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于具有荷尔蒙作用的环境污染物中已经引起了广泛的警惕。迄今为止报道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。氯化烃（例如 DDE 和甲氧氯）和非离子表面活性剂（例如壬基酚）属于令人关注的化学物质，它们的浓度足够高，足以激活雌激素级联途径，在不适当的时间开启受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节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生素转化途径的改变调节。这些包括类固醇氧化途径和第二相结合途径。这些包括类固醇氧化途径和第二相结合途径。我们的研究重点是了解阿波普卡湖高度污染的超级基金站点和佛罗里达州中部地区的许多农场中发现的大口黑鲈内分泌干扰机制。我们建议在实验室体内和体外实验中研究这些物种，以确定所涉及的机制。我们还计划开发一种专门针对鱼类的基于内分泌毒理学的基因表达阵列（DNA 芯片），可用于检测环境中内分泌干扰化合物的暴露情况。我们的具体目标包括1：评估基于雌激素受体的分子变化机制；图2：雌激素受体α和β在其作用模型中的表征； 3.测定天然和合成雌激素对外源生物转化的影响； 4：开发基于内分泌毒理学的基因表达阵列（DNA 芯片）以评估内分泌干扰。在该项目的最后阶段，我们将使用 DNA 芯片来评估阿波普卡湖和许多农场地区鱼类的基因诱导状态。