Effects of Environmental Estrogen Exposure on Spontaneous Copy Number Variation

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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.