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

描述（由申请人提供）：勃起功能障碍（艾德）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，加上部分无效的治疗，导致沉重的公共卫生负担。艾德也被认为是诊断心血管疾病的前哨。目前尚不清楚环境或职业因素是否有助于通过改进诊断检测到的艾德患病率的增加。然而，艾德是极少数与双酚A（BPA）暴露存在临床相关性的人类疾病之一，在这种情况下是职业风险。在GLP条件下，在功能上和潜在的细胞和分子病理生理学水平上证明艾德/BPA之间的联系，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，并对艾德预防和BPA真实的风险评估产生重大影响。 待检验的假设为：大鼠中艾德的评估将允许在以几种剂量暴露于BPA 1年和2年后确定：a）是否诱发艾德; B）这些效应背后的细胞和分子损伤及其假定机制; c）阴茎勃起反应的外周与中枢损害的作用，和d）低血清睾酮（T）和衰老的复合作用，双酚A的剂量与人体接触的剂量相适应。 具体目标：在目标1中，确定从妊娠期开始长期暴露于BPA对阴茎勃起以及在衰老的复合因素下参与这一过程的相关组织的影响，并确定外周效应背后的病理生理学的细胞和分子特征;以及在目的2中，BPA是否通过PPARgamma和/或EERgamma在阴茎海绵体中诱导有害的S11 C表型转换和异常干细胞谱系定型。 这一办法将涉及：1）勃起功能的测量; 2）用于躯体脂肪纤维变性或神经毒性的躯体、骨盆神经节和下丘脑组织病理学的细胞概况; 3）通过DNA微阵列和蛋白质组学的分子概况;和4）通过BPA对躯体平滑肌变化和干细胞谱系定型的PPARgamma /ERR gamma调节的作用的推定机制

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