Cellular-molecular signature and mechanism of BPA effects on penil erection

描述(申请人提供)：勃起功能障碍(ED)是一种非常普遍的疾病，严重损害患者及其性伴侣的生活质量，再加上部分无效的治疗，导致沉重的公共卫生负担。ED也被认为是诊断心血管疾病的哨兵。目前尚不清楚环境或职业因素是否导致诊断改进后发现的勃起功能障碍患病率上升。然而，ED是少数几种临床上与暴露于双酚A(BPA)有关的人类疾病之一，在这种情况下被报告为职业风险。在GLP条件下从功能和潜在的细胞和分子病理生理水平上证明ED/BPA的联系，以及衰老的复合效应，将有助于评估和合理化流行病学结果，并在很大程度上影响ED的预防和BPA真实风险的评估。要测试的假设是：对大鼠的勃起功能障碍的评估将允许在几种剂量的双酚A暴露1年和2年后确定：a)是否会诱发勃起功能障碍；b)这些影响背后的细胞和分子损害及其可能的机制；c)阴茎勃起反应的外周和中枢损害的作用；以及d)低血清睾酮(T)和衰老的复合影响，剂量与人类暴露的双酚A相适应。具体目的：在目标1中，确定孕期长期暴露于双酚A对阴茎勃起和参与这一过程的相关组织在复合老化因素下的影响，并建立作为外周效应基础的病理生理学的细胞和分子特征；在目标2中，双酚A是否通过PARGamma和/或EERGamma在阴茎海绵体中诱导有害的SI1C表型转换和异常的干细胞谱系定位。该方法将涉及：1)勃起功能的测量；2)体部、盆神经节和下丘脑的细胞图谱(S)体脂纤维变性或神经毒性的组织病理学；3)基因芯片和蛋白质组学的分子图谱；以及4)双酚A对PPAR-γ/ERR-γ调节平滑肌变化和干细胞谱系承诺的可能机制(S)。

DESCRIPTION (provided by applicant): Erectile dysfunction (ED) is a highly prevalent condition that severely impairs the quality of life of patients and their sexual partners, compounded by a partially ineffective therapy that leads to a heavy public health burden. ED is also considered to be a sentinel for the diagnosis of cardiovascular disease. It is unknown whether environmental or occupational factors have contributed to the increasing prevalence of ED detected by improved diagnosis. However, ED is one of the very few human conditions where a clinical correlation with exposure to Bisphenol A (BPA) has been reported, in this case as occupational risk. To demonstrate an ED/BPA link on an accepted model under GLP conditions both functionally and at the underlying cellular and molecular pathophysiological levels, as well as the compounding effects of aging, would help to assess and rationalize the epidemiological findings, and considerably impact ED prevention and the evaluation of BPA real risks. The hypotheses to be tested are: The assessment of ED in the rat will allow to define after 1 and 2 years of BPA exposure at several doses: a) whether ED is induced; b) the cellular and molecular damage underlying these effects and their putative mechanisms; c) the role of peripheral versus central damage of the penile erectile response, and d) the compounding effects of low serum testosterone (T) and aging, at BPA doses compatible with human exposure. Specific aims: To determine in aim 1 the effects of a chronic exposure from gestation to BPA on penile erection and the related tissues that participate in this process under the compounding factor of aging, and to establish the cellular and molecular signatures of the pathophysiology that underlies the peripheral effects; and in aim 2 whether BPA induces in the penile corpora cavernosa a detrimental SI\/1C phenotypic switch and abnormal stem cell lineage commitment, acting through the PPARgamma and/or EERgamma. The approach will involve: 1) measurements of erectile function; 2) cellular profile(s) of the corporal, pelvic ganglion and hypothalamic histopathology for lipofibrotic degeneration of the corpora or neural toxicity; 3) molecular profile by DNA microarrays and proteomics; and 4) putative mechanism(s) through BPA effects on the PPARgamma /ERRgamma modulation of corporal smooth muscle changes and stem cell lineage commitment