AhR- and ER-Regulated Genes in Brain Development

大脑发育中的 AhR 和 ER 调控基因

• 批准号: 7086218
• 负责人: SANDRA L PETERSEN
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086218
• 关键词: aromatic hydrocarbon receptor; developmental neurobiology; dioxins; environmental exposure; estradiol; estrogen receptors; gamma aminobutyrate; gender difference; gene environment interaction; gene expression; genetic transcription; glutamates; histochemistry /cytochemistry; in situ hybridization; laboratory rat; laser capture microdissection; ligands; longitudinal animal study; microarray technology; neurotoxicology; paraventricular nucleus; polymerase chain reaction; reproductive system disorder; site directed mutagenesis; testosterone

DESCRIPTION (provided by applicant): Our long-term objective is to determine the mechanisms by which developmental exposure to dioxins and other ubiquitous arylhydrocarbon receptor (AhR) ligands alters reproductive functions in adulthood. We recently showed that a single developmental exposure to the potent AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), interferes with estrogen-dependent sexual differentiation of the male anteroventral periventricular nucleus (AVPV). The AVPV controls the female pattern of luteinizing hormone (LH) release; therefore, TCDD-exposed males have a female-like AVPV structure and they show the female, cyclic pattern of LH release in adulthood. Considering that estradiol (E2) derived from fetal production of testosterone is responsible for the sexual differentiation process, we hypothesize that TCDD interferes with E2 regulation of a set of genes during development. To test this hypothesis, we will use Affymetrix microarrays and cluster analysis to identify sex-specific genes that are regulated by E2 and TCDD. We will use a "redundancy model", testing different animal treatments predicted by our hypothesis to target the same set of genes. We will validate our microarray findings using RT-QPCR, in situ hybridization histochemistry, developmental ontogeny studies, dose response studies and promoter analysis. Our findings will be important for identifying genes underlying effects of dioxins and other ubiquitous AhR ligands on reproductive toxicity, as well as on other neural functions disrupted by perinatal TCDD exposure in a sex-specific manner. Such findings will be important for mechanism-based risk assessment, as well as for development of pharmaceutical interventions to prevent neurotoxicity.

描述（由申请人提供）：我们的长期目标是确定发育过程中接触二恶英和其他普遍存在的芳基烃受体 (AhR) 配体改变成年期生殖功能的机制。我们最近表明，单次发育暴露于强效 AhR 配体 2,3,7,8-四氯二苯并-对二恶英 (TCDD)，会干扰雄性前腹侧室周核 (AVPV) 的雌激素依赖性性别分化。 AVPV 控制女性黄体生成素 (LH) 的释放模式；因此，暴露于 TCDD 的雄性具有类似雌性的 AVPV 结构，并且在成年期表现出雌性的 LH 释放循环模式。考虑到胎儿产生的睾酮产生的雌二醇 (E2) 负责性别分化过程，我们假设 TCDD 会干扰发育过程中一组基因的 E2 调节。为了检验这一假设，我们将使用 Affymetrix 微阵列和聚类分析来识别受 E2 和 TCDD 调节的性别特异性基因。我们将使用“冗余模型”，测试我们的假设预测的针对同一组基因的不同动物治疗方法。我们将使用 RT-QPCR、原位杂交组织化学、发育个体发育研究、剂量反应研究和启动子分析来验证我们的微阵列研究结果。我们的研究结果对于识别二恶英和其他普遍存在的 AhR 配体对生殖毒性以及围产期 TCDD 暴露以性别特异性方式破坏的其他神经功能的潜在影响基因非常重要。这些发现对于基于机制的风险评估以及预防神经毒性的药物干预措施的开发非常重要。