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. Site-specific methylation and resultant transcriptional regulation will be confirmed.
In Aim 3, we will directly test whether the genes epigenetically modified by estrogenic exposures play an active role in prostate gland carcinogenesis using a variety of in vitro and in vivo studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015584-05
Application #
8204516
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Schug, Thaddeus
Project Start
2008-01-15
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$467,162
Indirect Cost
$75,602
Name
University of Illinois at Chicago
Department
Urology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Cheong, Ana; Zhang, Xiang; Cheung, Yuk-Yin et al. (2016) DNA methylome changes by estradiol benzoate and bisphenol A links early-life environmental exposures to prostate cancer risk. Epigenetics :1-16
Lam, Hung-Ming; Ho, Shuk-Mei; Chen, Jing et al. (2016) Bisphenol A Disrupts HNF4α-Regulated Gene Networks Linking to Prostate Preneoplasia and Immune Disruption in Noble Rats. Endocrinology 157:207-19
Seachrist, Darcie D; Bonk, Kristen W; Ho, Shuk-Mei et al. (2016) A review of the carcinogenic potential of bisphenol A. Reprod Toxicol 59:167-82
Prins, Gail S; Calderon-Gierszal, Esther L; Hu, Wen-Yang (2015) Stem Cells as Hormone Targets That Lead to Increased Cancer Susceptibility. Endocrinology 156:3451-7
Tam, Neville Ngai-Chung; Zhang, Xiang; Xiao, Hong et al. (2015) Increased susceptibility of estrogen-induced bladder outlet obstruction in a novel mouse model. Lab Invest 95:546-60
Ho, Shuk-Mei; Cheong, Ana; Lam, Hung-Ming et al. (2015) Exposure of Human Prostaspheres to Bisphenol A Epigenetically Regulates SNORD Family Noncoding RNAs via Histone Modification. Endocrinology 156:3984-95
Wong, Rebecca Lee Yean; Wang, Quan; Treviño, Lindsey S et al. (2015) Identification of secretaglobin Scgb2a1 as a target for developmental reprogramming by BPA in the rat prostate. Epigenetics 10:127-34
Calderon-Gierszal, Esther L; Prins, Gail S (2015) Directed Differentiation of Human Embryonic Stem Cells into Prostate Organoids In Vitro and its Perturbation by Low-Dose Bisphenol A Exposure. PLoS One 10:e0133238
Leung, Yuet-Kin; Chan, Queeny Kwan-Yi; Ng, Chi-Fai et al. (2014) Hsa-miRNA-765 as a key mediator for inhibiting growth, migration and invasion in fulvestrant-treated prostate cancer. PLoS One 9:e98037
Prins, Gail S; Hu, Wen-Yang; Shi, Guang-Bin et al. (2014) Bisphenol A promotes human prostate stem-progenitor cell self-renewal and increases in vivo carcinogenesis in human prostate epithelium. Endocrinology 155:805-17

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