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

• 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
• 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

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（艾德）是一种高度流行的疾病，严重损害患者的生活质量 和他们的性伴侣，加上部分无效的治疗，导致沉重的公共健康 负担艾德也被认为是诊断心血管疾病的前哨。 环境或职业因素是否导致检测到的艾德患病率增加 改善诊断。然而，艾德是临床相关的极少数人类疾病之一， 在这种情况下，这是一种职业风险。演示艾德/BPA链接 在GLP条件下的公认模型上，在功能上以及在基础细胞和分子水平上 病理生理水平，以及老化的复合效应，将有助于评估和合理化 流行病学调查结果，并大大影响艾德预防和BPA真实的风险的评估。 假设。大鼠中艾德的评估将允许定义在BPA暴露1年和2年后， 几种剂量：a）是否诱导艾德; B）这些作用背后的细胞和分子损伤， 它们的假定机制; c）阴茎勃起反应的外周与中枢损伤的作用， 以及d）在与人体暴露相容的BPA剂量下，低血清T和衰老的复合效应。 具体目的：确定：目的1：从妊娠期长期暴露于BPA对阴茎的影响 勃起和参与这一过程的相关组织在老化的复合因素下， 确定外周效应背后的病理生理学的细胞和分子特征; 目标2：BPA是否在阴茎海绵体中诱导有害的SI/1C表型转换 和异常干细胞谱系定型，通过PPARgamma和/或EERgamma起作用。 方法：1）勃起功能的测量; 2）身体，盆腔神经节和 下丘脑组织病理学检查，以确定躯体脂肪纤维变性或神经毒性; 3）分子特征 通过DNA微阵列和蛋白质组学;和4）通过BPA对PPARgamma的影响的推定机制 /ERRgamma调节体平滑肌变化和干细胞谱系定型