Grantee Research Project Results
2010 Progress Report: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers
EPA Grant Number: R834678Center: Center for Integrative Research on Childhood Leukemia and the Environment - 2015
Center Director: Metayer, Catherine
Title: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers
Investigators: Woodruff, Tracey J. , Fisher, Susan J. , Steinauer, Jody , McMaster, Michael , Stotland, Naomi
Current 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 Period Covered by this Report: May 1, 2010 through April 30,2011
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 , Human Health
Objective:
RD834678C001: Assessing Maternal and Fetal Exposures to Chemicals during the Second Trimester
The specific aims of the project are to (1) compare maternal and fetal exposures to BPA during the second trimester, and (2) explore the feasibility and accuracy of using maternal biological biomonitoring results to predict fetal exposures.
RD834678C002: Assessing the Effects of BPA Exposure on Early Human Development
The objective of this research project is to gain an understanding of the effects of BPA exposure on early human development using human embryonic stem cells (hESC) as a model system. The specific aims are to (1) analyze the impact of BPA exposure on hESC gene expression, and (2) 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. The specific aims of the project have not been modified.
RD834678C003: Predictors of Maternal Exposure to BPA during the Second Trimester of Pregnancy
The specific aims of the project are to (1) investigate the determinants of maternal exposures to BPA during the second trimester of pregnancy, and (2) characterize the change in BPA levels in pregnant women associated with fasting.
Core B: Pregnancy Exposure to Environmental Contaminants (PEEC) Community Outreach and Translation Core (COTC)
The aims of the PEEC COTC are to (1) communicate the meaning of the PEEC Formative Center's research broadly, and (2) advance the integration of the science linking environment to children's health in clinical and policy arenas to accelerate prevention.
Progress Summary:
RD834678C001: Assessing Maternal and Fetal Exposures to Chemicals During the Second Trimester
We have developed a questionnaire on sources of exposure to BPA and have set up the infrastructure for the grant. Between September 2010 and August 2011, we recruited 110 women into the study and have collected 60 serum and 71 urine from women for the first day of their visit and 74 serum and 78 urine from women the second day of the visit, which is the day of their medical procedure. From the medical procedure, we have collected 29 umbilical cord bloods, 87 placentas and 91 fetal livers. Our collaborators in the Department of Laboratory Medicine at San Francisco General Hospital have undertaken method development to measure levels of BPA in maternal serum and urine.
RD834678C002: Assessing the Effects of BPA Exposure on Early Human Development
Experiments to date have focused on determining the effective doses of BPA, in the range of exposures documented to occur in pregnant women, that result in changes in transcription of specific sets of genes in cultured hESCs. For these experiments, we have focused on analyses of the UCSF4 cell line, which is included on the Federal Registry. Initial studies were carried out to determine the effective doses and time in culture when BPA effects were observed. We are adding BPA to hESC cultures in amounts that are comparable to the concentrations that have been measured in pregnancy (~10 ng/mL). We are also including lower (1 ng/mL) and higher (100 ng/mL) concentrations. As controls, we add 0.5 nM estradiol (E2) and 0.001% EtOH, the vehicle in which BPA was dissolved prior to addition to the medium.
We first sought to determine if acute exposure to BPA had significant effects of hESC differentiation and/or proliferation. Initial experiments failed to detect any effects of acute BPA exposure for 3 days on hESC self-renewal as monitored by the expression of a set of stage specific antigens which we routinely use to monitor pluripotency (e.g., SSEA4, Oct3/4, Nanog, GATA4) and differentiation to the major germ layers—ectoderm, mesoderm and endoderm. Accordingly, we adopted a chronic exposure model in which the cells were cultured for 3 passages in control and experimental conditions, which is designed to mimic the in vivo situation in which individuals are continuously exposed to environmental chemicals. We monitored the results in terms of mRNA levels for classical steroid receptors (ERα, ERβ, AR), orphan estrogen receptors (ERRα, ERRβ, ERRγ), PPARγ, alphafetoprotein (an endoderm marker) Brachyury (a mesodermal marker) and PAX6, which controls the proliferation of neuroepithelial precursors, and stemness markers including SSEA4 andOct3/4.
