Developmental reprogramming is an important mechanism by which early life exposures to environmental agents increase susceptibility to adult disease. For xenoestrogens such as BPA, additional research is required to understand how specific estrogen receptor (ER) subtypes and genomic vs. nongenomic signaling mediate this developmental reprogramming. Xenoestrogens can act as agonists or antagonists in different tissues, also pointing to the need for a better understanding of how specific ER coregulators (CoR) influence their activity. Finally, additional research is needed to identify the epigenetic effects of reprogramming that persist into adulthood and underlie adult disease, including prostate cancer (PCa). This Grand Opportunity (GO) grant addresses these research needs with an integrated, mechanistic assessment of how BPA induces developmental reprogramming to increase susceptibility to prostate carcinogenesis. The Specific Aims are 1) Global analysis of the BPA epigenome to define changes associated with developmental reprogramming and increased PCa risk and 2) Define the role of specific ER subtypes and CoRs as determinants of BPA activity. This project is appropriate for a GO grant: it is large;multi-investigator, multi-institutional, multi-disciplinary;will address a specific research need and make a significant research impact in 2 years. The research team is uniquely poised to accomplish the objectives, the project is ready to implement now, utilizes innovative technologies, and the results will advance the NIH mission to improve health and prevent disease. Neonates exposed to BPA during prostate development will be followed into adulthood to quantitate BPA-associated prostate lesions and susceptibility to develop lesions will be correlated with BPA induced changes in the prostate epigenome. These studies will fill specific data gaps in the BPA literature with oral exposures, internal measurements of dose and dose-response data for relevant disease endpoints (PIN and carcinoma). The in vivo studies will be informed by in vitro, multi-parametric mechanistic studies to elucidate how specific ERs (?, or ? homo- and ?/? hetero-dimers), nongenomic signaling and the p160 class CoRs (SRC-1, -2, -3) determine the effects of BPA in prostate epithelial cells. The prevalence of PCa is increasing world-wide with 1 in 6 men in the US currently at risk for developing this disease. There is a tremendous need to understand the early origins of PCa to determine if additional public health measures are necessary to prevent exposure to BPA, or other xenoestrogens, during critical windows of development. This highly novel, scientifically vigorous, multidisciplinary approach to model the developmental effects of BPA on the prostate will set new standards for weight-of-evidence assessment of the toxicology of BPA and other endocrine disruptors, and will significantly advance research in the fields of gene-environment interaction, non-Darwinian disease susceptibility and hormone receptor action.

PUBLIC HEALTH RELEVANCE: The broad question we wish to address in this proposal is how environmentally relevant low doses of BPA induce a long-lasting chromatin state via epigenetic reprogramming to increase the susceptibility to prostate carcinogenesis in adult life. The identification of a developmentally reprogrammable BPA-epigenome associated with prostate carcinogenesis and its dynamic changes throughout life will open opportunities to identify exposed and at-risk populations, which is the first step toward prostate cancer prevention. More importantly, the studies proposed in this application will provide the new and critical mechanistic data on the mechanism of action of BPA to assist agencies in setting regulatory guidelines for the safe use of BPA.

RC2ES018789

2009-09-24

2013-07-31