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Introduction
Bisphenol A (BPA), a high-volume chemical and widely used synthetic plasticizer, has known estrogenic activity and is a recognized endocrine-disrupting chemical (EDC). Extensive studies over the past two decades have evaluated its potential effects in multiple organs and biological systems including its capacity for augmenting carcinogenesis (Chapin et al. 2008; Gore et al. 2015; Rochester 2013; Seachrist et al. 2016). Although research consensus has not been reached on adverse outcomes from BPA doses relevant to human exposures, it is widely appreciated that the developmental period is particularly sensitive to BPA exposures that may lead to long-lasting effects over the life span.
The prostate gland is a hormone-dependent reproductive organ that possesses a high rate of disease with aging. Currently, prostate cancer is the most common noncutaneous cancer and the second leading cause of cancer-related deaths in U.S. men (Siegel et al. 2016). Whereas androgens are essential for prostate growth and function, substantial evidence indicates that estrogens play key roles in prostate homeostasis and disease (Nelles et al. 2011). Importantly, inappropriate estrogen exposures during prostate development, in terms of timing, type and dose, can reprogram the gland, drive differentiation defects and predispose to an increased risk of prostate cancer (Prins et al. 2001; Prins and Ho 2010). Work from our laboratory (Ho et al. 2006; Prins et al. 2011), recently confirmed in an independent study (Wong et al. 2015), determined that brief early-life exposure to low-dose BPA (10–50 μg/kg BW), although not sufficient to induce prostate lesions on its own, increased susceptibility to estrogen-driven prostatic intraepithelial neoplasia (PIN) in adulthood. This is germane because relative estradiol levels rise in the aging male (Vermeulen et al. 2002), estrogens can transform adult prostate epithelium (Bosland et al. 1995; Hu et al. 2011), accelerate cancer progression (Chakravarty et al. 2014; Setlur et al. 2008; Takizawa et al. 2015) and estrogen activity is amplified in advanced disease (Montgomery et al. 2008). Thus we posit that BPA reprograms prostate cells early in life resulting in a cellular memory that augments adult hormonal sensitivity. The molecular underpinnings of reprogramed prostatic memory appear to lie in epigenetic modifications that have been identified in prostates exposed perinatally to low-dose BPA that poise the cells for amplified responses to later estrogenic exposures. These include hypo-...