinen HM, Woodruff TJ. Response to correspondence by Heather Lynch, Julie Goodman and Nancy Beck Re:"Application of the Navigation Guide systematic review methodology to the evidence for developmental and reproductive toxicity of triclosan". Environ Int. 2017 Feb 21. pii:S0160-4120(17)30231-3. doi:10.1016/j.envint.2017.02.007. [Epub ahead of print] PubMed PMID:28236502. |
R835433 (2016) R835433 (Final) |
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Progress and Final Reports:
Original AbstractThe 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
- 2017 Progress Report
- 2016 Progress Report
- 2015 Progress Report
- 2013 Progress Report
- Original Abstract
48 journal articles for this center