Final Report: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers

EPA Grant Number: R834678
Center: Children's Environmental Health and Disease Prevention Research Center: Formative Center - University of California, San Francisco
Center Director: Woodruff, Tracey J.
Title: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers
Investigators: Woodruff, Tracey J. , Fisher, Susan J. , McMaster, Michael , Stotland, Naomi , Sutton, Patrice , Gerona, Roy
Institution: University of California - San Francisco
EPA Project Officer: Hahn, Intaek
Project Period: May 5, 2010 through May 4, 2014
Project Amount: $762,983
RFA: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers (with NIEHS) (2009) RFA Text |  Recipients Lists
Research Category: Children's Health , Health

Objective:

Project 1: Assessing Maternal and Fetal Exposures to Chemicals during the Second Trimester:

To generate unprecedented data on chemical exposures during the second trimester of pregnancy, when certain aspects of fetal development are particularly vulnerable to disruption. The specific aims of the project are to: (1) compare maternal and fetal exposures to BPA during the second trimester, and (2) to explore the feasibility and accuracy of using maternal biological biomonitoring results to predict fetal exposures.

Project 2: Assessing the Effects of BPA Exposure on Early Human Development:

To gain an understanding of the effects of BPA exposure on early human development using human embryonic stem cells (hESC) as a model system. To validate the candidate targets and pathways, we identify by differentiating BPA-treated hESCs and studying their composition with regard to the progeny of the three definitive germ layers.

Pilot Study: Predictors of Maternal Exposure to BPA during the Second Trimester of Pregnancy:

To generate unprecedented data on chemical exposures during the second trimester of pregnancy, when certain aspects of fetal development are particularly vulnerable to disruption. 

Community Outreach and Translation Core

Communicate PEEC Formative Center’s research broadly. Create a science-based foundation for clinical care and policy change. Sustain a collaborative network of partners. Advance public policy in the field of reproductive environmental health.

Summary/Accomplishments (Outputs/Outcomes):

Project 1: Assessing Maternal and Fetal Exposures to Chemicals during the Second Trimester:

We successfully recruited 181 women from September 2010 to April 2012 (target 100). We collected 125 urines and 111 urines on the first and second day visits of the participants (procedure second day). We collected 82 umbilical cord bloods, 162 placentas and 153 livers from the procedure.

Our collaborator, Dr. Roy Gerona, has developed an improved method for analyzing unconjugated BPA, BPA sulfate and BPA glucuronide and has measured all of these in our umbilical cord serum and urine samples and has completed the method development and preliminary analysis for a subset of the liver tissues (N = 20) and amniotic fluid samples (N = 7). Additionally, during the method development phase, Dr. Gerona discovered a source of BPA contamination in our maternal serum samples from the BD Vacutainer Push Button Blood Collection Set used in the hospital. He also determined there was no contamination from using straight needles. However, given the difficulty of using a straight needle versus a butterfly for the phlebotomists in the clinic, we were only able to collect 20% of our serum samples this way. We also tested 8 different models of butterfly vacutainers and have found 2 BPA-free replacements, and we implemented use of one (BD Vacutainer Eclipse 21G needle) starting on November 29, 2011. Results from the BPA contamination investigation have been submitted as a communication article to Chemosphere (currently under review). Finally, as a supplement to this project, we led and participated in a round robin for measuring unconjugated BPA in human blood with a goal of identifying whether unconjugated BPA could be measured accurately in human blood.

Results: Among our study participants, 100% had detectable BPA levels in non-fasting urine. Levels of total BPA, BPA glucuronide, BPA sulfate, and unconjugated BPA are up to three times higher compared to other studies measuring BPA in pregnant women in the United States and other countries worldwide, possibly due to underlying demographic and behavioral characteristics of our unique study population (lower income, 40% smokers, racially diverse population). BPA analytic methods may also contribute, as we use an LC-MS/MS technique to directly measure unconjugated BPA and BPA conjugates without enzyme hydrolysis used in previous studies. Enzyme hydrolysis could induce sample loss.

