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

BPA 影响阴茎勃起的细胞分子特征和机制

• 批准号: 8686844
• 负责人: Nestor F Gonzalez-Cadavid
• 金额: $ 0.61万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686844
• 关键词: Address; Affect; Age Factors; Aging; Animals; Area; Body Weight; Cardiovascular Diseases; Cell Culture Techniques; Cell Lineage; Cells; Chronic; Clinical; Corpora Cavernosa; DNA Microarray Chip; Data; Databases; Diagnosis; Disease; Dose; Epidemiology; Erectile dysfunction; Estradiol; Exposure to; Fibrosis; Functional disorder; Ganglia; Gene Expression; Goals; Histology; Histopathology; Human; Hypothalamic structure; In Vitro; Instruction; Lead; Life; Link; Longevity; Measurement; Mediation; Modeling; Molecular; Molecular Profiling; Myofibroblast; Nerve; Neuropathy; Occupational; Operative Surgical Procedures; Outcome; PPAR gamma; Parents; Patients; Pelvis; Penile Erection; Peripheral; Peroxisome Proliferator-Activated Receptors; Polycystic Ovary Syndrome; Pregnancy; Prevalence; Prevention; Procedures; Process; Prostate; Proteomics; Public Health; Quality of life; Questionnaires; Rattus; Relaxation; Reporting; Research Design; Risk; Risk Factors; Role; Route; Seminal Vesicles; Seminal fluid; Sentinel; Serum; Sexual Dysfunction; Sexual Partners; Smooth Muscle; Smooth Muscle Myocytes; Specimen; Stem cells; Testis; Testosterone; Time; Tissues; Toxic effect; Urine; Western Blotting; age effect; erection; estrogen-related receptor; exposed human population; good laboratory practice; human data; improved; male; men; postnatal; prevention evaluation; relating to nervous system; reproductive; response

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

勃起功能障碍（ED）是一种高度普遍的疾病，严重损害了患者的生活质量 以及他们的性伴侣，由于部分无效的疗法而加重了，这导致了大大的公共卫生 负担。 ED也被认为是诊断心血管疾病的哨兵 环境还是职业因素是否导致ED检测到的ED患病率的增加 通过改进的诊断。但是，ED是临床相关性的极少数人类状况之一 在这种情况下，已经报告了BPA的暴露，这是职业风险。演示ED/BPA链接 在GLP条件下，在功能和下面的细胞和分子上都可以接受的模型 病理生理水平以及衰老的复合作用将有助于评估和合理化 流行病学发现，并极大地影响了ED预防和BPA实际风险的评估。 假设。大鼠对ED的评估将允许在BPA暴露1和2年后定义 几种剂量：a）是否诱发ED； b）这些作用的基础细胞和分子损伤， 他们推定的机制； c）阴茎勃起反应的外围和中心损害的作用， d）低血清T和衰老的复合作用，与人类暴露兼容的BPA剂量。 具体目的：确定：目标1：从妊娠到BPA的慢性暴露对阴茎的影响 在衰老的复合因素下，勃起和参与此过程的相关组织， 建立构成周围作用的病理生理学的细胞和分子特征。 在AIM 2中：BPA是否诱导Penile Corpora Cavernosa a有害的SI \/1C表型开关 和异常的干细胞谱系承诺，通过ppargamma和/或eergamma作用。 方法：1）勃起功能的测量； 2）下士，骨盆神经节和 下丘脑组织病理学，用于脂纤维化的脂肪性变性或神经毒性； 3）分子轮廓 通过DNA微阵列和蛋白质组学； 4）通过BPA对PPARGAMMA的效应进行假定的机制 /士ergamma对体平滑肌肉变化和干细胞谱系承诺的调节