Project 2: Human Fetal Prostate and Endocrine Disruption

Human Fetal Prostate and Endocrine Disruption
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.

We use 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 longterm 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.

Specific Aims:

• Characterize human fetal prostate xenograft development by histopathology,immunohistochemical staining, and gene expression.
• Identify alterations in differentiation and carcinogenic effects of estradiol exposure of fetal prostate xenotransplants.
• Use a genome-wide approach to investigate epigenetic alterations induced by endocrine disruptive exposures during human prostate development.

Personnel:

Kim Boekelheide, MD, PhD
Project Leader
Kim_Boekelheide@brown.edu
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Moses Sandrof
Research Assistant
Moses_Sandrof@brown.edu