For the first time, we measured unconjugated and conjugated BPA in umbilical cord serum. We found a geometric mean for BPA glucuronide of 0.14 ng/mL, and 0.32 ng/mL for BPA sulfate. Unconjugated BPA was detected in 47% of umbilical cord serum samples, and 29% of samples had more unconjugated BPA than conjugated. Although unconjugated BPA was not universally detected, maximum concentrations of unconjugated BPA measured (52.3 ng/mL) are the highest reported to date. In a subset of matched umbilical cord serum and maternal urine samples (n = 29), we found higher levels of total BPA in umbilical cord serum in approximately 20% of samples, and higher levels of unconjugated BPA in umbilical cord serum in 45% of samples. We also observed positive correlations in unconjugated and conjugated BPA levels between urine and cord blood. Further, we have shown, for the first time in humans, the importance of the sulfonation metabolic pathway as an alternative to glucoronidation, likely due to immaturity of the UGT enzymes. Results on BPA analysis methods and umbilical cord serum BPA levels have been published in Environmental Science and Technology (PMID: 23941471).

In our analysis of the first 10 fetal liver samples, we have found that the major form of BPA is free or unconjugated BPA, which is present in 100% of the samples. In addition, we have found that BPA sulfate is slightly higher in these samples than BPA glucuronide and are the first to report the two conjugates differentiated. We are currently in process of analyzing the remaining liver samples for BPA. We have developed a method for BPA analysis in amniotic fluid and will be using it to analyze samples in our new PEEC Children’s Center Grant.

For the round robin, four labs participated (including our own). We identified collection materials and reagents that did not introduce BPA contamination. In the blinded spiked sample analysis, all labs were able to distinguish low from high values of unconjugated BPA and BPA glucuronide. By completion of the Round Robin, three labs had verified methods for the analysis of unconjugated BPA and two verified for the analysis of BPA glucuronide (determined by: 4 of 5 samples within 20% of spiked concentrations). In the analysis of BPA glucuronide only spiked samples, all laboratories reported BPA glucuronide was the majority of BPA detected (92.2 – 100%). Finally, labs were more likely to be verified using direct methods than indirect ones using enzymatic hydrolysis. A submitted paper is under review at Environmental Health. 

Project 2: Assessing the Effects of BPA Exposure on Early Human Development:

Initial experiments showed that BPA treatment of a Federally-approved hESC cell line (UCSF4) resulted in modulation of nuclear receptors, transcription factors and their target genes as well as markers of differentiation. For example, the brachyury gene, encoding a factor important for establishment of the mesodermal lineage during gastrulation in early human embryos, was upregulated by BPA treatment. We then focused our analyses on the effects of BPA on expression of families of transcriptional regulators known to play key roles in hESC self-renewal and differentiation. Hox family members (e.g., HOX-C6, -C9, -B13, -C12, -C10, and DLX2) involved in early morphogenesis were particularly sensitive to regulation by BPA. These and other data support the hypothesis that BPA tips the balance from proliferation in an undifferentiated state toward differentiation of particular lineages in early embryos. This conclusion is also bolstered by experiments showing that BPA treatment inhibits proliferation and increases differentiation as assessed by morphological changes we observed in hESC colonies. During the remainder of the funding period, we completed work on both Aims. Specifically, we performed microarray-based global transcriptional profiling experiments in which hESCs were exposed to BPA in 2 doses (10 and 50 nM) or to estrogen or vehicle/ethanol controls. The unexpected and very interesting result was that BPA had a global effect on mRNA splicing rather that frank changes in the levels of expression of individual genes. The microarray data analysis strategy to determine exon-level changes is not included in the established methodologies and required significant methods development in our group. The current generation of Affymetrix microarrays, whole gene arrays, use random primers to initiate cDNA formation, thus capturing the entire length of transcripts from the 5’ to the 3’ end. To complement this approach, the probes on the arrays are designed to cover the entire length of each transcript. Thus, a single chip provides approximately 200,000 probes for 100,000 exons to 20,000 annotated genes and allows interrogation of quantitative differences in specific mRNA transcripts, including splice variants, at the exon level. We adapted a method using whole gene arrays and open-source analytical tools within R/Bioconductor, which allowed us to interrogate the microarray data set for the presence and extent of alternative splicing across the genome that resulted from BPA treatment. Thus, a major outcome of this work is the development of bioinformatics approaches that allow us to interrogate the splicome using standard microarray datasets.

By applying this methodology, we showed that a number of genes with diverse functions in hESCs were alternatively spliced in response to BPA treatment. Two patterns were observed. In the first, BPA and estrogen had similar effects suggesting common pathways. In the second, BPA had effects that were not observed in the estrogen-treated samples. These results suggest that in the hESC system BPA had estrogenic and nonestrogenic effects.

