Role of fetal TCDD-activited AHR in adult heart disease

胎儿 TCDD 激活的 AHR 在成人心脏病中的作用

• 批准号: 6938879
• 负责人: CRAIG R TOMLINSON
• 金额: $ 6.52万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6938879
• 关键词: aorta; aromatic hydrocarbon receptor; atherosclerotic plaque; blood pressure; cardiovascular disorder risk; carotid artery; dioxins; disease /disorder etiology; disease /disorder onset; embryo /fetus toxicology; environmental toxicology; gene environment interaction; gene expression; genetic polymorphism; genetic susceptibility; genetically modified animals; gestational age; heart disorder; histopathology; laboratory mouse; longitudinal animal study; microarray technology; ventricular hypertrophy

DESCRIPTION (provided by applicant): The primary objective of the proposed studies is to study the effects of toxicant exposures during fetal development on the adult cardiovascular (CV) system. Little is known of the etiology and progression of cardiovascular disease (CVD) in adults resulting from toxicant exposures to the pregnant mother, and the proposed studies seek to uncover early markers of disease vital in the identification of signaling pathways involved in CVD. The effect of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in CVD from fetal exposure will be examined. TCDD, the prototypical dioxin, is pervasive in the environment and causes a large number of seemingly unrelated biological effects in humans. TCDD is one of the most potent ligands for the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor responsible for the regulation of many detoxification genes. Because the AHR plays a role in CV development and cross talks with other signaling pathways, and because TCDD causes ischemic heart disease in the adult and induces changes in cell signaling; the intent of this proposal is to test the hypothesis that activation of the AHR by TCDD in the fetus causes a reprogramming of gene expression in the fetal CV system that results in the adult onset of CVD. To test this hypothesis, the following specific aims are proposed. (1) Determine the window of fetal TCDD sensitivity and the effect that the TCDD-activated AHR during gestation has on CVD and CV global transcription of adult progeny from mouse strains that differ at the Ahr locus. We hypothesize that the genomic and physiological effects of an acute TCDD exposure on the fetus are dependent on the activation of the AHR during particular time frames of gestation. (2) Determine the effect of the activated AHR on the CV system of adult progeny following treatment with biologically relevant doses of TCDD during gestation. We hypothesize that the genomic and physiological effects of biologically relevant doses of TCDD on the fetus play a large role in adult CVD. We expect to link gene profiles of acute- and chronic-based TCDD exposures to specific CVDs and to integrate our data sets with other gene profiling data sets. The results will lead to a clearer understanding of the mechanisms that are initiated from fetal exposures that lead to adult disease, and with such knowledge, preventative measures can begin to be implemented to protect mother and fetus.

描述（由申请人提供）：拟议研究的主要目的是研究胎儿发育期间有毒物质暴露对成人心血管（CV）系统的影响。对于因怀孕母亲接触有毒物质而导致的成人心血管疾病 (CVD) 的病因和进展知之甚少，拟议的研究旨在揭示疾病的早期标志物，这对于识别 CVD 涉及的信号通路至关重要。将检查 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 对胎儿暴露引起的 CVD 的影响。 TCDD 是典型的二恶英，在环境中普遍存在，会对人类造成大量看似无关的生物效应。 TCDD 是芳烃受体 (AHR) 最有效的配体之一，AHR 是一种配体激活的转录因子，负责调节许多解毒基因。因为 AHR 在 CV 发育和与其他信号通路的交互中发挥作用，并且因为 TCDD 会导致成人缺血性心脏病并诱导细胞信号传导的变化；该提案的目的是检验以下假设：胎儿中 TCDD 激活 AHR 会导致胎儿 CV 系统中的基因表达重新编程，从而导致成人 CVD 发病。为了检验这一假设，提出了以下具体目标。 (1) 确定胎儿 TCDD 敏感性窗口以及妊娠期间 TCDD 激活的 AHR 对 Ahr 基因座不同的小鼠品系成年后代的 CVD 和 CV 整体转录的影响。我们假设急性 TCDD 暴露对胎儿的基因组和生理学影响取决于妊娠特定时间范围内 AHR 的激活。 (2) 确定妊娠期间用生物学相关剂量的 TCDD 治疗后激活的 AHR 对成年后代的 CV 系统的影响。我们假设生物相关剂量的 TCDD 对胎儿的基因组和生理学影响在成人 CVD 中发挥重要作用。我们希望将急性和慢性 TCDD 暴露的基因谱与特定 CVD 联系起来，并将我们的数据集与其他基因谱数据集整合。研究结果将有助于更清楚地了解胎儿接触导致成人疾病的机制，有了这些知识，就可以开始实施预防措施来保护母亲和胎儿。