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PROSTATE AND ENDOCRINE DISRUPTION
Impact/Purpose:
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 the prostate as a model to examine the developmental effects of endocrine disrupting chemicals. Following characterization of the maturation sequence, 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: Prostate cells 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.
Description:
This project offers the very distinct advantages of human relevance and enhanced susceptibility in the evaluation of environmental impacts on prostate development. The goal of this pilot project is to build a 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.