Interestingly, TIE1 transcripts encoding an angiopoietin receptor expressed by endothelial cells and hematopoietic precursors was alternatively spliced in response to both doses of BPA (but not estrogen). TIE1 regulates cell-adhesion molecules (VCAM-1, E-selectin and ICAM-1) and plays a key role in angiogenesis and blood vessel stability. Its role in early development is poorly understood, but alternatively spliced transcript variants encoding multiple isoforms with biological activity in vascular and inflammatory pathways have been described.

Another gene whose splicing was affected by BPA is SPG7, encoding paraplegin, part of the m-AAA protease complex responsible for ribosome assembly. Best known for mutations that cause spastic paraplegia type 7, altered splicing of this transcript has the potential to globally interfere with mRNA processing and translation, thereby affecting diverse cellular processes including membrane trafficking, organelle biogenesis, protein folding and proteolysis. A splice variant of SPG7 was recently described in mice that is implicated in neurodegenerative processes. Other pathways that our data suggest may be impacted in BPA-induced splicing variation included growth factor signaling, cell motility and mitosis.

Alternative splicing is a central process for modulation of gene expression, affecting over 90% of human genes and greatly increasing the number of distinct protein products encoded in the genome. Constitutive and alternative splicing pathways are well-characterized, involve hundreds of genes and are known to be affected by various drugs and xenobiotics. Our data showing BPA-induced disruption of pre-mRNA splicing in hESCs suggest that gestational exposure to this ubiquitous environmental chemical may interfere with early development by mechanisms that involves changes in protein isoform expression.

To pursue this hypothesis, we have extended our analyses to include specific inquiries into splicing changes induced by BPA and other environmental chemicals we are testing. These include disruptions in splicing machinery as well as changes observed in transcripts with known roles in controlling hESC renewal in an undifferentiated state or differentiation into cells with characteristics of differentiated embryonic lineages. In addition, the microarray datasets we have generated through this work, in both control (untreated) and test conditions, have formed the foundation for incorporating the transcriptome of hESCs into studies we are now carrying out that monitor changes in the epigenome (DNA methylation and histone modifications) that accompany altered transcription and pre mRNA splicing in response to xenobiotic exposures. 

Pilot Study: Predictors of Maternal Exposure to BPA during the Second Trimester of Pregnancy:

We developed the BPA Exposure Questionnaire based on literature reviews of human exposure to BPA and measurements of BPA in various food and consumer products, and was used to evaluate dietary and non-dietary sources of exposure to BPA. The survey instrument included 197 questions regarding consumption of foods and beverages that could be contaminated with BPA due to packaging or preparation as well as occupational and non-occupational contact with paper receipts. Specifically, we asked about foods and beverages packaged in cans, cartons or paper, or served on paper plates, napkins or cups, as well as wine and beer consumption. We asked questions to capture both short-term (i.e., "today," "yesterday") as well as long-term dietary practices in order to assess the effects of acute and continuous BPA exposure. Finally, we also included questions about knowledge and avoidance of BPA. Seven percent of our study sample completed a self-administered questionnaire (n = 8) as part of the field testing of the questionnaire, while the remaining 93% completed an interview-administered survey supported by pictures and cue-cards (the BPA Exposure Questionnaire is available upon request). Previously, we identified that the length of the questionnaire was interfering with study recruitments so we reduced the number of questions based on preliminary responses to the questionnaire. Additional medical and demographic information (such as age, race/ethnicity, medications taken, smoking status etc.) were obtained from patient medical charts. We have completed all data entry and data validation for questionnaire and medical charts data in accordance with our Quality Management Plan. Among the 181 women recruited, 112 participants completed a questionnaire assessing potential sources of BPA exposure, and provided a urine sample sufficient for BPA and creatinine analysis. In addition to the questionnaire data, we have also collected 80 matched pairs of fasting and non-fasting maternal urine (from both days of the medical procedure).

Results: The questionnaire data reflect the socioeconomic status of our study population: 65% percent of participants had 12th grade or lower education, 81% used public health insurance, and 54% received food stamp assistance. We also have found that our study population consumes high quantities of fast foods and other paper-packaged take-out food, with a mean of 6 times/week. Total BPA concentration measured in our study population are up to three times higher compared to other studies measuring BPA in pregnant women in the United States and other countries worldwide.

