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

基本信息

批准号：
8265089
负责人：
Nestor F Gonzalez-Cadavid
金额：
$ 1.02万
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：
2010
资助国家：
美国
起止时间：
2010-08-10 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8265089
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

项目摘要

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。 Bisphenol A（BPA）是聚碳酸酯塑料和Epoxi树脂的关键成分，是尿液中存在的主要内分泌干扰化学（EDC）。 BPA对实验动物的生殖系统的剂量低于LOAEL（最低观察到的不良反应水平）是有害的。衍生物徽章是过氧化物酶体增生剂激活的受体伽马（PPAR3）拮抗剂。最近，在暴露于BPA的男性工人中描述了自我报告的勃起功能障碍（ED），但尚未评估测量阴茎勃起的测量。在动物模型中，ED是由阴茎体平滑肌和硝化神经，纤维化和氧化应激的丧失引起的，部分由PPAR3抵消，并通过涉及内源性OCT-4+干细胞的组织修复进行了预测。上loael剂量的BPA会导致大鼠模型中阴茎体组织的合规性脂肪纤维化变性和障碍。这需要在子层水平上进行确认，并进行机械澄清。假设。成年大鼠长时间暴露于BPA，剂量可与男性的职业暴露相当，可能以剂量的剂量提示环境风险:: a）导致其在参与阴茎勃起外围机制的组织中积累； b）引起炎症和氧化应激，然后引起负责勃起的体平滑肌的纤维成肌浸润，还干扰了其硝化调节，以某些剂量导致ED； c）破坏PPAR3介导的途径触发了ED的组织病理学，并损害了组织修复过程中内源性干细胞的分化。具体目标。确定：1。大鼠长时间暴露于低剂量的BPA引起ED以及全身和局部BPA水平的升高，导致由于纤维化和脂肪浸润而导致Corpora Cavernosa的组织病理学，并最终ED。 2。这是由异常的PPAR3信号传达介导的，此外，通过将内源性干细胞细胞分化为关键的体体细胞系和硝化神经末端，会破坏体内炎症/氧化应激后的组织修复。设计。将使用PPAR3激动剂和拮抗剂评估年轻大鼠以各种剂量暴露于BPA及其对勃起功能的影响，其对勃起功能的影响。 BPA对平滑肌细胞的作用机理和Penile Oct-4+干细胞的分化也将在体外以及基因表达的DNA微阵列分析中研究。关联。 1. ED严重影响患者和公共卫生保健的生活质量，而BPA可能会通过职业接触而增加。 2。低剂量BPA的概念证明可以证明未来的发展研究是合理的。 3。可以描述一种新型的BPA作用机理。公共卫生相关性：Bisphenol A（BPA）是某些塑料和树脂的关键成分，是尿液中存在的环境和职业污染物，并且是一种内分泌干扰化学物质，被认为在某些暴露水平的暴露水平上构成生殖风险。最近，自我报告的勃起功能障碍在暴露于BPA的男性工人的职业中描述了，但尚未通过阴茎勃起的直接测量来验证。当前的提案旨在通过在动物和细胞培养模型中确定各种剂量的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性干细胞的随后的组织修复，通过与新型机制不同的新机制来验证和理解这些发现。 BPA众所周知的雌激素样作用。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chronic high dose intraperitoneal bisphenol A (BPA) induces substantial histological and gene expression alterations in rat penile tissue without impairing erectile function.

DOI：
10.1111/jsm.12336
发表时间：
2013-12
期刊：
The journal of sexual medicine
影响因子：
0
作者：
Kovanecz I;Gelfand R;Masouminia M;Gharib S;Segura D;Vernet D;Rajfer J;Li DK;Liao CY;Kannan K;Gonzalez-Cadavid NF
通讯作者：
Gonzalez-Cadavid NF

Oral Bisphenol A (BPA) given to rats at moderate doses is associated with erectile dysfunction, cavernosal lipofibrosis and alterations of global gene transcription.

DOI：
10.1038/ijir.2013.37
发表时间：
2014-03
期刊：
INTERNATIONAL JOURNAL OF IMPOTENCE RESEARCH
影响因子：
2.6
作者：
Kovanecz, I.;Gelfand, R.;Masouminia, M.;Gharib, S.;Segura, D.;Vernet, D.;Rajfer, J.;Li, D. K.;Kannan, K.;Gonzalez-Cadavid, N. F.
通讯作者：
Gonzalez-Cadavid, N. F.