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: 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
• 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

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）：背景和原理。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物（EDC）。BPA在低于LOAEL（最低观测不良反应水平）的剂量下对实验动物的生殖系统有害。衍生物BADGE是过氧化物酶体增殖物激活受体γ（PPAR 3）拮抗剂。最近，自我报告的勃起功能障碍（艾德）被描述为男性工人职业暴露于BPA，但这还没有评估测量阴茎勃起。动物模型中的艾德是由阴茎海绵体平滑肌和氮能神经的损失、纤维化和氧化应激引起的，部分地被PPAR 3抵消，并且通过涉及内源性Oct-4+干细胞的组织修复而坏死。在大鼠模型中，超LOAEL剂量的BPA导致阴茎组织脂肪纤维变性和顺应性受损。这需要在低于LOAEL水平下进行确认，并从机理上进行澄清。假设。成年大鼠长期暴露于BPA，剂量与男性职业暴露相当，可能暗示环境风险：a）导致其在阴茎勃起外周机制相关组织中蓄积; B）引起炎症和氧化应激，随后引起负责勃起的身体平滑肌的非脂肪形成性浸润，并且还干扰其氮能调节，在某些剂量下导致艾德;和c）破坏触发艾德潜在的组织病理学的PPAR 3介导的途径，并在组织修复期间损害内源性干细胞的分化。具体目标。要确定是否：1.大鼠长期暴露于低剂量BPA会导致艾德性ED和全身和局部BPA水平的增加，导致海绵体由于纤维化和脂肪浸润而发生组织病理学改变，最终导致ED。这是由异常的PPAR 3信号传导介导的，该信号传导还通过改变内源性干细胞分化成关键的躯体细胞系和氮能神经末梢来破坏躯体炎症/氧化应激后的组织修复。设计将年轻大鼠暴露于不同剂量的BPA 3个月，并使用PPAR 3激动剂和拮抗剂评价其对勃起功能和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研究，并通过基因表达的DNA微阵列分析。本案无关1.艾德严重影响患者的生活质量和公共卫生保健，BPA可能通过职业暴露增加它。2.低剂量BPA的概念验证可能证明未来的发展研究是合理的。3.可以描述BPA的新的PPAR 3作用机制。 公共卫生相关性：双酚A（BPA）是一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品，被认为在一定程度的暴露下会造成生殖风险。最近，在职业暴露于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。目前的建议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的涉及内源性干细胞的组织修复引起艾德，通过一种不同于BPA众所周知的雌激素样作用的新机制来验证和理解这些发现。

项目成果

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
• 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.