Early life stage exposure to TCDD produces persistent, heritable cardiac toxicity

生命早期接触 TCDD 会产生持久的、遗传性的心脏毒性

• 批准号: 7485893
• 负责人: Tisha C. King-Heiden
• 金额: $ 0.96万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2008-07-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485893
• 关键词: Adolescent; Adult; Barker Hypothesis; Biochemical; Cardiac; Cardiotoxicity; Cardiovascular Diseases; Congenital Heart Defects; Development; Dioxins; Embryo; Embryonic Development; End Point; Environmental Pollution; Epigenetic Process; Exposure to; Fertilization; Foundations; Gene Expression; Generations; Goals; Growth and Development function; Health; Heart; Heart Diseases; Heart failure; Human; Hypoplastic Left Heart Syndrome; Larva; Lead; Life; Modeling; Organ; Predisposition; Process; Research; Research Proposals; Risk; Staging; Syndrome; Testing; Tetrachlorodibenzodioxin; Time; Toxic effect; Work; Zebrafish; congenital heart disorder; day; environmental agent; heart function; improved

DESCRIPTION (provided by applicant): Since congenital heart defects constitute an important health concern, and the relationship between exposure to environmental contaminants during early development and adult-onset of cardiovascular disease is not well understood, there is a clear need for the generation of models to explain the processes by which environmental contaminants contribute to cardiac malformation and heart failure. TCDD (2,3,7,8- tetrachlorodibenzo-p-dioxin) is an environmental contaminant known to pose significant health risks. For example, exposure to dioxins such as TCDD is associated with congenital heart disease. Research by the Peterson/Heideman group has revealed that the heart is a target organ for TCDD-induced developmental toxicity in zebrafish, and it's effects on the heart resemble hypoplastic left heart syndrome in humans. My preliminary results show for the first time in zebrafish that exposure to sublethal concentrations of TCDD during early development and juvenile stages results in cardiac toxicity that persists in adults. The overall goal of this work is to determine if persistent, heritable cardiac toxicity is induced by sublethal exposure to TCDD during early life stages. To accomplish this goal, I will use zebrafish to test three hypotheses. First, I will test the hypothesis that sublethal exposure to TCDD during embryonic development will cause endpoints of cardiac toxicity and changes in gene expression that are similar to those caused by lethal TCDD exposure. Information obtained from these studies will help us to understand the mechanisms by which early developmental exposure to TCDD induces hypoplastic heart syndrome and heart failure in zebrafish. Second, I will test the hypothesis that exposure to TCDD during early life and juvenile stages will result in cardiac toxicity that persists in adults. These results will enable us to develop models for correlating exposure to TCDD during early development with adult-onset of heart disease. Third, I will test the hypothesis that sublethal exposure to TCDD during early life and juvenile stages results in cardiac toxicity that is heritable, and that their offspring show reduced development, growth and survival associated with impaired cardiac health. I will use biochemical approaches to confirm that reduced health and survival of the F1 generation is not the result of TCDD exposure via maternal transfer. Results obtained will lay the foundation for determining whether TCDD can induce cardiac disease via epigenetic mechanisms. This work will significantly contribute to our understanding of how exposure to sublethal concentrations of TCDD during early life stages contributes to susceptibility to heart disease later in life.

描述（由申请方提供）：由于先天性心脏缺陷构成了一个重要的健康问题，并且尚未充分了解早期发育期间暴露于环境污染物与成人心血管疾病发作之间的关系，因此明确需要生成模型来解释环境污染物导致心脏畸形和心力衰竭的过程。TCDD（2，3，7，8- tetrachlorodibenzo-p-dioxin）是一种环境污染物，对人体健康有很大危害。例如，暴露于二恶英（如TCDD）与先天性心脏病有关。Peterson/Heideman小组的研究表明，心脏是TCDD诱导的斑马鱼发育毒性的靶器官，它对心脏的影响类似于人类的左心发育不良综合征。我的初步研究结果表明，第一次在斑马鱼，暴露于亚致死浓度的TCDD在早期发展和少年阶段的心脏毒性，持续在成年人的结果。这项工作的总体目标是确定是否持续的，遗传的心脏毒性是由亚致死暴露于TCDD在生命早期阶段。为了实现这一目标，我将使用斑马鱼来测试三个假设。首先，我将测试的假设，亚致死暴露于TCDD在胚胎发育过程中将导致心脏毒性和基因表达的变化，这是类似于致命的TCDD暴露所造成的终点。从这些研究中获得的信息将有助于我们了解早期发育暴露于TCDD诱导斑马鱼心脏发育不良综合征和心力衰竭的机制。其次，我将测试的假设，暴露于TCDD在生命早期和少年阶段将导致心脏毒性，持续在成年人。这些结果将使我们能够建立模型，将早期发育过程中暴露于TCDD与成人心脏病发作相关联。第三，我将测试的假设，亚致死暴露于TCDD在生命早期和青少年阶段的心脏毒性是可遗传的，他们的后代表现出减少的发展，生长和生存与受损的心脏健康。我将使用生物化学的方法来证实，减少健康和生存的F1代是不是通过母体转移TCDD暴露的结果。研究结果将为确定TCDD是否通过表观遗传机制诱发心脏病奠定基础。这项工作将大大有助于我们了解如何暴露于亚致死浓度的TCDD在生命早期阶段有助于心脏病的易感性在以后的生活。

项目成果

Quantum dot nanotoxicity assessment using the zebrafish embryo.

• DOI: 10.1021/es801925c
• 发表时间: 2009-03-01
• 期刊: ENVIRONMENTAL SCIENCE & TECHNOLOGY
• 影响因子: 11.4
• 作者: King-Heiden, Tisha C.;Wiecinski, Paige N.;Mangham, Andrew N.;Metz, Kevin M.;Nesbit, Dorothy;Pedersen, Joel A.;Hamers, Robert J.;Heideman, Warren;Peterson, Richard E.
• 通讯作者: Peterson, Richard E.