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

BPA 对阴茎勃起影响的细胞分子特征和机制

基本信息

批准号：
8230318
负责人：
Nestor F Gonzalez-Cadavid
金额：
$ 1.88万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-19 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8230318
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 Testing Testis Testosterone Time Tissues Toxic effect Urine Western Blotting age effect bisphenol A erection estrogen-related receptor exposed human population good laboratory practice human data improved male men postnatal prevention evaluation relating to nervous system reproductive response

项目摘要

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

描述（由申请人提供）：勃起功能障碍（ED）是一种非常普遍的疾病，严重损害了患者及其性伴侣的生活质量，这会导致部分无效的治疗，从而导致沉重的公共健康负担。 ED也被认为是诊断心血管疾病的前哨。未知环境或职业因素是否导致通过改善诊断检测到的ED患病率的增加。但是，在这种情况下，ED是极少数人的人类条件之一，即与暴露于双酚A（BPA）的临床相关性是职业风险。在GLP条件下在功能和潜在的细胞和分子病理生理水平以及衰老的复合效应下，在GLP条件下在公认的模型上展示ED/BPA链接，将有助于评估和合理化流行病学的发现，并相当影响预防ED ED的预防结果以及对BPA实际风险的评估。要测试的假设是：大鼠对ED的评估将允许以多剂剂量的BPA暴露1和2年后定义：a）a）是否诱导ED； b）这些作用及其假定机制的细胞和分子损伤； c）阴茎勃起反应的外周与中心损害的作用，d）低血清睾丸激素（T）和衰老的复合作用，与人类暴露兼容的BPA剂量。具体目的：在目标1中确定从妊娠到BPA的慢性暴露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，并建立了构成病理生理学的细胞和分子特征。外围效应；在AIM 2中，BPA是否在Penile Corpora Cavernosa中诱导了有害的Si \/1c表型转换和异常的干细胞谱系承诺，它通过ppargamma和/或eergamma作用。该方法将涉及：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的细胞谱，用于脂纤维化的脂质纤维化变性或神经毒性； 3）DNA微阵列和蛋白质组学的分子谱； 4）通过BPA对体平滑肌变化和干细胞谱系承诺的PPARGAMMA /ERRGAMMA调制的效果，假定的机制