BISPHENOL A EFFECTS ON THE PERIPHERAL MECHANISMS OF PENILE ERECTION

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EPOXI树脂的关键成分，是尿液中存在的一种主要内分泌干扰物(EDC)。BPA在低于LOAEL(观察到的最低不良反应水平)的剂量下对实验动物的生殖系统有害。一种名为BAGE的衍生物，是一种过氧化物酶体增殖物激活受体γ(PPAR3)拮抗剂。最近，自我报告的勃起功能障碍(ED)在职业暴露于BPA的男性工人中被描述，但这还没有被评估测量阴茎勃起。动物模型中的ED是由阴茎体部平滑肌和氮能神经的丧失、纤维化和氧化应激引起的，PPAR3部分抵消了这一过程，可能是通过涉及内源性Oct-4+干细胞的组织修复。超LOAEL剂量的双酚A可导致大鼠阴茎下体组织的脂肪纤维变性和顺应性受损。这需要在次级LOAEL级别进行确认，并进行机械性的澄清。假设。成年大鼠长期暴露在BPA下，剂量与男性职业暴露相当，可能也有环境风险：a)导致BPA在参与阴茎勃起外围机制的组织中蓄积；b)导致炎症和氧化应激，随后成纤维脂肪渗入负责勃起的阴茎平滑肌，还干扰其氮能调节，在一定剂量下导致勃起功能障碍；c)扰乱PPAR3介导的通路，引发勃起功能障碍的组织病理学，并损害组织修复过程中内源性干细胞的分化。明确的目标。目的：1.大鼠长期暴露于低剂量BPA是否会导致ED和全身及局部BPA水平升高，从而导致海绵体纤维化和脂肪渗出的组织病理学改变，最终导致ED。2.这是由异常的PPAR3信号介导的，PPAR3信号异常还通过改变内源性干细胞向关键的躯体细胞系和氮能神经末梢的分化来扰乱全身炎症/氧化应激后的组织修复。设计。将幼年大鼠暴露于不同剂量的双酚A 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、阴茎和盆神经节组织学的影响。BPA对平滑肌细胞的作用机制和阴茎OCT-4+干细胞的分化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可通过职业性暴露增加其影响。2.低剂量双酚A的概念验证可能会证明未来的发育研究是正确的。3.可描述一种新的双酚A的PPAR3作用机制。 与公众健康相关：双酚A(BPA)是一些塑料和树脂的关键成分，是尿液中存在的一种环境和职业污染物，也是一种内分泌干扰性化学物质，被认为在一定水平的暴露下会造成生殖风险。最近，自我报告的勃起功能障碍在职业暴露于双酚A的男性工人中被描述，但尚未通过阴茎勃起的直接测量来证实。目前的建议旨在通过在动物和细胞培养模型中确定不同剂量的双酚A是否通过改变阴茎组织学和生化以及随后涉及内源性干细胞的组织修复来引起勃起功能障碍，从而验证和理解这些发现，这是一种不同于众所周知的雌激素样作用的新机制。

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.