BISPHENOL A EFFECTS ON THE PERIPHERAL MECHANISMS OF PENILE ERECTION

描述（由申请人提供）：背景和基本原理。双酚A （BPA）是一种主要的内分泌干扰化学物质，存在于尿液中，是聚碳酸酯塑料和环氧树脂的关键成分。BPA在低于LOAEL（最低观察到的不良影响水平）的剂量下对实验动物的生殖系统有害。其衍生物BADGE是过氧化物酶体增殖激活受体γ (PPAR3)拮抗剂。近年来，在职业暴露于双酚a的男性工人中出现了自我报告的勃起功能障碍（ED），但尚未对其阴茎勃起进行评估。动物模型中的ED是由阴茎下体平滑肌和氮神经的丧失、纤维化和氧化应激引起的，部分由PPAR3抵消，据推测由内源性Oct-4+干细胞参与的组织修复。在一个大鼠模型中，超loael剂量的BPA引起脂肪纤维化变性和阴茎下体组织顺应性损伤。这需要在loael以下级别进行确认，并进行机制澄清。假设。成年大鼠长期暴露于双酚a，其剂量与男性的职业暴露相当，且剂量可能表明存在环境风险：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，随后纤维脂肪性浸润负责勃起的下体平滑肌，并干扰其氮代谢调节，在一定剂量下导致ED；c)破坏ppar3介导的通路，触发ED的组织病理学，并在组织修复过程中损害内源性干细胞的分化。具体的目标。判断方法如下：1；大鼠长期暴露于低剂量双酚a可引起ED，全身和局部双酚a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，最终导致ED。这是由异常的PPAR3信号介导的，此外，PPAR3信号通过改变内源性干细胞向关键的下体细胞系和氮神经末梢的分化，破坏了下体炎症/氧化应激后的组织修复。设计。使用PPAR3激动剂和拮抗剂，将幼鼠暴露于不同剂量的双酚a 3个月，并评估其对勃起功能和阴茎下体和盆腔神经节组织学的影响。BPA对阴茎平滑肌细胞和Oct-4+干细胞分化的作用机制也将在体外进行研究，并通过DNA微阵列分析基因表达。相关性。1。ED严重影响患者的生活质量和公共卫生保健，BPA可通过职业暴露增加ED。2. 低剂量双酚A的概念证明可能证明未来的发展研究是正确的。3. 可以描述一种新的PPAR3对BPA的作用机制。

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.