qRT-PCR showed that BPA upregulated transcription of genes encoding steroid receptors and steroid responsive genes. Markers of stemnes and differentiation were also modulated by BPA treatment. Representative data showing that BPA upregulated expression of mRNA encoding ERRα is shown in Fig. 1. Interestingly, nonmonotonic effects were evident for ERRα and PAX6 as the largest increases were in cultures that were dosed with 10 nM BPA as compared to 100 mM of this compound. Similar results have been reported by other investigators studying different cell types. Thus, the results of these experiments suggest that BPA promotes hESC differentiation, possibly toward mesoderm and away from neuroectoderm.
RD834678C003: Predictors of Maternal Exposure to BPA during the Second Trimester of Pregnancy
The first several months of the grant were spent developing and pilot testing a questionnaire, which covers sources of BPA exposure through foods and beverages stored in containers that may contain BPA, and other sources that have been recently identified, such as cash register receipts. We modified the questionnaire in October 2010 from self-administered to an interview format in order to accommodate study participants. We have recruited and collected questionnaire data from over 110 study participants. However, we have identified that the length of the questionnaire was interfering with recruitment. Subsequently, we evaluated the responses to the questionnaire and identified questions that were duplicative, or had less than a 10–20% response rate. We have also developed a database using REDCap to enter the questionnaire data and have completed data entry and data validation in accordance with our Quality Management Plan.
Core B: PEEC COTC
- Hired Jessica Trowbridge at 100 percent to advance our COTC's communication strategy and other COTC activities (June 2011).
- Strengthened our network of collaborators, including convening two meetings of PRHE's From Advancing Science to Ensuring Prevention (FASTEP) Advisory Council (February and September 2011).
- Published 11 blogs about our scientists, research and related topics in Mission Local, a local online and print newspaper for the San Francisco Mission District.
- Communicated the results and public health significance of PRHE research via 45 media stories, including in the San Francisco Chronicle; USA Today online; LA Times; and interviews by KCBS and KCBS Radio.
- Contributed to NIEHS news article "Advising Parents in the Face of Scientific Uncertainty: An Environmental Health Dilemma."
- Redesigned our website. We are currently working with a Web design company to implement our improved website. Our website redesign includes better graphics, compatibility with mobile devices, and integration and usability for our collaborators.
- Advanced the development of a novel methodology to translate the science linking the environment and health in clinical and policy spheres. To this end, we published the methodology in Health Affairs, convened the inaugural meeting of the Navigation Guide Working Group, and initiated the application of the Navigation Guide methodology to one or more case studies including the relationship between exposure to perflourinated compounds and birth weight.
- Produced and distributed a wide range of educational materials to support the integration of the science in clinical spheres, including four patient-centered brochures co-branded with FASTEP and other collaborators: Toxic Matters (low-literacy versions in English and Spanish); Work Matters; What To Eat?; and Pesticides Matter: A Primer for Reproductive Health Professionals.
- Worked to integrate the science into the purview and activities of the American Congress of Obstetricians & Gynecologists (ACOG) and other professional societies. PRHE served as a member of ACOG District IX's (California) legislative committee and as science advisors on reproductive environmental health issues to ACOG District IX and national ACOG; PRHE helped to bring together ACOG and the U.S. Environmental Protection Agency (EPA) leadership, who in turn identified potential areas of future collaboration; we also conducted a survey of practicing obstetricians' knowledge, practices and attitudes related to the environment and reproductive health in collaboration with ACOG. We were invited to serve as a member of the California Preconception Care Council, and we compiled and disseminated a searchable database of policy statements from health professional organizations related to environmental health: http://prhe.ucsf.edu/prhe/pdfs/Professional%20Statements%20Database.pdf. As listed below, we made many presentations to clinicians and published articles in publications read by obstetricians.
