Developmental exposure to natural or environmental estrogens predisposes to prostate carcinogenesis with aging;however, the molecular underpinnings of this phenomenon are unclear. We present evidence that developmental reprogramming of the prostate by estrogens may be mediated, in part, through epigenetic alterations. Using methylation-sensitive fingerprinting (MSRP) as an initial screen for genome-wide methylation changes, we identified multiple prostatic genes whose methylation status was permanently altered in rats as a result of neonatal estradiol and bisphenol A (BPA) exposures at environmentally relevant doses. Detailed characterization of phosphodiesterase 4D4 (PDE4D4) and HPCAL, enzymes involved in cAMP breakdown and formation, respectively, revealed aberrant promoter CpG island methylation patterns with resultant changes in gene transcription as the animals aged. Importantly, these epigenetic alterations were associated with increased susceptibility to hormonal carcinogenesis of the rat prostate gland. Thus we hypothesize that early estrogenic """"""""imprinting"""""""" of the prostate gland with resultant predisposition to carcinogenesis with aging is mediated through epigenetic modifications which permanently affect gene expression in the gland. The objectives of the present proposal are to further characterize our model of developmental reprogramming by low dose estradiol or BPA, to characterize in detail the prostatic gene methylation and transcriptional alterations which result from early -life estrogenic exposures and to identify the methylation candidate genes contribute to increased carcinogenic potential in the developmentally estrogenized prostate glands.
In Aim 1, we will determine the dose-response relationship for prostatic- BPA effects and establish the developmental windows of susceptibility. We will also use a novel tissue recombination model to test whether BPA modifies carcinogenic susceptibility and methylation patterns in human prostate-like structures.
In Aim 2, we will characterize in detail the altered rat prostate methylome with resultant alterations in gene expression as a result of developmental exposures to environmentally relevant doses of BPA or estradiol. MSRP and methylation arrays will be used to expand our prostatic screen to identify a full panel of candidate genes and a stringent algorithm will be followed to identify candidates with regulatory CpG islands.
There is increasing evidence that a number of adult diseases may have a fetal basis of origin and this may apply to the prostate gland regarding fetal estrogenic exposures and increased risk of prostate cancer with aging. Identification of methylation fingerprints and specific genes with permanent methylation alterations may serve as molecular markers for developmental estrogenic exposures and provide molecular insight into the epigenomic plasticity that predisposes to prostate cancer with aging. The findings will serve as a model for human exposures to prevalent environmental endocrine disruptors (e.g. BPA) with suspected carcinogenic potential.
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