Grantee Research Project Results
2016 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, 2016 through May 31,2017
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:
The hypothesis of our PEEC Children’s Center is that environmental chemical (EC) 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 brominated diphenyl ether‐47 (BDE‐47), a flame retardant (FR), and perfluorooctanoic acid (PFOA), a repellent, on human placental development. 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 BDE‐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 ECs 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.
Progress Summary:
Research Project I: Modeling the Effects of EDCs on Early Stages of Human Placental Development
During the fourth project period, we continued to make progress on Aims 1-3 using human cytotrophoblast (CTB) cells, a model system in which we have over 20 years of experience, to study placentation in normal pregnancy and in pregnancy complications. We also selected this primary placental cell model to leverage recently generated transcriptomic and epigenomic data due to our participation in the NIH-funded Roadmap Epigenome Mapping Center (1). From these studies, we gained a unique 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, the goal of this project.
With regard to Aims 1 and 2, we conducted transcriptomic and methylation analyses of the effects of BDE-47 exposure in our CTB model system. Based on our dose/time response investigations completed in Year 1 and 2 which established relevant timing and dosage parameters in our model, we conducted transcriptomic and epigenomic analyses in Year 3, which included: 1) a sub-cytotoxic concentration of BDE-47 (1μM) 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. In CTBs, we examined responses to BDE-47 exposures after 24h due to reports suggesting PBDEs to alter gene/protein expression in trophoblast cell lines at equivalent exposure durations (2) and our initial dose-response investigations in Years 1 and 2. We collected RNA/DNA samples simultaneously from 3 independent cultures of 2nd trimester human CTBs which were exposed to either BDE-47 (1 μM) or vehicle control (1% DMSO; 12 total samples for each analysis). To evaluate gene expression, we used Affymetrix GeneChip Human Gene 2.0 ST Arrays, which contains probes for over 30,000 coding transcripts and includes multiple probes per gene to measure splicing events and transcript variants. Sample processing and hybridization was performed by the UCSF Gladstone Institute. For 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.
In Year 4, we continued to finalize the analysis of these datasets and initiate experimental studies aimed at confirming changes on the RNA/protein level of specific targets. Following data normalization, we applied a fixed effects linear model (ANOVA) to determine differentially expressed (DE) genes due to BDE-47 exposure, culture time, and gestational age. Our previous experiments in (unexposed) cultured CTBs (3) 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 535 genes to be significantly differentially expressed (DE) due to BDE-47 exposure (ANOVA: p≤ 0.025, absolute FC > 1.25). In general, expression changes due to exposure of BDE-47 were similar between the two 24h-exposure intervals despite CTBs being exposed at two different timepoints (3 vs. 15h post-plating), with 100% of DE genes displaying common trends in response to BDE-47. Alterations due to BDE-47 were similar between the two-24h exposure durations (y=0.91x, R2 = 0.69), with 100% of genes displaying common trends in dysregulation. In total, 285 (53%) genes were upregulated (Cluster I) and 250 (47%) genes were downregulated due to BDE-47 exposure. Fifty-three percent of this subset were coding mRNAs, with others representing non-coding transcripts, e.g., pseudogenes, antisense, miRNAs, and snoRNAs. We observed significant enrichment of GO terms, including: System and Vasculature Development, Blood Vessel Morphogenesis, Cell Differentiation, Cell Motility/Migration, Cell Surface Receptor Signaling Pathway, Inflammatory/Cytokine Response, Chemical Homeostasis, Response to Hormone, Secretion, and Negative Regulation of Cell Proliferation. Specific pathways, such as Inflammation/Cytokine Response have been previously proposed to be modified by PBDEs (2). In addition, we identified several novel targets associated with PBDE exposure. We evaluated the effects of five concentrations (0.1-10μM) of BDE-47 on specific DE targets, using qRT-PCR, to verify our microarray results and interrogate the dose response relationship between exposure and expression. We used independent experimental sets of CTBs (n≥3) and the CTB-samples applied in our microarray analyses. We confirmed DE of nine targets, eight of which that followed significant monotonic dose-response relationships with BDE-47 exposure (ANOVA, p<0.05). We observed significant upregulation of IL6, MMP1, GREM1, FABP4, and PLAC4; and downregulation