From preliminary data, maternal urinary conjugated BPA (BPA glucuronide and BPA sulfate) levels were positively associated with educational attainment, non-African American ethnicity, household income, occupational and non-occupational exposure to paper receipts and use of food processors, and negatively associated with wine consumption. Unconjugated BPA was negatively associated with maternal BMI. Our initial analysis indicates that receipt-related BPA exposure is a strong predictor of maternal urinary BPA, and can come from both occupational and non-occupational receipt exposures. Further analysis is warranted, but if confirmed, it would provide scientific evidence for an important, yet often neglected, route of exposure. Another notable finding is that participants who have knowledge of BPA do not have lower urinary BPA levels, despite 40% of participants stating that they know about BPA and 27% of participants stating that they avoid BPA. A manuscript on results of urinary BPA levels and potential sources of BPA exposure is currently under review at Environmental Sciences and Technology. Some preliminary results have also been presented as abstracts or posters at conferences, such as the BPA Grantee Meeting, 2012, the annual Children’s Center Meeting, 2013, and the annual International Society of Environmental Epidemiology (ISEE) Conference, 2013. Fasting urinary BPA levels data and questionnaire results are currently still in data analysis phase. 

Community Outreach and Translation Core

Health Professional Outreach and Education Provided support to the American Congress of Obstetricians and Gynecologists (ACOG) on reproductive environmental health pursuant to its development of a Committee Opinion. In collaboration with ACOG, we surveyed the attitudes, beliefs and practices of U.S. obstetricians and gynecologists to inform our efforts to advance the science among reproductive health professionals; nominated Jeanne Conry, M.D., Ph.D., for EPA’s Environmental Health Champion award - EPA Administrator presented the award to Dr. Conry at UCSF on January 8, 2012; co-organized and attended a September 6-7, 2012, meeting of clinicians and scientists to explore issues related to prenatal environmental exposures and health outcomes. The meeting launched an ongoing partnership to address environmental health during the prenatal and preconception period, known as the Reproductive and Children’s Environmental Health Working Group; Dr. Woodruff presented a lecture to UCSF medical students on reproductive environmental health, possibly the first time the topic was a requirement for medical students; Dr. Gould organized medical students at UCSF around the topic at Student Organizing Fair Day at UCSF, and through a follow-up, meetings to advance students’ ideas for lectures about environmental health as an elective in their curriculum; Dr. Gould served on the Preconception Health Care Council and attended quarterly meetings in Sacramento, CA; held quarterly meetings of our From Advancing Science to Ensuring Prevention Alliance (FASTEP) and collaborated throughout the year with our FASTEP partners; Dr. Gould served on the UCSF Academic Senate Sustainability Task Force, which has the aim of implementing university-wide practices beneficial to environmental and public health; Dr. Gould served as a delegate to the California Medical Association and on the Santa Clara County Medical Association’s Environmental Health Committee. In 2012, CMA adopted 6 policies related to improved environmental health. Dr. Gould participated in a Reproductive Health Training at Commonweal, November 13-15, 2012.

Navigating the Science - Completed the first case study demonstrating proof of concept of the Navigation Guide, a systematic and transparent method to synthesize environmental health research to make it actionable by decision-makers in clinical and policy spheres; conducted extensive outreach and education on the method and expanded our network of over 60 clinical and environmental health collaborators on the Navigation Guide Work Group; held 3 Work Group webinars to gather input on the methods development and disseminate our findings.

Disseminated the Science - Disseminated 21,924 hardcopy and 60,435 PDF copies of our All that Matters brochures to health professionals, patients and the public; made over 14 presentations; published 7 articles directed to health professionals featured in Scientific American, Environmental Health News, the San Francisco Chronicle, and references in the New York Times; participated in a January 17, 2013 Informational Briefing on How the Environment Affects Children’s Health - Reports From Children’s Environmental Health Research Leaders.

 

Conclusions:

Project 1: Assessing Maternal and Fetal Exposures to Chemicals during the Second Trimester:

Among our study participants, 100% had detectable BPA levels in non-fasting urine. Levels of total BPA, BPA glucuronide, BPA sulfate, and unconjugated BPA are up to three times higher compared to other studies measuring BPA in pregnant women in the United States and other countries worldwide, possibly due to underlying demographic and behavioral characteristics of our unique study population (lower income, 40% smokers, racially diverse population). 

Project 2: Assessing the Effects of BPA Exposure on Early Human Development:

Evidence from our group and others increasingly supports the hypothesis that endocrine disruptors like BPA exert at least a portion of their developmental effects by altering the epigenome in early development.

Pilot Study: Predictors of Maternal Exposure to BPA during the Second Trimester of Pregnancy:

Our initial analysis indicates that receipt-related BPA exposure is a strong predictor of maternal urinary BPA, and can come from both occupational and non-occupational receipt exposures. 


