Obstructive voiding disorder (OVD) and high-grade prostatic intraepithelial neoplasia (HGPIN) are common diseases of aging in men. HGPIN is a precancerous lesion that usually leads to aggressive therapy upon detection. There has long been speculation that the age-related increase in estradiol in men plays a role in prostate disease and urethral abnormalities. Virtually all men in the USA are exposed to the environmental estrogen bisphenol A (BPA), and the National Health and Nutrition Examination Survey (NHANES 2003/4) showed that men reporting urine flow problems had significantly higher (by 64%) urine levels of BPA than men without voiding problems. Preliminary experiments with CD-1 mice show that a combination of low-dose exposure to BPA during fetal life followed by adult exposure to estradiol causes both OVD and HGPIN in a majority of male mice. These males die due to retention of urine in the bladder associated with extensive periurethral gland hyperplasia;all of these mice also have HGPIN in a majority of prostate acini. The 1st hypothesis is that BPA contributes to expression of OVD and prostate disease by increasing the body burden of estrogen during aging. To test this hypothesis the 1st specific aim is to conduct a study relating serum and urine BPA, in addition to endogenous estradiol, with OVD and prostate disease in aging men using multiple clinical and epidemiological assessment methods. The 2nd hypothesis is that exposure of fetal mice to low vs. high doses of BPA will have different effects on gene activity in both periurethral and prostate fetal mesenchyme and epithelium as well as during adult BPA exposure-induced OVD and HGPIN. To test this hypothesis, the 2nd specific aim is to conduct experiments using two strains of mice with low (CD-1 mice) and high (C57BL/6 mice) expression of OVD and HGPIN with just adult estrogen treatment;these strain differences imply a genetic component to risk of disease associated with BPA exposure. Methods used involve: 1. Fetal exposure to a 4-log range of BPA doses and adult exposure to BPA at human exposure levels (with measurement of BPA in fetal and adult serum);2. Assessment of uno-flow and bladder during progression of OVD;3. Examination of both fetal and adult periurethral and prostate gland stroma and epithelium gene activity in specific regions by laser capture microscopy (LCM) coupled with real time RT-PCR;4. Analysis of morphological changes in the fetal urogenital sinus by computer-assisted reconstruction coupled with immunocytochemistry for identification of cell types and cell proliferation;and 5.Analysis of the estrogen receptor (ER) sub-type that mediates the fetal and adult response to BPA by using ER knockout mice. This innovative approach using LCM and real-time RT-PCR avoids the problems inherent in examining gene activity in non-homogeneous tissue. Epidemiologic studies that relate to mechanistic findings in animals are given considerable weight in the risk management process. These parallel animal and human experiments should enhance the case for reducing adult BPA exposure standards and generate new therapeutic approaches.

Public Health Relevance

Obstructive voiding disorder (OVD) and high-grade prostatic intraepithelial neoplasia (HGPIN) are common diseases of aging in men. Epidemiologic studies that relate to mechanistic findings in animals are given considerable weight in the risk management process, particularly when the underlying response system (estrogen receptor mechanisms) is known to be fundamentally the same in humans and the model animal. Animal and human experiments relating BPA exposure to the most common diseases of aging in men are thus likely to assist the risk management process, and likely will enhance the case for reducing adult BPA exposure standards. Relating these diseases to estrogen exposure are likely to generate new therapeutic approaches based on blocking estrogen actions in the male urogenital system.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
High Impact Research and Research Infrastructure Programs (RC2)
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Special Emphasis Panel (ZES1-LWJ-J (O1))
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Heindel, Jerrold
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University of Missouri-Columbia
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