of GPR34, SCD, HMGCS1 and FABP7 with BDE-47. These validated targets represent key members of diverse functional pathways involved in placental development, including: trophoblast differentiation, inflammation, fatty acid metabolism, steroid metabolism and/or morphogenesis (4-7). Previous concentration and time-dependent analyses of BDE-47 exposures in HTR-8/SV neo trophoblast cells suggest inflammatory (i.e., IL-6, -8) and oxidative stress mediators to be linked with PBDE-induced cytotoxicity (8). Using protein samples isolated from independent cultures of CTBs exposed to 1% DMSO (vehicle control), BDE-47 or -99 (1 or 5μM), we extended these RNA analyses to examine protein expression levels of MMP1, PLAC4, HMGCS1, and SCD via immunoblot. These preliminary investigations suggest positive correlations between RNA and protein levels. In summary, our transcriptomic results suggest BDE-47, in a concentration dependent manner, to perturb known and undefined pathways critical for trophoblast function and placental development. We are currently finalizing our transcriptomic data analyses to be able to pinpoint specific targets in which we will conduct a focused analysis of methylation levels between BDE-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, proteomic) that will be initiated in the near future.
As related to Aim 3, we developed tests to evaluate 1) migratory activity or 2) the ability of cells to invade using enhanced workflows that include fixation, nuclear staining/immunofluorescence, multiple image capture (Leica), and semi-automated data content analysis (Volocity). We added automated components to classical methodologies to reduce human error and increase efficiency in assessing functional endpoints across multiple conditions. We determined key timepoints in culture by conducting time-course evaluations of migratory activity and cell invasion. Using the standard 2-D culture system described above, in unexposed cultures, we quantified migratory activity/aggregation of CTBs within the first 40h of culture by measuring the average distance between >20,000 cells per well as a parameter of activity. To assess cell invasion, we cultured cells in a suspended transwell (Corning) insert covered with Matrigel and auto-counted (Volocity) the total number of cellular projections penetrating the substrate that appear on the underside of the permeable filter. Similar to migration assays, we observed significant invasion within the first 40h of culture, suggesting that the invasive/migratory programming that these cells undergo in vivo is conserved in culture. We are currently finalizing the data in which we assessed BDE-47 or -99 exposed vs. control CTBs. In our initial experiments, cell invasion was inhibited at concentrations of 5μM BDE-47 or -99. These assays will 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., BDE-47 and PFOA) effects in CTBs. Aim 3 experiments are designed to analyze the functions of molecules that are targets of the ECs 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.
To understand the relevancy of concentrations tested and determine the degree of bioaccumulation and metabolism of BDE-47 in our CTB model system, we quantified BDE-47 and hydroxylated metabolites of the parent species, i.e., 5-OH-BDE-47, 6-OH-BDE-47, in CTBs (cell and media fractions) exposed to BDE-47 via liquid chromatography–mass spectrometry (LC-MS). The results indicated that BDE-47 significantly bioaccumulated in the cellular fraction, in a concentration-dependent manner. After 24h, BDE-47 concentrations were 0.7μM or 1.2μM in the supernatant of cells initially exposed to 1μM or 5μM, respectively. Additionally, we computed the total μg recovered of BDE-47 in the media and cellular fractions. BDE-47 media (μg) to cell (μg) ratios differed between the two dose groups (1 vs 5μM). In cultures exposed to 1μM BDE-47, we observed a cell:media ratio of 0.6:1μg. In cultures exposed to 5μM, BDE-47 partitioned between the cell and media fractions at 3.1:1μg. These results suggest bioaccumulation of BDE-47 in the cellular fraction, and the rate of cellular uptake to be dependent on the magnitude of the initial testing concentration. Total recovery (media + cellular fractions) were within 10% of expected estimates. Limited metabolism of BDE-47 was observed in CTBs exposed to 1 or 5μM, with only ~0.0003% of the total BDE-47 recovered (media and cellular fractions) present in the hydroxylated form. Furthermore, only the 6-OH-BDE-47 metabolite (not the 5-OH), was identified in the cellular fraction in one of the three CTB samples evaluated. In addition to BDE-47, four of the eighteen PBDE congeners evaluated, i.e., -17, 28, -85, -99, were detected at low levels in the majority of all samples, representing <0.4% of the ΣPBDEs. No form of BDE-47 was present in any samples exposed to the vehicle control. Overall, these results indicate that hydroxylated metabolism occurred in CTBs within the first 24h of exposure.
