Background: In 2007, an expert panel reviewed associations between bisphenol A (BPA) exposure and reproductive health outcomes. Since then, new studies have been conducted on the impact of BPA on reproduction. Objective: In this review, we summarize data obtained since 2007, focusing on a) findings from human and animal studies, b) the effects of BPA on a variety of reproductive end points, and c) mechanisms of BPA action. Methods: We reviewed the literature published from 2007 to 2013 using a PubMed search based on keywords related to BPA and male and female reproduction. Discussion: Because BPA has been reported to affect the onset of meiosis in both animal and in vitro models, interfere with germ cell nest breakdown in animal models, accelerate follicle transition in several animal species, alter steroidogenesis in multiple animal models and women, and reduce oocyte quality in animal models and women undergoing in vitro fertilization (IVF), we consider it an ovarian toxicant. In addition, strong evidence suggests that BPA is a uterine toxicant because it impaired uterine endometrial proliferation, decreased uterine receptivity, and increased implantation failure in animal models. BPA exposure may be associated with adverse birth outcomes, hyperandrogenism, sexual dysfunction, and impaired implantation in humans, but additional studies are required to confirm these associations. Studies also suggest that BPA may be a testicular toxicant in animal models, but the data in humans are equivocal. Finally, insufficient evidence exists regarding effects of BPA on the oviduct, the placenta, and pubertal development. Conclusion: Based on reports that BPA impacts female reproduction and has the potential to affect male reproductive systems in humans and animals, we conclude that BPA is a reproductive toxicant. Citation: Peretz J, Vrooman L, Ricke WA, Hunt PA, Ehrlich S, Hauser R, Padmanabhan V, Taylor HS, Swan SH, VandeVoort CA, Flaws JA. 2014. Bisphenol A and reproductive health: update of experimental and human evidence, 2007–2013. Environ Health Perspect 122:775–786; http://dx.doi.org/10.1289/ehp.1307728

Targeting androgens/androgen receptor (AR) functions via androgen deprivation therapy (ADT) remains the standard treatment for prostate cancer. However, most tumors eventually recur despite ADT. Here we demonstrate that the prostate AR may function as both a suppressor and a proliferator to suppress or promote prostate cancer metastasis. Results from orthotopically recombining stromal WPMY1 cells with epithelial PC3 prostate cancer cells in mice demonstrated that restoring AR in epithelial PC3 cells or knockdown of AR in stromal WPMY1 cells suppressed prostate cancer metastasis. Knockdown of the AR in epithelial CWR22rv1 prostate cancer cells also resulted in increased cell invasion in vitro and in vivo . Restoring AR in PC3 cells (PC3-AR9) results in decreased invasion in bone lesion assays and in vivo mouse models. Mice lacking the prostate epithelial AR have increased apoptosis in epithelial luminal cells and increased proliferation in epithelial basal cells. The consequences of these two contrasting results led to the expansion of CK5/CK8-positive intermediate cells, and mice developed larger and more invasive metastatic tumors in lymph nodes and died earlier than wild-type littermates. Mechanistic dissection suggested that androgens/AR might directly or indirectly modulate metastasis-related genes and suppression of TGFβ1 signals results in the partial inhibition of AR-mediated metastasis. Collectively, our understanding of these opposing roles of prostatic AR may revolutionize the way we combat prostate cancer, and allow the development of new and better therapies by targeting only the proliferative role of AR.

Developmental studies of the prostate have established that ductal morphogenesis, epithelial cytodifferentiation, and proliferation/apoptosis are regulated by androgens acting through stromal androgen receptor (AR). Here, we found mice lacking epithelial AR within the mature prostate (pes-ARKO) developed prostate tissue that was less differentiated and hyperproliferative relative to WT littermates. Epithelial AR protein was significantly decreased in 6-week-old mice and was nearly absent by ≥24 weeks of age. Circulating levels of testosterone, external genitalia, or fertility were not altered in pes-ARKO mice. A significant ( P < 0.05) increase in bromo-deoxyuridine-positive epithelia was observed in ventral and dorsal-lateral prostates of pes-ARKO mice at 24 weeks of age. Less differentiation was observed as indicated by decreased epithelial height and glandular infolding through 24 weeks of age, differentiation markers probasin, PSP-94, and Nkx3.1 were sig nificantly decreased, and epithelial sloughing and luminal cell apoptosis increased from 6 to 32 weeks of age in pes-ARKO mice. Gain of function occurred by crossing pes-ARKO to the T857A transgenic mice containing constitutively activated AR. In T857A-pes-ARKO mice prostates were of normal size, contained glandular infoldings, and maintained high secretory epithelium, and the appropriate prostatic epithelial proliferation was restored. Collectively, these results suggest that prostatic epithelial AR plays an important role in the homeostasis of the prostate gland. These data support the hypothesis that epithelial AR controls prostate growth by suppressing epithelial proliferation in the mature gland.