Molecular mechanism of endocrine disruption

内分泌干​​扰的分子机制

• 批准号: 6664567
• 负责人: Nancy D Denslow
• 金额: $ 13.16万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-25 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6664567
• 关键词: chlorohydrocarbon; environmental contamination; environmental exposure; environmental toxicology; estrogen analog; fish; gene expression; hazardous substances; hormone receptor; hormone regulation /control mechanism

Exposure of wildlife and humans to environmental contaminants that behave as hormones has caused widespread alarm. Reproductive damages reported to date include reduced fertility, reduced hatchability, reduced viability of offspring, impaired hormone activity and altered sexual behavior. Chlorinated hydrocarbons, such as DDE and methoxychlor, and non ionic surfactants, such as nonylphenol, are among the chemicals of concern and these are present in sufficiently high concentrations to activate the estrogen cascade pathway, turning on the expression of genes controlled by estrogen at inappropriate times. In addition, another key modulator mechanism of action of environmental estrogens may be through non-estrogen receptor pathways, in particular estrogen-mediated altered regulation of xenobiotic transformation pathways. These include steroid oxidation pathways and phase II conjugation pathways. These include steroid oxidation pathways and phase II conjugation pathways. We have centered our studies on understanding the mechanisms involved in endocrine disruption of largemouth bass found in the highly polluted, superfund site at Lake Apopka and the much farms in the area of central Florida. We propose to study these species in laboratory in vivo and in vitro experiments to define the mechanisms involved. We also plan to develop an endocrine toxicology based gene expression array (DNA chip) specific for fish that can be used to detect exposure to endocrine disrupting compounds in the environment. Our specific aims include 1: Evaluation of mechanism for estrogen receptor based molecular change; 2: Characterization of the estrogen receptors alpha and beta in their model of action; 3. Determination of the effects of natural and synthetic estrogens on xenobiotic biotransformation; and 4: Development of an endocrine toxicology based gene expression array (DNA chip) to evaluate endocrine disruption. In the final phases of this project we will use the DNA chip to evaluate the gene induction status of fish from Lake Apopka and much farm regions.

野生动物和人类暴露在表现为荷尔蒙的环境污染物中，引起了广泛的警觉。到目前为止，报告的生殖损害包括生育力下降、孵化率下降、后代生存能力下降、激素活性受损和性行为改变。氯代烃，如DDE和甲氧氯胺，以及非离子表面活性剂，如壬基酚，都是令人担忧的化学物质，它们的浓度足够高，可以激活雌激素级联通路，在不适当的时间启动雌激素控制的基因的表达。此外，环境雌激素作用的另一个关键调控机制可能是通过非雌激素受体途径，特别是雌激素介导的异种转化途径的调节改变。这些途径包括类固醇氧化途径和II相结合途径。这些途径包括类固醇氧化途径和II相结合途径。我们的研究重点是了解在高度污染的超级基金地点阿波普卡湖和佛罗里达州中部地区的许多养殖场发现的大口鲈鱼内分泌干扰的机制。我们建议在实验室、体内和体外实验中对这些物种进行研究，以确定涉及的机制。我们还计划开发一种基于内分泌毒理学的鱼类特有的基因表达阵列(DNA芯片)，可以用来检测环境中暴露于内分泌干扰化合物的情况。我们的具体目标包括1：评估基于雌激素受体的分子变化的机制；2：表征雌激素受体α和β的作用模式；3.确定天然和合成雌激素对异种生物生物转化的影响；以及4：建立基于内分泌毒理学的基因表达阵列(DNA芯片)来评估内分泌干扰。在这个项目的最后阶段，我们将使用DNA芯片来评估来自阿波普卡湖和许多养殖场地区的鱼类的基因诱导状态。