Studies using rodent and adult human prostate stem-progenitor cell models suggest

Studies using rodent and adult human prostate stem-progenitor cell models suggest that developmental exposure to the endocrine disruptor Bisphenol-A (BPA) can predispose to prostate carcinogenesis with aging. prostate specification by combined exposure to WNT10B and FGF10. Matrigel culture for 20C30 days in medium containing R-Spondin-1, Noggin, EGF, retinoic acid and testosterone was sufficient for mature prostate organoid development. Immunofluorescence and gene expression analysis confirmed that organoids exhibited cytodifferentiation and functional properties of the human prostate. Exposure to 1 nM or 10 nM BPA throughout differentiation culture disturbed early morphogenesis in a dose-dependent manner with 1 nM BPA increasing and 10 nM BPA reducing the number of branched structures formed. While differentiation of Rabbit Polyclonal to Stefin B branched structures to mature organoids seemed largely unaffected by BPA exposure, the stem-like cell population increased, appearing as focal stem cell nests that have not properly entered lineage commitment rather than the rare isolated stem cells found in normally differentiated structures. These findings provide the first direct evidence that low-dose BPA exposure targets hESC and perturbs morphogenesis as the embryonic cells differentiate towards human prostate organoids, suggesting that the developing human prostate may be susceptible to disruption by BPA exposures. Introduction The human prostate gland has a high incidence of abnormal growth and carcinogenesis with aging, contributing to extensive morbidity and mortality in men [1]. Despite considerable research, the basis for the high rates of prostate disease remains poorly understood. The prostate is derived embryologically from the endodermal urogenital sinus (UGS) which contrasts with the other male accessory sex glands that arise from the mesodermal Wolffian ducts [2]. Since seminal vesicle or vas deferens carcinoma is exceedingly rare, it has been postulated that the unique embryologic origin of the prostate gland contributes to its differential disease propensity [3]. Thus modeling prostate developmental events is an essential step towards understanding the basis of adult prostate disease. It is well established that several hormones, including androgens and estrogens, play fundamental roles in normal prostate development and homeostasis and that imbalances in their level and activity contribute to aging-associated prostatic diseases [2]. Further, epidemiologic studies indicate that elevated estrogen levels can predispose to an increased risk of prostate cancer later in life [4] which supports the paradigm of a GSK126 manufacture developmental basis for adult disease. This is corroborated by considerable evidence using rodent models which determined that brief early-life exposures to exogenous estradiol can permanently reprogram the prostate gland, both structurally and epigenetically, and render it more susceptible to prostate cancer with aging [5C7]. In addition to natural estrogens, there is a rising concern regarding peri-natal exposures to endocrine disrupting chemicals (EDCs), many of which have estrogen-like actions. One prevalent endocrine disruptor, bisphenol A (BPA), initially synthesized in 1891, GSK126 manufacture was identified as a synthetic estrogen in 1936 [8]. Today, BPA is a high-production chemical GSK126 manufacture used in a wide range of consumer products including polycarbonate plastics, epoxy resins, carbonless paper receipts and dental sealants [9, 10]. Unfortunately, bioactive BPA monomers leach from these products, accumulate in the environment and are taken up by animals and humans [11C16]. Consequently, BPA and its metabolite BPA-glucuronide are detectable in the urine of most adults and children [16, 17], serum of pregnant women and newborns [18, 19], breast milk [20], amniotic fluid [21], cord blood [22, 23] and fetal livers [24]. Although BPA is rapidly metabolized to glucuronidated BPA (BPA-G) which lacks bioactivity and is excreted within 6C24 hour, free BPA has been detected in human sera at 0.2 to 1 1.0 ng/ml levels [22, 25]. While free BPA binds to nuclear estrogen receptors (ERs) with reduced affinity relative to 17-estradiol [26], it possesses equivalent activational capacity for membrane ERs [27]. Thus, there is potential for this compound as a toxicant to developing, estrogen-sensitive human tissues. Studies from our laboratory using a GSK126 manufacture rat model found that transient neonatal exposure to low-dose BPA significantly increased the incidence of hormone-driven prostate carcinogenesis with aging [28] and modified the stem cell niche [29] which may underpin increased cancer susceptibility with aging. To test whether the human prostate may be similarly influenced, epithelial stem-progenitor cells were isolated from prostates of adult organ donors [30]. Exposure to estradiol or BPA activated membrane-initiated ER signaling, increased stem and progenitor cell proliferation, altered their transcriptome and modified noncoding RNA expression through histone modifications [31]. Further, when grafted into nude mice, transient exposure to low-dose BPA increased hormonal carcinogenesis in the human prostate epithelium [32]. Unclear at present is whether the human fetal prostate is equally susceptible to BPA exposures. Progress towards this goal has largely been impeded by restricted access to human fetal tissues and the lack of a suitable model for human embryonic prostate development. During the past decade, several investigators have reported.

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