BISPHENOL A EFFECTS ON THE PERIPHERAL MECHANISMS OF PENILE ERECTION

双酚 A 对阴茎勃起外围机制的影响

• 批准号: 8126452
• 负责人: Nestor F Gonzalez-Cadavid
• 金额: $ 22.66万
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126452
• 关键词: Abbreviations; Adult; Adverse effects; Affect; Agonist; Animal Model; Animals; Beverages; Biochemistry; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell model; Chemicals; Child; Complex; Conflict (Psychology); Consumption; Corpora Cavernosa; DNA Microarray Chip; Data; Development; Diabetes Mellitus; Dose; Endocrine Disruptors; Environmental Exposure; Environmental Hazards; Environmental Risk Factor; Environmental and Occupational Exposure; Erectile dysfunction; Estrogens; Ethers; Excretory function; Exposure to; Fatty acid glycerol esters; Fibrosis; Food; Functional disorder; Future; Ganglia; Gene Expression; Health; Healthcare; Histology; Histopathology; Human; Hypothalamic structure; Image Analysis; Impairment; In Vitro; Infiltration; Inflammation; Intake; Investigation; Journals; Kidney; Literature; Male sexual dysfunction; Measures; Mediating; Mediation; Mediator of activation protein; Microarray Analysis; Milk; Modeling; Nature; Nerve; Nitric Oxide Synthase Type I; Nitroxidergic Nerves; Occupational; Occupational Exposure; Organ; Oxidative Stress; PPAR gamma; Paper; Pathway interactions; Patient Self-Report; Patients; Pelvis; Penile Erection; Peripheral; Pit and Fissure Sealants; Plant Resins; Plastics; Population; Process; Public Health; Published Comment; Publishing; Quality of life; Questionnaires; Rattus; Reactive Oxygen Species; Relaxation; Reporting; Reproductive system; Research; Research Personnel; Risk; Risk Factors; Role; Sales; Selective Estrogen Receptor Modulators; Sex Behavior; Sex Functioning; Sexual Dysfunction; Signal Transduction; Smoking; Smooth Muscle; Smooth Muscle Myocytes; Stem cells; Teenagers; Time; Tissues; Urine; Veno-occlusive; Water; Wound Healing; base; bisphenol A; cost; design; dosage; editorial; erection; human NOS3 protein; human data; human male; inhibitor/antagonist; male; male health; mature animal; men; monomer; novel; older men; penis; phosphodiesterase V; polycarbonate; polycarbonate plastic; public health relevance; repaired; reproductive; reproductive function; research study; statistics; stem; stem cell differentiation; water environment; working men

DESCRIPTION (provided by applicant): Background and Rationale. Bisphenol A (BPA), a key ingredient of polycarbonate plastics and epoxi resins, is a major endocrine disrupting chemical (EDC) present in urine. BPA is noxious to the reproductive system of experimental animals at doses below the LOAEL (Lowest Observed Adverse Effect Level). A derivative, BADGE, is a peroxisome-proliferator-activated receptor gamma (PPAR3) antagonist. Recently, self-reported erectile dysfunction (ED) was described in male workers occupationally exposed to BPA, but this has not been evaluated measuring penile erection. ED in animal models is caused by a loss of penile corporal smooth muscle and nitrergic nerves, fibrosis and oxidative stress, counteracted in part by PPAR3 and putatively by tissue repair involving endogenous Oct-4+ stem cells. BPA at supra-LOAEL doses causes lipofibrotic degeneration and impairment of compliance of penile corporal tissue in a rat model. This requires confirmation at sub-LOAEL levels, and a mechanistic clarification. Hypotheses. Prolonged exposure of adult rats to BPA, at doses comparable to occupational exposures in men, and possibly at doses suggestive of environmental risk:: a) leads to its accumulation in tissues involved in the peripheral mechanism of penile erection; b) causes inflammation and oxidative stress, followed by fibro- adipogenic infiltration of the corporal smooth muscle responsible for erection, and also interferes with its nitrergic modulation, leading at certain doses to ED; and c) disrupts PPAR3-mediated pathways triggering the histopathology underlying ED, and impairing the differentiation of endogenous stem cells during tissue repair. Specific Aims. To determine whether: 1. Prolonged exposure of rats to low doses of BPA causes ED and an increase of systemic and local BPA levels, leading to histopathology of the corpora cavernosa due to fibrosis and fat infiltration, and eventually ED. 2. This is mediated by abnormal PPAR3 signaling that in addition disrupts tissue repair after corporal inflammation/ oxidative stress, by altering endogenous stem cell differentiation into key corporal cell lines and nitrergic nerve terminals. Design. Young rats will be exposed for 3 months to BPA at various doses and its effects on erectile function and the penile corporal and pelvic ganglion histology will be evaluated, using PPAR3 agonists and antagonists. The mechanism of action of BPA on smooth muscle cells and differentiation of penile Oct-4+ stem cells will also be studied in vitro, and by DNA microarray analysis of gene expression. Relevance. 1. ED affects seriously the quality of life of patients and public health care, and BPA may increase it by occupational exposure. 2. A proof of concept at low doses of BPA may justify future developmental studies. 3. A novel PPAR3 mechanism of action for BPA, may be described. PUBLIC HEALTH RELEVANCE: Bisphenol A (BPA), a key ingredient of some plastics and resins, is an environmental and occupational contaminant present in urine, and an endocrine disrupting chemical that is assumed to pose a reproductive risk at certain levels of exposure. Recently, self- reported erectile dysfunction was described in male workers occupationally exposed to BPA, but has not yet been validated by direct measures of penile erection. The current proposal aims to validate and understand these findings by determining in animal and cell culture models whether BPA at various doses causes ED by altering the penile histology and biochemistry as well as the subsequent tissue repair involving endogenous stem cells, through a novel mechanism different from the well known estrogenic-like action of BPA.