We published a manuscript entitled “Transcriptional Dynamics of Cultured Human Villous Cytotrophoblasts”, in Endocrinology (3). This manuscript describes a global transcriptional analysis of time-dependent changes in gene expression occurring in primary CTBs as they differentiate in vitro. This study serves as a baseline for our environmental investigations. We will present our transcriptomic analyses of BDE-47 and complementary results in an abstract: "Toxicogenomic Profiling of BDE-47 Effects in Human Primary Villous Cytotrophoblasts”, at the Teratology Society Annual Meeting in Denver, CO in June, 2017. Dr. Robinson has also presented results from these analyses in several forums at UCSF, including for the Department of Obstetrics, Gynecology & Reproductive Sciences, “Grand Rounds”, and Center for Reproductive Sciences, “Annual Retreat”.
Research Project II: Mid-Gestational Exposure to EDCs and Effects on Placental Development
Objective(s) of the Research: Our project tests the hypotheses that 1) polybrominated diphenyl ethers (PBDEs), perfluorinated chemicals (PFCs), and select environmental organic acids (EOAs) accumulate differently in human fetuses than in pregnant women during the 2nd 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 will also 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 2nd trimester pregnancies. We will analyze the samples for 17 PBDEs and 12 PFCs. We will also use a novel biomonitoring approach based on Time-of-Flight Liquid Chromatography-Mass Spectrometry (LC-QTOF/MS) combined with traditional analytic methods to identify and quantify exposure to the 5 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 placenta development in the 2nd 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 will also 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.
Working with our Community Outreach and Translation Core, we will translate our findings to the clinical and policy communities, thus providing key inputs for improving public policy approaches to identifying, assessing and preventing human risks from these endocrine disrupting chemicals.
Progress Summary/Accomplishments (Outputs/Outcomes):
• In FY3, we collected 133 matched sets of maternal serum, fetal liver, and placenta. Demographics of our study population are described in the cumulative enrollment table attached to this report.
