Cellular-molecular signature and mechanism of BPA effects on penile 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：
8477038
负责人：
Nestor F Gonzalez-Cadavid
金额：
$ 7.58万
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/8477038
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

项目摘要

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）是一种非常普遍的疾病，严重损害患者的生活质量及其性伴侣，再加上部分无效的治疗，导致严重的公共卫生问题负担。 ED也被认为是诊断心血管疾病的哨兵未知环境或职业因素是否导致了 ED 患病率的增加通过改进诊断。然而，ED 是极少数与临床相关的人类疾病之一。已有报道称接触 BPA，在本例中为职业风险。演示 ED/BPA 链接在 GLP 条件下的公认模型上，无论是在功能上还是在基础细胞和分子上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，并极大地影响 ED 预防和 BPA 实际风险的评估。假设。大鼠 ED 的评估将允许确定 BPA 暴露 1 和 2 年后的情况：多次给药：a) 是否诱发 ED； b) 这些影响背后的细胞和分子损伤以及他们的假定机制； c) 阴茎勃起反应的外周损伤与中枢损伤的作用， d) 在与人体接触的 BPA 剂量相匹配的情况下，低血清 T 和衰老的复合效应。具体目标：确定：目标 1：妊娠期间长期接触 BPA 对阴茎的影响在衰老的复合因素下，勃起以及参与这一过程的相关组织，建立外周效应背后的病理生理学的细胞和分子特征；目标 2：BPA 是否会在阴茎海绵体中诱导有害的 SI\/1C 表型转换以及通过 PPARgamma 和/或 EERgamma 发挥作用的异常干细胞谱系定型。方法：1）测量勃起功能； 2) 下体、骨盆神经节和下丘脑组织病理学检查以确定体脂纤维变性或神经毒性； 3) 分子概况通过 DNA 微阵列和蛋白质组学； 4) BPA 对 PPARgamma 影响的推定机制 /ERRgamma 调节下体平滑肌变化和干细胞谱系定向