Environmental Estrogen Exposure During Fetal Life: A Time Bomb for Prostate Cancer

Abstract

In this issue, Prins et al (1) elegantly describe how exposure to bisphenol A (BPA) during development could modify prostate cell fate in adulthood. This group, involved in research to understand prostate cancer (PCa) development for many years, first determined the effect of BPA on human prostate epithelial stem-like cells obtained from young men. This allowed them to determine that these cells are highly and equally sensitive to estrogens and BPA and are able to amplify. Estradiol and BPA maintain the stem-like state within the normal prostate epithelial population as demonstrated by a higher accumulation of genes such as TBX3 and NANOG. Conversely, epithelial differentiation genes such as NKX3.1 and CK18 are at a low level. In addition to this work on cell culture, Prins et al (1) demonstrated estradiol and BPA effects during prostate development using an ingenious mouse model by xenografting chimeric human-rat prostate tissues in Nude mice (2) and found that low-dose BPA exposure increases estrogen-driven carcinogenesis of human prostate epithelium. As a result of this experimental tour de force, this team has described the missing link between estrogen-like endocrine disrupters and PCa. The Holy Grail has been found: environmental estrogen exposure will modify the fate of prostate stem cells, making them more sensitive to estrogen during adulthood and more prone to develop PCa. Development is a tightly controlled process that involves thousands of genes and hundreds of signaling molecules (hormones and growth factors) and cell interactions (junctions and synapses) that will allow correct cell migration. Like a Lego model, all of the interlocking “bricks” must be assembled correctly to produce a normal individual. Such precise mechanisms are involved that it is easy to understand that any defect in a signaling molecule or, on the contrary, an abnormal activation of a usually silent pathway can produce cell defects. Estrogen-like endocrine disruptors have been considered for many years as putatively responsible for various health defects by interfering with the synthesis, metabolism, binding, or cellular responses of natural estrogens (3). These molecules can be found in various plastic products, flame retardants, pesticides, and many other products that are needed for daily use. Among them, BPA is considered as the paradigm of these environmental estrogen-like molecules. Even though BPA was banned from being used in baby bottles by the European Union in 2011 (4) and by the United States in 2012, over 3 million tons per year of this estrogenic monomer have been used to manufacture polycarbonate plastic products, in resins lining metal cans, in dental sealants, and in blends with other types of plastic products, thus suggesting that adults can be overexposed to it. The ester bond linking BPA molecules in polycarbonate and resins undergoes hydrolysis, resulting in the release of free BPA into food, beverages, and the environment, and numerous monitoring studies now show almost ubiquitous human exposure to biologically active levels of this chemical. BPA exerts estrogenic effects through the classical nuclear estrogen receptors, and BPA acts as a selective estrogen receptor modulator (5). However, BPA also initiates rapid responses via estrogen receptors presumably associated with the plasma membrane. Similar to estradiol, BPA causes changes in some cell functions at the tiniest con-