描述（由申请人提供）：背景和理由。双酚 A (BPA) 是聚碳酸酯塑料和环氧树脂的关键成分，是尿液中存在的主要内分泌干扰化学物质 (EDC)。当剂量低于 LOAEL（最低观察到的不良影响水平）时，BPA 对实验动物的生殖系统有害。其衍生物 BADGE 是一种过氧化物酶体增殖物激活受体 γ (PPAR3) 拮抗剂。最近，在职业接触 BPA 的男性工人中描述了自我报告的勃起功能障碍 (ED)，但尚未通过测量阴茎勃起进行评估。动物模型中的 ED 是由阴茎体平滑肌和氮能神经丧失、纤维化和氧化应激引起的，PPAR3 可以部分抵消 ED，并且可能通过涉及内源性 Oct-4+ 干细胞的组织修复来抵消。在大鼠模型中，高于 LOAEL 剂量的 BPA 会导致脂肪纤维变性和阴茎体组织顺应性受损。这需要在低于 LOAEL 水平上进行确认，并进行机械澄清。假设。成年大鼠长期接触 BPA，其剂量与男性职业接触剂量相当，并且可能存在环境风险的剂量： a) 导致其在参与阴茎勃起外周机制的组织中积累； b) 引起炎症和氧化应激，随后导致负责勃起的下体平滑肌的纤维脂肪浸润，并且还干扰其氮能调节，在一定剂量下导致 ED； c) 破坏 PPAR3 介导的途径，引发 ED 的组织病理学，并在组织修复过程中损害内源干细胞的分化。具体目标。确定是否： 1. 大鼠长期暴露于低剂量 BPA 会导致 ED 以及全身和局部 BPA 水平升高，导致海绵体因纤维化和脂肪浸润而发生组织病理学变化，最终导致 ED。 2. 这是由异常的 PPAR3 信号介导的，该信号此外还通过改变内源干细胞分化为关键的下体细胞系和氮能神经末梢来破坏下体炎症/氧化应激后的组织修复。设计。幼鼠将接触不同剂量的 BPA 3 个月，并使用 PPAR3 激动剂和拮抗剂评估其对勃起功能以及阴茎体和骨盆神经节组织学的影响。 BPA 对平滑肌细胞和阴茎 Oct-4+ 干细胞分化的作用机制也将在体外进行研究，并通过基因表达的 DNA 微阵列分析。关联。 1. ED严重影响患者的生活质量和公共医疗保健，而BPA可能因职业接触而加重。 2. 低剂量 BPA 的概念证明可能会证明未来的发展研究是合理的。 3. 可以描述 BPA 的一种新的 PPAR3 作用机制。 公共健康相关性：双酚 A (BPA) 是某些塑料和树脂的关键成分，是一种存在于尿液中的环境和职业污染物，也是一种内分泌干扰化学物质，在一定程度的接触下会造成生殖风险。最近，在职业接触 BPA 的男性工人中描述了自我报告的勃起功能障碍，但尚未通过阴茎勃起的直接测量来验证。目前的提案旨在通过在动物和细胞培养模型中确定不同剂量的 BPA 是否通过改变阴茎组织学和生物化学以及随后涉及内源干细胞的组织修复而导致 ED，从而验证和理解这些发现，通过一种不同于众所周知的 BPA 雌激素样作用的新机制。