The role of ERR-gamma in the developmental toxicity of bisphenol A

ERR-gamma 在双酚 A 发育毒性中的作用

• 批准号: 8111879
• 负责人: Robyn L Tanguay
• 金额: $ 17.5万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111879
• 关键词: Adult; Affect; Affinity; Agonist; Behavior; Behavioral; Binding; Biological Markers; Brain; Communities; Data; Development; Diet; Dose; Embryo; Epigenetic Process; Estradiol; Estrogen Nuclear Receptor; Estrogen Receptors; Estrogens; Exhibits; Exposure to; Fertilization; Fishes; Future; Gene Expression; Genes; Grant; Health; Human; Immunohistochemistry; Industry; Investigation; Larva; Learning; Life; Ligands; Mediating; Methylation; Modeling; Modification; Molecular; Motor Activity; Mus; National Toxicology Program; Nervous System Physiology; Nervous system structure; Neuraxis; Neurons; Nuclear Receptors; Oligonucleotides; Outcome; Phenotype; Placenta; Population; Propane; Protocols documentation; Receptor Activation; Reporting; Research; Response Elements; Risk; Rodent; Role; Sex Characteristics; Space Perception; Staging; Structure; System; Testing; Time; Tissues; Toxic effect; Toxicogenomics; Transcript; Transgenic Organisms; Translations; Zebrafish; abstracting; bisphenol A; comparative; critical period; epidemiology study; estrogen-related receptor; genome-wide; in vivo; molecular marker; nervous system development; neuron development; performance tests; public health relevance; receptor; research study; response

DESCRIPTION (provided by applicant): Abstract Low levels of bisphenol A (BPA; 2,2-bis(4-hydroxyphenyl)propane) are detectable throughout the US population. Whether these low levels of exposure pose a human health risk remain controversial and uncertain. Comparable low levels of BPA cause behavioral abnormalities in adult rodents exposed during critical periods of central nervous system (CNS) development, leading the National Toxicology Program to recently report concern that low dose BPA exposure can impair CNS development. The predominant assumption that BPA exerts its CNS effects through estrogen receptor (ER) activation is unlikely due to BPA's weak binding affinity for classical ERs. However, BPA exhibits 100- to 10,000-fold greater binding affinity for estrogen related receptor gamma (ERR3). ERR3 is a nuclear receptor that is highly expressed in the brain and placenta during critical periods of development, has no known endogenous ligand, and is constitutively active at estrogen response elements (EREs). This proposal will test the hypothesis that low dose developmental BPA exposure perturbs CNS development and behavior by maintaining ERR3 constitutive activity during critical windows of development resulting in abnormal expression of genes containing EREs or ERREs. Preliminary studies conducted to support this two year exploratory grant suggest that developmental exposure to non-teratogenic, low concentrations (<1<M) of BPA increases motor activity in larval and adult zebrafish. Two specific aims have been developed to define the role of ERR3 in mediating the physical and behavioral effects of low dose BPA. In the first Specific Aim, we will determine whether environmentally relevant concentrations of BPA affect nervous system development and functions in zebrafish developmentally exposed to low concentrations of BPA. The role of ERR3 in producing these responses will be determined by repressing ERR3 expression specifically during the BPA exposure window. In the second Specific Aim, comparative gene expression studies will be used to identify in vivo functional biomarkers and determine the role of ERR3 in their expression. We will also utilize a powerful, newly described transgenic methylation-responsive fish to investigate epigenetic effects of BPA exposure specifically in the brain. These experiments will probe for the first time a potential epigenetic mechanism by which low concentration BPA exposure impairs CNS function, and define the role of ERR3 in mediating these effects. The role of ERR3 in mediating low dose BPA effects on the CNS has not been previously investigated. The zebrafish model is ideally suited to quickly and definitively answer whether ERR3 is central to the mechanism of BPA's action on the developing CNS. This proposal will benefit the scientific community, industry, and the public by defining whether the most likely candidate receptor, ERR3, mediates BPA's low dose effects on CNS development and behavior. PUBLIC HEALTH RELEVANCE: In recent years the public and the scientific community have become concerned with the risk that bisphenol A (BPA) may pose to human health. This project will use the unique advantages of the embryonic zebrafish model to dissect the mechanism by which low concentrations of BPA interact with and perturb central nervous development and function.

描述(由申请人提供)：摘要低水平的双酚A(BPA；2，2-双(4-羟基苯基)丙烷)在整个美国人口中都可以检测到。这些低水平的接触是否会对人类健康构成风险仍然存在争议和不确定性。在中枢神经系统(CNS)发育的关键时期，低水平的BPA会导致成年啮齿动物的行为异常，导致国家毒理学计划最近报告了对低剂量BPA暴露可能损害中枢神经系统发育的担忧。BPA通过激活雌激素受体(ER)发挥其中枢神经系统作用的主要假设不太可能，因为BPA与经典ER的结合亲和力很弱。然而，BPA与雌激素相关受体γ(ERR3)的结合亲和力是雌激素相关受体伽马(ERR3)的100到10,000倍。ERR3是一种核受体，在发育的关键时期在大脑和胎盘中高表达，没有已知的内源性配体，在雌激素反应元件(ERE)中具有结构性活性。这一提议将检验这一假说，即低剂量的发育性BPA暴露通过在发育的关键窗口维持ERR3的结构活性，导致含有ERE或ERRES的基因的异常表达，从而扰乱中枢神经系统的发育和行为。为支持这项为期两年的探索性拨款而进行的初步研究表明，发育过程中暴露于非致畸、低浓度(&lt；1&lt；M)双酚A会增加幼体和成年斑马鱼的运动活动。已经开发了两个特定的目标来定义ERR3在调节低剂量BPA的生理和行为效应中的作用。在第一个具体目标中，我们将确定环境相关浓度的双酚A是否会影响低浓度双酚A对斑马鱼神经系统发育和功能的影响。ERR3在产生这些反应中的作用将通过在BPA暴露窗口中特异性地抑制ERR3的表达来确定。在第二个具体目标中，将使用比较基因表达研究来确定体内功能生物标记物，并确定ERR3在其表达中的作用。我们还将利用一种新描述的强大的转基因甲基化反应鱼来研究BPA暴露的表观遗传效应，特别是在大脑中。这些实验将首次探索低浓度双酚A暴露损害中枢神经系统功能的潜在表观遗传学机制，并确定ERR3在介导这些影响中的作用。ERR3在调节低剂量双酚A对中枢神经系统影响中的作用以前还没有被研究过。斑马鱼模型非常适合于快速和明确地回答ERR3是否是BPA对发育中的中枢神经系统的作用机制的核心。这项建议将通过确定最有可能的候选受体ERR3是否介导双酚A对中枢神经系统发育和行为的低剂量影响，使科学界、行业和公众受益。 公共卫生相关性：近年来，公众和科学界开始关注双酚A(BPA)可能对人类健康构成的风险。该项目将利用斑马鱼胚胎模型的独特优势，剖析低浓度双酚A与中枢神经发育和功能相互作用和干扰的机制。