Grantee Research Project Results

2010 Progress Report: Formative Center for the Evaluation of Environmental Impacts on Fetal Development

EPA Grant Number: R834594
Center: 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 , Thanos Scientific Consulting Group , Women & Infants Hospital of Rhode Island
Current 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, 2010 through February 14,2011
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:

The research focuses on collecting human fetal tissues to correlate morphological and molecular biomarkers with exposures to common environmental pollutants and stressors. Three research projects examine xenotransplanted tissues as models for dysregulation of tissue differentiation and epigenetic programming by environmental agents.

Progress Summary:

Research Project 1 (Gruppuso) Human Fetal Liver and the Metabolic Syndrome

We have been focused on developing a model in which human fetal liver is transplanted into nude rats. Tissue from a number of human donors has been transplanted into nude rats at the renal subcapsular and subcutaneous sites. Donors have ranged from 13 to 22 weeks gestational age. The pre-implant tissues have had the appearance of normal fetal liver with no evidence of necrosis. However, transplanted tissue has consistently shown signs of hepatocyte necrosis at times ranging from 24 to 72 hr. Results indicated that the transplanted liver tissue was losing viability and, when viability is satisfactory, hepatocytes are not engrafting. In order to abrogate cell-mediated immunity (active in the nude rats originally used) or inadequate vascularization, we are investigating the use of SCID mice.

Research Project 2 (Boekelheide) Human Fetal Prostate and Endocrine Disruption

Developmental exposures to estrogenic endocrine disrupting chemicals may play a large role in prostate cancer. In this project, human fetal prostates from 2^nd trimester spontaneous abortions are being xenotransplanted into the renal subcapsular space of immunodeficient rodent hosts. Following characterization of the developmental sequence in these xenografts, estradiol exposure during early development will be evaluated. Semi-quantitative histopathological assessment will be combined with immunohistochemical staining and gene expression analysis to identify estradiol-induced alterations in ductal morphogenesis and carcinogenesis.

Research Project 3 Human Fetal Lung, Arsenic Exposure, and Tissue Remodeling

Our work has focused on the establishment of the human fetal lung xenograft model. Human fetal lung tissues, derived from 11 13-22 weeks gestation stillbirths, were implanted below the kidney capsule (n = 32 recipient animals) and/or subcutaneously (n = 12 animals). Three to four lung samples (0.5 to 2 mm³) were implanted in each kidney and, in some cases, subcutaneously. Rats were sacrificed and grafts dissected at 2 and 4 weeks post-transplantation. Lung grafts were snap-frozen for future molecular genetic/epigenetic studies or formalin-fixed for morphologic studies. From these first studies, we conclude that harvesting, implantation and retrieval of human fetal lung xenografts is feasible, and that the development of human fetal lung xenografts parallels that of human fetal lungs in utero.

We will use the human fetal lung xenotransplantation model to investigate the effects of environmentally relevant arsenic exposures in utero on postglandular lung remodeling. These studies will give insight into the etiology of arsenic-induced respiratory disease and lung cancers and may lead to the elucidation of molecular targets and biomarkers of inorganic arsenic exposure during lung development. Furthermore, this pilot study will provide a framework for future studies investigating the effects of other environmental toxicants on developing human lungs.

Future Activities:

Project 1: If ongoing experiments indicate that the liver xenotransplants are not surviving, then we will consider options, including transplantation to the surface of the liver to allow for faster and more robust vascularization of the transplanted tissue. In addition to these two approaches, we have begun to explore the possibility of using an in vitro approach, liver slices.

Project 2: We will initiate the planned high density arrays for characterizing DNA methylation status in the transplants.

Project 3: We are poised to start the arsenic exposure experiments. Recipient rats will be exposed to water containing environmentally relevant levels of arsenic (10 or 100 ppb) or control water (0 ppb). The effects of arsenic exposure on lung growth dynamics, gene expression and epigenetics will be studied in close collaboration.

Journal Articles: 8 Displayed | Download in RIS Format

Publications Views
Other center views:	All 13 publications	8 publications in selected types	All 8 journal articles

Publications
Type	Citation	Sub Project	Document Sources
Journal Article	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)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: EHP-Full Text PDF Abstract: EHP-Abstract and Full Text HTML
Journal Article	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)	Full-text from PubMed Abstract from PubMed Associated PubMed link Abstract: Wiley-Abstract Exit
Journal Article	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)	Full-text from PubMed Abstract from PubMed Associated PubMed link Abstract: Taylor & Francis-Abstract Exit
Journal Article	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)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: EHP-Full Text PDF Abstract: EHP-Abstract and Full Text HTML
Journal Article	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)	Full-text from PubMed Abstract from PubMed Associated PubMed link Abstract: Taylor & Francis-Abstract Exit
Journal Article	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)	Full-text from PubMed Abstract from PubMed Associated PubMed link Abstract: Wiley-Abstract Exit
Journal Article	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)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: Oxford-Full Text PDF Exit Abstract: Oxford-Abstract and Full Text HTML Exit
Journal Article	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)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit

Supplemental Keywords:

in utero exposure, mammalian, metals, bisphenol A, developmental biology, perinatal programming, Health, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, Health Risk Assessment, Risk Assessments, Biology, Risk Assessment, biological pathways, children's health, fetal exposure, bioavailability, developmental effects, perinatal exposure, biochemical research

Relevant Websites:

http://biomed.brown.edu/CEH/ Exit

Progress and Final Reports:

Original Abstract

2011 Progress Report

2012 Progress Report

Final Report

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

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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.