Grantee Research Project Results

Final Report: Prostate and Endocrine Disruption

EPA Grant Number: R834594C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R834594
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Formative Center for the Evaluation of Environmental Impacts on Fetal Development
Center Director: Boekelheide, Kim
Title: Prostate and Endocrine Disruption
Investigators: Boekelheide, Kim
Institution: Brown University
EPA Project Officer: Hahn, Intaek
Project Period: December 1, 2009 through November 30, 2012
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:

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 was tested by xenotransplanting human fetal prostate into immunodeficient rodent hosts and studying the effects of estradiol exposure on maturation and development. Specific Aims 1 and 2 were completed, clearly demonstrating an effect of estradiol exposure on maturation and development. Specific Aim 3 has been partially fulfilled, evaluating epigenetic alterations induced by estradiol exposure on the developing human fetal prostate. The evaluation of other endocrine disrupting chemicals (genistein, bisphenol A) was not achieved because of running out of time. The originally stated Specific Aims, shown below, provided a roadmap to guide the project:

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.

Summary/Accomplishments (Outputs/Outcomes):

Significant Results (Positive and Negative):

Human fetal prostate can be xenotransplanted into either rat or mouse immunodeficient hosts and remains viable.
The xenotransplanted fetal prostate tissue undergoes rapid proliferation and differentiation when exposed to an adult male hormonal host environment.
Immunohistochemical and gene expression analyses provide detailed information about the differentiation and maturation of the xenotransplanted prostate tissue.
Prostate maturation and differentiation follow a predictable histological and molecular sequence that is reminiscent of normal prostate development in the intact human, although much accelerated.
Estradiol exposure alters normal differentiation and maturation, producing histopathological and molecular alterations consistent with hyperplasia, including significantly increased proliferation in the epithelium.
Epigenetic effects of estradiol exposure are most prominent in the stroma, as determined by laser capture microdissection separation of stromal and epithelial prostate tissue.
The predominant stromal epigenetic effect was DNA hypomethylation.
In addition to the published manuscripts listed below, a manuscript titled Developmental exposure to estrogen alters differentiation and epigenetic programming in a human fetal prostate xenograft model is currently in review with Endocrinology

Conclusions:

This was a highly successful Pilot Project. Previous studies of early life exposure to xenoestrogens in rats showed induction of prostatic epithelial and stromal hyperplasia, inflammation, and prostatic intraepithelial neoplasia (PIN) lesions. We used our human fetal prostate xenograft model to evaluate the response of human fetal prostate implants to estrogen during both an early acute exposure, as well as an additional later exposure. Interestingly, in response to estrogen, the human prostate xenografts demonstrated primarily basal cell hyperplasia, while the endogenous rat prostate exhibited atypical hyperplasia.

Journal Articles on this Report : 4 Displayed | Download in RIS Format

Publications Views
Other subproject views:	All 4 publications	4 publications in selected types	All 4 journal articles
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	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	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

Supplemental Keywords:

In utero exposure, mammalian, metals, bisphenol A, perinatal programming, bioavailability, exposure assessment, biochemical research, intrauterine exposure, developmental effects, perinatal exposure, children's health, biological pathways, Health, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, POLLUTANTS/TOXICS, Health Risk Assessment, Risk Assessments, Biology, Chemicals, Risk Assessment, bioavailability, perinatal exposure, fetal exposure, children's health, biological pathways, developmental effects, endocrine disruptors, exposure assessment

Progress and Final Reports:

Original Abstract

2010

2011

Main Center Abstract and Reports:

R834594 Formative Center for the Evaluation of Environmental Impacts on Fetal Development

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.