Novel Action of Estrogenic Molecules During Early Neural Development

雌激素分子在早期神经发育过程中的新作用

• 批准号: 7012463
• 负责人: R DAVID HEATHCOTE
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-09 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7012463
• 关键词: Xenopus; antisense nucleic acid; autoradiography; biological signal transduction; cell differentiation; central neural pathway /tract; dopamine; embryo /fetus toxicology; endocrine disrupting compound; estradiol; estrogen analog; estrogen receptors; estrogens; gene expression; gene targeting; metamorphosis; neuroendocrine system; neurogenesis; neurotoxicology; nonmammalian vertebrate embryology; oligonucleotides; phenols; radioimmunoassay; radiotracer; receptor expression; sex determination; Xenopus; antisense nucleic acid; autoradiography; biological signal transduction; cell differentiation; central neural pathway /tract; dopamine; embryo /fetus toxicology; endocrine disrupting compound; estradiol; estrogen analog; estrogen receptors; estrogens; gene expression; gene targeting; metamorphosis; neuroendocrine system; neurogenesis; neurotoxicology; nonmammalian vertebrate embryology; oligonucleotides; phenols; radioimmunoassay; radiotracer; receptor expression; sex determination

DESCRIPTION (provided by applicant): The objective of this proposal is to understand how a novel action of estrogen and man-made xenoestrogens affect the initial patterning and development of the nervous system. This will expand our knowledge of the signaling pathways that regulate a specific type of neuron. It also identifies a potential cellular target of endocrine disruptor molecules, which may be related to long-term effects on organismal development. These studies utilize Xenopus laevis, an NIH model organism. The first specific aim tests whether the amount and location of estrogen plays a role in the normal development of dopaminergic neurons and if exogenous estrogen and xenoestrogens are localized near the affected neuron population. The second aim identifies the molecular signaling pathway utilized by estrogen to affect dopaminergic neurons through loss- and gain-of-function experiments with different estrogen receptors. These experiments use antisense morpholinos to knock down specific estrogen receptors and the RNA of individual receptors to achieve their overexpression. The effects will be measured on the dopaminergic neuron population during normal development and in response to additional estrogen. The third aim tests the long- term consequences of brief embryonic exposure to estrogen and xenoestrogens. Prolonged exposure to estrogen during later periods of development affects sex determination and metamorphosis in Xenopus. Given the pronounced cellular effect on dopaminergic neurons after brief embryonic exposure, they could mediate these developmental changes. If estrogenic molecules including Bisphenol A and Octylphenol can alter sex determination and metamorphosis in developing Xenopus, it would indicate there are potential hazards associated with embryonic exposure to estrogenic compounds in a wide range of vertebrates, including humans. Relevance to public health. Endocrine disrupters are man-made molecules present in the environment that interfere with the normal hormonal signaling pathways in humans and animals alike. This proposal examines the molecular mechanisms used by estrogen and endocrine disrupters that mimic it (xenoestrogens) to affect the initial development of a specific population of neurons and its potential long term effects on the organism.

描述（由申请人提供）：该提案的目的是了解雌激素和人造异种雌激素的新作用如何影响神经系统的初始图案和发展。这将扩大我们对调节特定类型神经元的信号通路的了解。它还确定了内分泌干扰物分子的潜在细胞靶标，这可能与对生物发育的长期影响有关。这些研究利用了NIH模型生物Xenopus laevis。第一个特定的目的测试雌激素的数量和位置是否在多巴胺能神经元的正常发育中起作用，以及外源性雌激素和异种雌激素是否位于受影响的神经元种群附近。第二个目标确定了雌激素利用的分子信号通路，以通过不同的雌激素受体的损失和功能获得实验来影响多巴胺能神经元。这些实验使用反义形态学来击落特定的雌激素受体和单个受体的RNA以实现其过表达。这种影响将在正常发育过程中对多巴胺能神经元种群进行测量，并响应其他雌激素。第三个目标测试了短暂的胚胎暴露于雌激素和异种雌激素的长期后果。晚期发育期间长时间暴露于雌激素会影响爪蟾的性别确定和变形。鉴于短暂的胚胎暴露后，明显的细胞对多巴胺能神经元的影响，它们可以介导这些发育变化。如果包括双酚A和辛基酚在内的雌激素分子可以改变性爪蟾的性别测定和变形，这将表明在包括人类在内的各种脊椎动物中，胚胎暴露于雌激素化合物（包括人类）中存在潜在的危害。与公共卫生有关。内分泌脱落是存在于人类和动物中正常激素信号通路的环境中的人造分子。该提案研究了模仿IT（异种雌激素）的雌激素和内分泌的分子机制，以影响特定神经元群体的初始发展及其对生物体的潜在长期影响。