Journal Articles: 16 Displayed | Download in RIS Format

Other center views: All 79 publications 20 publications in selected types All 16 journal articles
Type Citation Sub Project Document Sources
Journal Article Gerona RR, Woodruff TJ, Dickenson CA, Pan J, Schwartz JM, Sen S, Friesen MW, Fujimoto VY, Hunt PA. Bisphenol-A (BPA), BPA glucuronide, and BPA sulfate in midgestation umbilical cord serum in a northern and central California population. Environmental Science & Technology 2013;47(21):12477-12485. R834678 (Final)
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  • Journal Article 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. R834678 (Final)
    R835433 (2014)
    R835433 (Final)
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  • Journal Article 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. R834678 (Final)
    R835433 (2014)
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  • Journal Article 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.). R834678 (Final)
    R835433 (2014)
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  • Journal Article Sutton P, Conry J, Rodriguez P, Woodruff T. The Navigation Guide: an evidence-based tool to bridge the gap between clinical practice and environmental health science. San Francisco Medicine: Journal of the San Francisco Medical Society 2010;83(3):25-26. R834678 (Final)
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  • Journal Article Sutton P, Giudice LC, Woodruff TJ. Reproductive environmental health. Current Opinion in Obstetrics and Gynecology 2010;22(6):517-524. R834678 (2012)
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  • Journal Article Sutton P, Woodruff TJ, Vogel S, Bero LA. Conrad and Becker's "10 Criteria" fall short of addressing conflicts of interest in chemical safety studies. Environmental Health Perspectives 2011;119(12):A506-507. R834678 (2010)
    R834678 (2011)
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  • Journal Article Sutton P, Wallinga D, Perron J, Gottlieb M, Sayre L, Woodruff T. Reproductive health and the industrialized food system: a point of intervention for health policy. Health Affairs 2011;30(5):888-897. R834678 (2010)
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  • Journal Article Sutton P, Woodruff TJ, Conry J, Giudice LC. Toxic matters and fertility: what can a doctor do? San Francisco Medicine: Journal of the San Francisco Medical Society 2012;85(5)20-22. R834678 (2012)
    R834678 (Final)
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  • Journal Article Sutton P, Woodruff TJ, Perron J, Stotland N, Conry JA, Miller MD, Giudice LC. Toxic environmental chemicals: the role of reproductive health professionals in preventing harmful exposures. American Journal of Obstetrics and Gynecology 2012;207(3)164-173. R834678 (2010)
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  • Journal Article Sutton P, Woodruff TJ. Risk communication and decision tools for children's health protection. Birth Defects Research Part C: Embryo Today: Reviews 2013;99(1):45-49. R834678 (2012)
    R834678 (Final)
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  • Journal Article 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. A round robin approach to the analysis of bisphenol A (BPA) in human blood samples. Environmental Health 2014;13(1):25 (20 pp.). R834678 (Final)
    R834678C001 (Final)
    R835436 (2014)
    R835436 (2015)
    R835436 (2017)
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  • Journal Article Woodruff TJ, Sutton P. Pulling back the curtain: improving reviews in environmental health. Environmental Health Perspectives 2010;118(8):a326-a327. R834678 (Final)
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  • Journal Article Woodruff TJ, Sutton P, Navigation Guide Work Group. An evidence-based medicine methodology to bridge the gap between clinical and environmental health sciences. Health Affairs 2011;30(5):931-937. R834678 (2010)
    R834678 (2011)
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  • Journal Article Woodruff TJ, Burke TA, Zeise L. The need for better public health decisions on chemicals released into our environment. Health Affairs 2011;30(5):957-967. R834678 (2011)
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  • Journal Article 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. R834678 (Final)
    R835433 (2014)
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  • Supplemental Keywords:

    Risk assessment, metabolism, bioavailability, ethnic groups, endocrine disruptors, sensitive populations, decision making, measurement methods, RFA, Health, Scientific Discipline, Health Risk Assessment, Biochemistry, Children's Health, Biology, prenatal exposure, biological response, assessment of exposure

    Relevant Websites:

    UCSF Program on Reproductive Health and the Environment Exit

    Progress and Final Reports:

    Original Abstract
  • 2010 Progress Report
  • 2011 Progress Report
  • 2012 Progress Report
  • Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R834678C001 Assessing Maternal and Fetal Exposure to Chemicals
    R834678C002 Assessing the Effects of BPA Exposure on Early Human Development
    R834678C003 (Pilot Study): Predictors of Maternal Exposure to BPA During Pregnancy