- Collaborated on national efforts to strengthen and build a bridge between the Pediatric Environmental Health Specialty Units and obstetricians and their professional organizations in order to ensure a strong referral network for practicing obstetricians who identify a hazardous environmental or occupational exposure.
Future Activities:
RD834678C001: Assessing Maternal and Fetal Exposures to Chemicals during the Second Trimester
In the coming year we plan to recruit an additional 50 women into the study in order to increase the projects sample size and to collect BPA-free serum. Methods development is almost complete for BPA analysis in urine and serum. We anticipate having data on the urine levels by the end of 2011, with serum shortly to follow. Method development for placenta and fetal liver will take place during December of 2011 and amniotic fluid and cord blood during the first quarter of 2012.
RD834678C002: Assessing the Effects of BPA Exposure on Early Human Development
The project is progressing as expected. With regard to Aim 1, performance of transcriptional microarrays to determine the effects of BPA exposure on hESC gene expression, we are currently treating cultures of the UCSF4 hESC line with BPA, estradiol and the appropriate controls to collect and purify RNA that will be used for the microarrays. With regard to Aim 2 experiments, these will commence when we get the transcriptional microarray results.
RD834678C003: Predictors of Maternal Exposure to BPA during the Second Trimester of Pregnancy
In the coming year, we plan to administer the modified questionnaire on an additional 50 participants in order to increase the sample size of our study population. Further analysis will be conducted once additional data has been collected from our study team.
Core B: PEEC COTC
We will continue to actively communicate the meaning of the science broadly through presentations; publications; and our interactive website, blog, print, and other media and social network channels. To advance our efforts to integrate environmental health science in clinical spheres, we will be leading the Navigation Guide Working Group and completing and disseminating our case studies of the application of the Navigation Guide methodology in collaboration with colleagues at EPA and the National Toxicology Program. We will also be conducting a formal evaluation of clinician uptake of our patient-centered brochure, Toxic Matters, and analyzing and disseminating the results of our research on obstetrician knowledge, attitudes and practices. We will continue to work to strengthen and increase collaboration between the Pediatric Environmental Health Specialty Units and obstetricians and their professional organizations in order to ensure a strong referral network for practicing obstetricians who identify a hazardous environmental or occupational exposure. Together, these activities will inform a strategy to design and implement a randomized controlled trial of a clinical intervention on patient, clinical, health care institutional, and policy levels to prevent or reduce preconception and prenatal exposure to environmental contaminants.
Journal Articles: 11 Displayed | Download in RIS Format
| Other center views: | All 73 publications | 15 publications in selected types | All 11 journal articles |
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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. |
R834678C001 (Final) R834678C003 (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. |
R834678 (Final) R835433 (Final) |
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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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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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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) R834678 (2011) R834678 (2012) |
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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) |
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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) R834678 (2011) R834678 (2012) |
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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) |
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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. A round robin approach to the analysis of bisphenol A (BPA) in human blood samples. Environmental Health 2014;13(1):25 (20 pp.). |
R834678C001 (Final) R835436 (2014) R835436 (2015) R835436 (2017) |
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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) R834678 (2012) |
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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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Supplemental Keywords:
Risk assessment, metabolism, bioavailability, ethnic groups, endocrine disruptors, sensitive populations, decision making, measurement methods, Navigation Guide, preconception, prenatal;, RFA, Scientific Discipline, Health, Health Risk Assessment, Biochemistry, Children's Health, Biology, prenatal exposure, biological response, assessment of exposureRelevant Websites:
Advising Parents in the Face of Scientific Uncertainty: An Environmental Health Dilemma
MissionLocal Exit
An Ecological Approach to Healthy Aging Across the Lifespan Exit
Navigating the Science: Evaluating Research Quality Exit
Progress and Final Reports:
Original Abstract Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
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
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.