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

勃起功能障碍(ED)是一种高度流行的疾病，严重影响患者的生活质量 和他们的性伴侣，再加上部分无效的治疗，导致严重的公共健康 负担。ED也被认为是诊断心血管疾病的哨兵，目前还不清楚 环境或职业因素是否导致勃起功能障碍患病率上升 通过改进诊断。然而，ED是极少数与临床相关的人类疾病之一 与双酚A的接触已被报告，在这种情况下是职业风险。演示ED/BPA链接 在GLP功能和潜在细胞和分子条件下的可接受模型 病理生理水平以及衰老的复合效应将有助于评估和合理化 流行病学调查结果，对ED的预防和BPA真实风险的评估有很大影响。 假设。对大鼠ED的评估将允许在BPA暴露1年和2年后在 几种剂量：a)是否诱发ED；b)这些效应背后的细胞和分子损伤以及 其推测的机制；c)阴茎勃起反应的外周损害与中枢损害的作用， 以及d)在与人体暴露相适应的双酚A剂量下，低血清T和衰老的复合效应。 具体目标：确定：目标1：从怀孕开始长期暴露于双酚A对阴茎的影响 在衰老的复合因素下，勃起和参与这一过程的相关组织，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； 目标2：双酚A是否在阴茎海绵体诱导有害的SI1C表型转换 和异常的干细胞谱系承诺，通过PPAR和/或EERGamma起作用。 方法：1)勃起功能的测量；2)躯体、盆神经节和 体脂纤维变性或神经毒性的下丘脑组织病理学；3)分子图谱 通过DNA微阵列和蛋白质组学；以及4)通过双酚A对PPARγ的影响而推测的机制 /ERRGamma对体部平滑肌改变和干细胞谱系承诺的调节

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 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. Hypotheses. 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 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. Approach: 1) measurements of erectile function; 2) cellular profile 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 through BPA effects on the PPARgamma /ERRgamma modulation of corporal smooth muscle changes and stem cell lineage commitment