Effects of Environmental Estrogen Exposure on Spontaneous Copy Number Variation

描述（由申请人提供） 候选人的长期目标是在一所研究型大学获得教职，这样她就可以继续独立研究环境雌激素如何影响人类。短期目标是确定环境雌激素是否能够改变脊椎动物的基因组。近期目标是发展必要的技能和培训，主要是阵列比较基因组杂交（CGH）和吗啉代注射，以开发使用这些方法和技能的独立研究计划。虽然CGH的使用不是一项新技术，但其作为确定正常个体之间是否存在基因组变化的方法的使用只是最近才被使用。 李博士是这项技术的先驱，在他在布里格姆妇女医院的指导下，以及在哈佛医学院高度合作的教育环境下，候选人将被允许学习和掌握其使用。候选人完全相信，这是一个理想的环境，以促进他们的职业生涯，并利用这个奖项成为独立的调查员。环境雌激素是环境中改变天然雌激素或与天然雌激素相互作用的化学物质。这些化学物质包括一系列广泛的化合物，如滴滴涕农药，增塑剂，如双酚A和药物，如人类避孕药（17-α-乙炔基炔雌醇; EE 2）。 尽管这些化学品与环境有关，并且已知和怀疑对人类和动物有影响，但尚未进行任何研究来确定这些化学品是否会引起基因组水平的变化。本研究的目的是确定环境相关浓度的EE 2是否能够使用模式生物斑马鱼诱导基因组水平的变化。基因组变化将被确定为拷贝数变异的自发或从头变化的诱导。将进行额外的研究，以确定自发CNV如何产生，并评估EE 2如何改变或损害旨在防止此类变化的DNA修复机制。 公共卫生相关性：环境雌激素存在于世界各地的地表水和地下沃茨中，已知对野生动物和潜在的人类健康有重大影响。这些化学物质是否能改变脊椎动物的基因组目前尚不清楚。该项目将确定这些化学物质是否可以改变脊椎动物的基因组，并有可能通过疾病的发生和发展影响人类健康。

DESCRIPTION (provided by applicant) The candidate's long-term goal is to obtain a faculty position at a research university so that she can continue to independently investigate how environmental estrogens affect humans. The short-term goal is to determine if environmental estrogens are able to alter vertebrate genomes. The immediate goal is to develop the skills and training necessary, primarily array comparative genomic hybridization (CGH) and morpholino injection, to develop an independent research program using these approaches and skills. While the use of CGH is not a new technique, its use as a method of determining whether genomic changes are present between normal individuals has only recently been used. Dr. Lee pioneered this technique and under his mentorship at Brigham and Women's Hospital, and the highly collaborative, educational environment at Harvard Medical School, the candidate will be allowed to learn and master its use. The candidate fully believes that this is an ideal environment to advance their career and the use this Award to become and independent investigator. Environmental estrogens are chemicals in the environment that alter or interact with native estrogen. These chemicals include a broad array of compounds from pesticides such as DDT, plasticizers such as Bisphenol A and pharmaceuticals such as human birth control pills (17-alpha-ethynylestradiol; EE2). Despite their relevance in the environment and known and suspected effects on humans and animals, no studies have been done to determine whether these chemicals induce genomic level changes. The purpose of this study is to determine whether environmentally relevant concentrations of EE2 are able to induce genomic level changes using the model organism zebrafish. Genomic changes will be determined as the induction of spontaneous, or de novo, changes in copy number variation. Additional studies will be performed to determine how spontaneous CNVs arise and evaluate how EE2 alters or impairs the DNA repair mechanisms that are designed to prevent such changes. Public Health Relevance: Environmental estrogens are found in surface and ground waters worldwide and are known to have significant affects on wildlife and potentially human health. Whether or not these chemicals can alter vertebrate genomes is currently unknown. This project will determine if these chemicals can alter vertebrate genomes and have the potential to impact human health through the initiation and progression of disease.