Grantee Research Project Results
2012 Progress Report: Formative Center for the Evaluation of Environmental Impacts on Fetal Development
EPA Grant Number: R834594Center: Formative Center for the Evaluation of Environmental Impacts on Fetal Development
Center Director: Boekelheide, Kim
Title: Formative Center for the Evaluation of Environmental Impacts on Fetal Development
Investigators: Boekelheide, Kim , De Paepe, Monique E , Thanos, Christopher , Phipps, Maureen , Brown, Phil , Gruppuso, Phillip , Kostadinov, Stephan
Current Investigators: Boekelheide, Kim , De Paepe, Monique E , Thanos, Christopher , Phipps, Maureen , Brown, Phil , Gruppuso, Phillip
Institution: Brown University , Women & Infants Hospital of Rhode Island
EPA Project Officer: Hahn, Intaek
Project Period: February 15, 2010 through February 14, 2014
Project Period Covered by this Report: February 15, 2012 through February 14,2013
Project Amount: $1,189,575
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:
RD834594C001: Liver and the Metabolic Syndrome
Study the effect of environmental toxicants on human fetal development and the fetal origins of metabolic dysfunction in the offspring.
RD834594C002: The Effects of Endocrine Disruption on the Developing Human Fetal Prostate
Project 2 has been guided by the following working hypothesis: Exposure of the human fetal prostate to estrogenic chemicals during development results in epigenetic modifications that alter differentiation and predispose to carcinogenesis. This hypothesis is being tested by performing the following Specific Aims:
Specific Aim 1. Characterize the differentiation of human fetal prostate xenotransplants using immunohistochemical markers and gene expression following a time-course study.
Specific Aim 2. Examine the differentiation and carcinogenesis of human fetal prostate xenotransplants following estrogenic exposures.
Specific Aim 3. Investigate the epigenetic alterations induced by estradiol, genistein and bisphenol A exposure during human fetal prostate development using a genome-wide approach.
RD834594C003: Lung, Arsenic Exposure and Tissue Remodeling
This project is guided by the hypothesis that arsenic exposure of human fetal lung xenotransplants results in disrupted lung growth mediated by molecular and epigenetic alterations. The Specific Aims of the original application have remained unchanged. They are to: (1) develop and characterize a human fetal lung xenograft model of in utero arsenic exposure; (2) determine the effects of arsenic exposure on growth dynamics and gene expression in the developing human lungs; and (3) determine arsenic-induced epigenetic changes in the developing human lung.
Progress Summary:
RD834594C001: Liver and the Metabolic Syndrome
Our research project is still focused on the same overall goal—to assess the effect of environmental factors on the fetus with an emphasis on fetal origins of metabolic syndrome in the offspring. During the first year of the proposal, it became apparent that fetal liver transplantations were not feasible because of hepatocyte loss. We therefore initiated studies on a white adipose tissue (WAT) xenograft model.
The WAT model has proved successful. Implants are viable for up to 4 months. They display the normal histological phenotype of adipose tissue at all the time points beyond 2 weeks, which is the earliest date at which the transplants become established. Immunohistochemical characterization of the transplants indicates ongoing adipogenesis that declines slightly with time but is nonetheless persistent. We have also observed very active angiogenesis in these transplants.
It is well established that prenatal factors predispose the offspring to development of obesity, metabolic syndrome and type 2 diabetes. The significance of this project lies in its potential to develop a model system to study the relevant pathophysiological mechanisms. This is a goal that is not possible with available methodologies. Achieving this goal would permit us to study the effect of environmental toxicants on fetal development relating to postnatal metabolic syndrome and obesity. In addition, we hope to succeed in establishing a well-characterized model that can be used by other investigators.
RD834594C002: The Effects of Endocrine Disruption on the Developing Human Fetal Prostate
The basic characterization of the human fetal prostate xenotransplant model has been completed (Specific Aim 1). Using a wide variety of immunohistochemical markers, we have shown the progressive differentiation and proliferation of the stromal and epithelial compartments after xenotransplantation. Examining the implants at 7, 30, 90 and 200 days post-transplantation, epithelial and stromal compartments demonstrate differentiation as indicated by the epithelial marker prostate specific antigen (PSA), as well as the stromal marker caldesmon. The differentiation markers detected by immunohistochemistry are associated with complementary DNA methylation epigenetic modifications. For example, the promoter regions of proteins highly expressed in the stroma are relatively hypomethylated compared to these same regions in epithelium, and vice versa. In summary, our characterization of this model demonstrates the utility of the xenotransplant approach for studying human prostate development and possible disruptions of development resulting from endocrine disrupting chemical exposure.