• Placenta samples were fixed in formalin for future immunohistochemistry analyses. Based on findings in Project I, which evaluated the effects of BDE-47 on functional and transcriptomic levels in 2nd trimester human primary cytotrophoblasts, potential biomarkers of PBDE exposure have been identified. We selected four of these targets to further interrogate as potential biomarkers of PBDE exposure in vivo, which included, MMP1 1-3 and PLAC4 4, molecules with suspected roles in placental development; and HMGCS15 and SCD6, members of the cholesterol/fatty acid biosynthesis pathway. We also added proposed biomarkers of pre-eclampsia (GH2, PLAC1) and negative controls/molecules not altered by PBDEs in vitro (NOTUM, EFEMP1) to our analyses. Using antigen-specific antibodies, we independently evaluated the localized expression of each of these targets within a subset of placentas (n=12), pre-identified to be in the upper (>10%) or bottom (>90%) percentiles of ΣPBDE burden within our sample set. Two sections from each placenta were probed and scored blindly by two investigators to determine the relative expression of each marker using a semi-automated method that we developed to quantify relative immunofluorescence intensity within regions of the maternal-fetal interface. We analyzed six regions in total: 1) CTBs invading into the decidua (interstitial invasion); 2) decidual cells; 3) CTBs of the proximal and distal column, 4) villous trophoblasts (STBs and CTBs), 5) mesenchymal cells within the floating villous, and 6) CTBs invading the maternal artery (endovascular invasion). All sections were co-stained with cytokeratin (CK), a marker of CTB populations, and 4', 6-diamidino-2-phenylindole (Dapi), a DNA nuclear binding molecule. Specific patterns were observed. For example, SCD was expressed highest in the floating villous CTBs, whereas PLAC4 was predominately expressed in the villous core mesenchyme, interstitial CTBs, and decidua. Relative intensity values for each of the eight biomarkers were summarized. We observed good agreement between investigators (r=0.8) and across technical replicates (r=0.7). Staining patterns varied across individual placentas. Ongoing studies aim to examine correlations via k-means clustering and regression analyses to test relationships between expression profiles of these targets (and potential morphological pathologies) with ΣPBDE concentration levels in maternal serum and placenta in a larger sample set (n>100). These results will provide unique insight into the relationship between proposed molecular PBDE-targets in the placenta and ΣPBDE levels during mid-gestation, when pathologic alterations with the greatest functional significance may occur.
• Methods for PBDE analysis in serum and liver were 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 was also finalized. In December of 2016, we completed PBDE chemical analysis on all 130 matched sets of maternal serum, placenta, and fetal liver.
• Methods for PFCs analysis in serum was developed by Dr. Roy Gerona at UCSF Department of OB/Gyn and Reproductive Sciences. In consultation with our project officers at NIEHS and EPA, a decision was made for the Gerona Lab to analyze PFCs in maternal serum only. It was costlier and took more time to develop the method than anticipated, and to meet budget and time goals, we modified the scope to measure PFCs in maternal serum only.
• Dr. Roy Gerona has completed methods for non‐targeted analysis of EOAs in serum using LC‐QTOF/MS, and a manuscript has been submitted and is currently under review. • We will continue with data analysis and manuscript preparation in FY5.
Research Project III: Effects of EDCs and Chronic Psychosocial Stress of Fetal Growth
Objective(s) of the Research: This project will examine the hypothesis that prenatal exposures to endocrine disrupting chemicals (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 - polybrominated diphenyl ethers (PBDEs) and perfluorinated chemicals (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 is 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.
Progress Summary/Accomplishments (Outputs/Outcomes): Fund Year 4 (FY) was spent continuing to recruit participants at Zuckerberg San Francisco General Hospital (ZSFG), and the Betty Irene Moore Women’s Health Hospital at Mission Bay (MB). Currently recruitment takes place at the prenatal clinics at ZSFG and MB, although we do some 2nd trimester participant visits at Moffitt Long Hospital at Parnassus.
We have enrolled 484 participants at a rate of approximately four participants per week. This enrollment rate represents an increase compared with the rate reported in the FY3 report (2/week) and is an indicator of the success in our increase in staffing and improvement in research operations. We anticipate recruitment of study participants will be complete in August or September of 2017.
To date we have collected maternal serum on 474 out of 475 participants (at second trimester and/or at delivery). We have 467 2nd trimester maternal blood samples, 305 3rd trimester maternal blood samples, and 271 cord blood samples that are matched with material blood samples. PBDE methods development in serum has been completed by our collaborators at California Department of Toxic Substances Drs. Myrto Petreas and June-Soo Park; 234 maternal serum samples were transported to the DTSC for PBDEs analysis in August of 2016 and an additional 190 2nd trimester maternal serum samples were transported in June 2017 for further PBDEs analysis. The first batch of PDBEs analysis is expected to be complete by the end of August 2017 with the remaining samples to be analyzed in the fall of 2017.
