With an increasing incidence worldwide. prostate adenocarcinoma is the most common non-skin cancer diagnosis and the second leading cause of death in men in the U.S. Estrogenicity during in utero development has been associated with later life risk of prostate adenocarcinoma, raising concern that early life exposures to endocrine disrupting chemicals may be contributing to this disease burden. This pilot project uses xenotransplantation of human fetal prostate (gestational age 12-22 weeks) as a model to examine the developmental effects of endocrine disrupting chemicals. Following characterization of the maturation sequence in the xenografts, dysregulation of this developmental sequence by estradiol exposure, with and without a second later exposure, will be determined. Histopathological and biomarker assessment will identify estradiol-induced pre-cancerous alterations in ductal morphogenesis, and the long-term effects of estradiol exposure, including the occurrence of prostatic intraepithelial neoplasia, will be identified. Building on this basic characterization of the model, early developmental exposures to the environmental endocrine disruptors bisphenol A and genistein will be compared with estradiol for epigenetic modifications. The working hypothesis is: Human fetal prostate xenotransplants respond to estrogenic endocrine disrupting chemical exposure with aberrant differentiation due to altered DNA methylation. Rodents have been useful models for the study of prostate carcinogenesis;however, spontaneous prostate neoplasia in rodents is rare while humans are uniquely susceptible. Therefore, this project offers the very distinct advantages of human relevance and enhanced susceptibility in the evaluation of environmental impacts on fetal prostate development. The goal of this pilot project is to build a human-based platform to evaluate the developmental origins of later life prostate disease associated with endocrine disrupting chemical exposure, focusing on the underlying epigenetic mechanisms that control disease induction and progression.

Public Health Relevance

The overarching goal of this Formative Center is to develop novel biomarkers for the adverse effects of environmental exposures that impact fetal development and produce childhood and adult disease. Using an interdisciplinary approach, research, educational. and training interventions will be designed to address the concerns that pregnant women, families, and communities have about environmental chemicals and the health of their developing children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory Grants (P20)
Project #
5P20ES018169-03
Application #
8375004
Study Section
Special Emphasis Panel (ZES1-LKB-G)
Project Start
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$48,268
Indirect Cost
$16,919
Name
Brown University
Department
Type
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Saffarini, Camelia M; McDonnell-Clark, Elizabeth V; Amin, Ali et al. (2015) Developmental exposure to estrogen alters differentiation and epigenetic programming in a human fetal prostate xenograft model. PLoS One 10:e0122290
Huse, Susan M; Gruppuso, Philip A; Boekelheide, Kim et al. (2015) Patterns of gene expression and DNA methylation in human fetal and adult liver. BMC Genomics 16:981
De Paepe, Monique E; Chu, Sharon; Hall, Susan J et al. (2015) Intussusceptive-like angiogenesis in human fetal lung xenografts: Link with bronchopulmonary dysplasia-associated microvascular dysangiogenesis? Exp Lung Res 41:477-88
Saffarini, Camelia M; McDonnell-Clark, Elizabeth V; Amin, Ali et al. (2015) A human fetal prostate xenograft model of developmental estrogenization. Int J Toxicol 34:119-28
Spade, Daniel J; McDonnell, Elizabeth V; Heger, Nicholas E et al. (2014) Xenotransplantation models to study the effects of toxicants on human fetal tissues. Birth Defects Res B Dev Reprod Toxicol 101:410-22
Garcia, Briana; Francois-Vaughan, Heather; Onikoyi, Omobola et al. (2014) Xenotransplantation of human fetal adipose tissue: a model of in vivo adipose tissue expansion and adipogenesis. J Lipid Res 55:2685-91
Saffarini, Camelia M; McDonnell, Elizabeth V; Amin, Ali et al. (2013) Maturation of the developing human fetal prostate in a rodent xenograft model. Prostate 73:1761-75
De Paepe, Monique E; Chu, Sharon; Heger, Nicholas et al. (2012) Resilience of the human fetal lung following stillbirth: potential relevance for pulmonary regenerative medicine. Exp Lung Res 38:43-54
Campion, Sarah; Catlin, Natasha; Heger, Nicholas et al. (2012) Male reprotoxicity and endocrine disruption. EXS 101:315-60
Panikkar, Bindu; Smith, Natasha; Brown, Phil (2012) Reflexive research ethics in fetal tissue xenotransplantation research. Account Res 19:344-69

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