We have completed the collection of samples and will soon begin to determine the effects of estrogen exposure on human fetal prostate xenografted into both rat and athymic nude mouse hosts (Specific Aim 2). The dosing paradigm evaluates the effects of exposure to estradiol at both early (7 and 90 days) and later-life time points (200 and 250 days) of human implants following xenotransplantation. After implantation, xenografts receive an “early-life” exposure to either corn oil or estradiol every other day for a total of three injections. Some xenografts are collected at 7 and 90 days, while those receiving a “later-life” exposure receive an additional dose of estrogen beginning at day 90 for 110 days (until 200 days postimplantation). Some xenografts are immediately collected at day 200, while some are allowed a recovery period and are collected at day 250 (Figure 1).
Figure 1.
 and gene expression (additional microarrays, additional confirmatory analyses). In addition, we will start to study of the effects of arsenic exposure on lung epigenetic marks using the material assembled during the previous years.</p>
</blockquote>
<p></p>
<br>
<strong>Journal Articles:</strong> <font size=)
8 Displayed | Download in RIS Format
| Other center views: | All 13 publications | 8 publications in selected types | All 8 journal articles |
|---|
| Type | Citation | ||
|---|---|---|---|
|
|
Boekelheide K, Blumberg B, Chapin RE, Cote I, Graziano JH, Janesick A, Lane R, Lillycrop K, Myatt L, States JC, Thayer KA, Waalkes MP, Rogers JM. Predicting later-life outcomes of early-life exposures. Environmental Health Perspectives 2012;120(10):1353-1361. |
R834594 (Final) R834594C002 (Final) |
|
|
|
De Paepe ME, Chu S, Hall S, Heger NE, Thanos C, Mao Q. The human fetal lung xenograft: validation as model of microvascular remodeling in the postglandular lung. Pediatric Pulmonology 2012;47(12):1192-1203. |
R834594 (2012) R834594 (Final) R834594C003 (Final) |
Exit |
|
|
De Paepe ME, Chu S, Heger N, Hall S, Mao Q. Resilience of the human fetal lung following stillbirth: potential relevance for pulmonary regenerative medicine. Experimental Lung Research 2012;38(1):43-54. |
R834594 (2012) R834594 (Final) R834594C003 (Final) |
Exit |
|
|
Heger NE, Hall SJ, Sandrof MA, McDonnell EV, Hensley JB, McDowell EN, Martin KA, Gaido KW, Johnson KJ, Boekelheide K. Human fetal testis xenografts are resistant to phthalate-induced endocrine disruption. Environmental Health Perspectives 2012;120(8):1137-1143. |
R834594 (Final) R834594C002 (Final) |
|
|
|
Panikkar B, Smith N, Brown P. Reflexive research ethics in fetal tissue xenotransplantation research. Accountability in Research 2012;19(6):344-369. |
R834594 (2012) R834594 (Final) |
Exit |
|
|
Saffarini CM, McDonnell EV, Amin A, Spade DJ, Huse SM, Kostadinov S, Hall SJ, Boekelheide K. Maturation of the developing human fetal prostate in a rodent xenograft model. The Prostate 2013;73(16):1761-1775. |
R834594 (2012) R834594 (Final) R834594C002 (Final) |
Exit |
|
|
Spade DJ, Hall SJ, Saffarini CM, Huse SM, McDonnell EV, Boekelheide K. Differential response to abiraterone acetate and di-n-butyl phthalate in an androgen-sensitive human fetal testis xenograft bioassay. Toxicological Sciences 2014;138(1):148-160. |
R834594 (Final) R834594C002 (Final) |
Exit Exit |
|
|
Thompson MR, Boekelheide K. Multiple environmental chemical exposures to lead, mercury and polychlorinated biphenyls among childbearing-aged women (NHANES 1999-2004): body burden and risk factors. Environmental Research 2013;121:23-30. |
R834594 (Final) |
Exit Exit Exit |
Supplemental Keywords:
Adipogenesis, in utero exposure, mammalian, metals, developmental biology, perinatal programming, human fetal prostate, differentiation, endocrine disrupting chemicals, arsenic, children's environmental health;, Health, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, Health Risk Assessment, Risk Assessments, Biology, Risk Assessment, bioavailability, fetal exposure, perinatal exposure, biological pathways, children's health, developmental effects, biochemical researchProgress 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).
R834594C001 Liver and the Metabolic Syndrome
R834594C002 Prostate and Endocrine Disruption
R834594C003 Lung, Arsenic Exposure, and Tissue Remodeling
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.