The Fisher lab completed CRH methods and in August of 2016, 240 maternal plasma samples were transported to the Fisher Lab to begin preliminary analysis. Also, in July of 2016, the Blackburn Lab completed telomere analysis on 99 cord whole blood samples and in August 2017 we received the telomere results for these samples. Additional telomere data will arrive in July 2017.
The Gerona Lab completed methods development and preliminary PFCs analysis on a subset of our CIOB2 maternal serum samples (This lab is also conducting non-targeted chemical analysis with support of an EPA STAR grant). However, in our successful application to the ECHO program (which includes PFC analysis), we made the decision to work with the Department of Toxic Substances Control a high capacity lab, that would be able to conduct PFC analysis on over 1400 maternal serum samples for both the UCSF and University of Illinois pregnancy cohorts. Because many of our CIOB2 participants have agreed to enroll into our ECHO cohort, so that we can follow and assess their offspring through four years of age, the team decided it would be best to have the same lab conduct the PFC analysis for all study participants. As a result, in consultation with our Project Officers at NIEHS and EPA, we transferred the CIOB2 PFCs analysis to our colleagues at the Department of Toxics Substances Control in January of 2017. The timeline for completion of PFCs analysis in 2nd trimester maternal serum is fall of 2017.
We anticipate sample collection to be complete and by January 2018 and we plan for data analysis and paper writing to continue through the remainder of FY4 and in FY5.
With support from an Administrative Supplement, we collected 50 placentas from women in our CIOB2 cohort. In Project 1 of our UCSF PEEC Children's Center, we have developed an in vitro model of human placentation to study the effects of PBDEs and PFCs on trophoblasts—the basic building blocks of this organ—at transcriptomic, epigenomic and functional levels. In Project 2, we are integrating exposure science with placental biology by using targeted and non-targeted biomonitoring methods to measure human maternal and fetal exposures to PBDEs, PFCs and Environmental Organic Acids (EOAs) during the second trimester, and the relationship between these exposures and morphological and molecular markers of placental development.
We now seek to assess the validity of these in vitro an in vivo pathological features and molecular markers of adverse placental effects observed during early periods of fetal development for placental effects during the third trimester of pregnancy in our CIOB2 pregnancy cohort. This integrated, longitudinal analytical approach will enhance scientific understanding of how chemicals exert adverse fetal growth effects through placental pathways, throughout pregnancy. In June 2017, we submitted a proposal, entitled: “Profiling Environmental Chemical Biomarkers in Human Placentas,” in response to the RFA-ES-17-005: Environmental influences on Placental Origins of Development to conduct an analysis of differences in the expression of molecular markers and pathological features revealed in our previous in vitro and in vivo work among high versus low endocrine disrupting chemical (EDC) exposed maternal groups.
We are also collaborating with a colleague at San Francisco State University in our pending application in response to USEPA’s Early Career Awards: Using a Total Environment Framework (Built, Natural, Social Environments) to Assess Life-long Health Effects of Chemical Exposures, EPA-G2017-STAR-D2 to leverage the CIOB cohort data to examine interactions between aspects of the built, natural, and social environment on birth outcomes. Exposures of interest will include 1) residential proximity to traffic and traffic-related air pollution; 2) neighborhood green space; and 3) neighborhood social stressors related to gentrification and housing instability.
Future Activities:
Research Project I: Modeling the Effects of EDCs on Early Stages of Human Placental Development
At the beginning of the year 5, we will finalize and write-up the analyses of the data that we have obtained so far on the transcriptome and epigenome in BDE-47 exposed and control CTBs. In independent cultures, we will continue to confirm and interrogate DE targets due to PBDE exposures on molecular levels in a dose-dependent manner. Examples of targets include MMP1 and PLAC4, in which, we have interrogated the dose-response relationship of using qRT-PCR or immunoblot. We will continue to pursue other targets of interest using these methodologies. Using our initial methylation data analyses, we plan to conduct focused assessments of promoter regions of genes significantly altered by BDE-47 to identify potential altered epigenetic markers. We will summarize these findings and use this information to inform the design of future experiments. As we finalize and coalesce these datasets, we will select targets on which the functional analyses will concentrate for Aim 3. With supplemental funds, proteomic analyses of BDE-47 and PFOA are also underway. Therefore, we will analyze these data in comparison with transcriptomic/methylation datasets, and expand our targeted studies to include molecules altered by BDE-47 and/or PFOA. We plan to submit a manuscript which describes the effects of BDE-47 in the human primary CTB model with a focus on the transcriptomic alterations.
