Brief exposure of rodents to high doses of natural or synthetic estrogens during the developmental period results in permanent alterations in growth and differentiation of the prostate gland. This process, referred to as developmental estrogenization or estrogen imprinting, is associated with an increased incidence of prostatic lesions as the animals age including epithelial hyperplasia, severe dysplasia (PIN) and adenocarcinoma. Thus we hypothesize that abnormal estrogenic exposures during developmental critical periods may be a predisposing factor for prostatic disease later in life. Less clear, however, is the effect of exposures to low doses of estrogens or environmentally relevant doses of xenoestrogens during the critical period of prostate morphogenesis. While some have demonstrated a permanent stimulatory effect on the prostate, other investigations have refuted this data. It is established, however, that adult exposures to estrogens can drive carcinogenesis in animal models, which is significant since estrogen levels rise in the aging male. Since recent findings in the female have shown that developmental low-dose estrogen exposure can sensitize the uterus to later estrogen exposures, it is possible that low levels of natural or environmental estrogens may increase susceptibility to estrogen-induced prostatic tumors. We will test this """"""""two-hit"""""""" scenario in Specific Aim 1 of the present application using the rat neonatal model where we will assess the effects of early exposures to high and low doses of estradiol or Bisphenol A followed by adult estrogen exposure as the animals age. The mechanism whereby estrogens permanently influence the prostate gland long after the withdrawal of the hormone is poorly understood. A possible mechanism is through alterations in developmental methylation of specific genes. Such alterations could reprogram the prostate such that it becomes more sensitive to disease induction later in life. This will be addressed in Specific Aim 2 where we will perform differential methylation detection using a highly innovative technology (methylation-sensitive DNA fingerprinting or MS-AP-PCR) to identify genes that are hypermethylated in rat prostate glands developmentally exposed to varying doses of either estradiol or Bisphenol A. Establishing a link between hypermethylation (silencing) of specific genes during development to adult-onset prostate neoplasia as a result of early estrogenic exposures may provide a cause-and-effect relationship needed to elucidate the fetal basis for the high incidence of prostate cancer in men. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES012281-01
Application #
6645324
Study Section
Special Emphasis Panel (ZRG1-REB (50))
Program Officer
Heindel, Jerrold
Project Start
2003-06-01
Project End
2006-02-28
Budget Start
2003-06-01
Budget End
2004-02-29
Support Year
1
Fiscal Year
2003
Total Cost
$141,903
Indirect Cost
Name
University of Illinois at Chicago
Department
Urology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Prins, Gail S; Tang, Wan-Yee; Belmonte, Jessica et al. (2008) Perinatal exposure to oestradiol and bisphenol A alters the prostate epigenome and increases susceptibility to carcinogenesis. Basic Clin Pharmacol Toxicol 102:134-8
Tam, Neville N C; Szeto, Carol Ying-Ying; Sartor, Maureen A et al. (2008) Gene expression profiling identifies lobe-specific and common disruptions of multiple gene networks in testosterone-supported, 17beta-estradiol- or diethylstilbestrol-induced prostate dysplasia in Noble rats. Neoplasia 10:20-40
Prins, Gail S; Birch, Lynn; Tang, Wan-Yee et al. (2007) Developmental estrogen exposures predispose to prostate carcinogenesis with aging. Reprod Toxicol 23:374-82
Ho, Shuk-mei; Tang, Wan-yee (2007) Techniques used in studies of epigenome dysregulation due to aberrant DNA methylation: an emphasis on fetal-based adult diseases. Reprod Toxicol 23:267-82
Tang, Wan-yee; Ho, Shuk-mei (2007) Epigenetic reprogramming and imprinting in origins of disease. Rev Endocr Metab Disord 8:173-82
Ho, Shuk-Mei; Leung, Yuet-Kin; Chung, Irving (2006) Estrogens and antiestrogens as etiological factors and therapeutics for prostate cancer. Ann N Y Acad Sci 1089:177-93
Prins, Gail S; Huang, Liwei; Birch, Lynn et al. (2006) The role of estrogens in normal and abnormal development of the prostate gland. Ann N Y Acad Sci 1089:1-13
Ho, Shuk-Mei; Tang, Wan-Yee; Belmonte de Frausto, Jessica et al. (2006) Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res 66:5624-32