Research Project II: Mid-Gestation Exposure to EDCs and Effects on Placental Development
In the next reporting period we will continue to measure PFC levels in maternal serum and conduct non-targeted analysis of EOA's in matched samples of maternal serum, fetal liver and placenta, and morphological and molecular assessment of placenta samples. In addition, we will continue with data analysis and manuscript preparation.
Research Project III: Effects of EDCs and Chronic Psychosocial Stress of Fetal Growth
We plan to continue with recruitment and sample collection and we anticipate that we will reach our recruitment goal on N=500 by October 2017. Sample collection will be complete soon after. Analysis of chemicals and stress biomarkers will continue; manuscript writing and plans to disseminate findings are underway and will continue through FY5.
Community Outreach and Translation Core (COTC)
We will continue to train the next generation of reproductive health professionals to become champions of environmental health. Specifically we will continue to advance reproductive environmental health among health professional societies and health care institutions; integrate environmental health in medical education by organizing an elective, video taping the lectures and disseminating widely and writing modules to align with the opportunities in the curriculum that we have already identified; and create opportunities for internships and other avenues of engagement with students to ensure a pipeline of scientists and healthcare professionals steeped in the science linking the environment to children’s health. We will generate a pipeline of scientists who will carry systematic review methods forward and sustain the use of improved methods in the future. In collaboration with the NTP and other Navigation Guide Work Group members, and building off our formaldehyde and asthma case study and other case studies of the Navigation Guide, and the NTP’s handbook for systematic reviews, we will develop curriculum and implement web-based trainings and practicums, and disseminate these materials widely to seed the development of standardized training programs in academic and other settings. We will publish two additional case studies of applying the Navigation Guide systematic review method: (2) Exposure to PBDEs and IQ and ADHD (in review); Exposure to formaldehyde and asthma (in preparation). We will also publish an invited article in PLOS Biology collection “Challenges in Environmental Health: Closing the Gap between Evidence and Regulations.” The Collection aims to highlight gaps between emerging or consensus evidence of harm and existing policies and regulations to protect public and environmental health and NIEHS Director Dr. Linda Birnbaum and PLOS Biology Senior Editor Liza Gross will oversee the collection. We will continue to routinely communicate the science through print, electronic and social media, and our website, which is currently undergoing an update. We will continue to produce and disseminate our Spanish translations of our All That Matters series of brochures. We will complete the adaptation of All That Matters brochures into the SafetyNest app. We will make presentations at grand rounds and scientific conference. And we will continue to promote the uptake of the Navigation Guide through meetings and presentations and comments.
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.). |
R835433 (2017) R835433 (Final) |
Exit Exit |
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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. |
R835433 (2015) R835433 (Final) |
Exit Exit Exit |
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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.). |
R835433 (2015) R835433 (2017) R835433 (Final) |
Exit Exit |
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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. |
R835433 (2017) R835433 (Final) R835643 (2017) |
Exit |
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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. |
R835433 (Final) |
Exit Exit |
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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;. |
R835433 (Final) |
Exit Exit |
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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) |
Exit |
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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) |
Exit Exit Exit |
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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) |
Exit Exit Exit |
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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) |
Exit Exit |
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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) |
Exit Exit Exit |
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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) |
Exit |
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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) |
Exit Exit |
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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) |
Exit Exit |
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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
- 2015 Progress Report
- 2014 Progress Report
- 2013 Progress Report
- Original Abstract
48 journal articles for this center