The overarching goal of the proposed research is to elucidate mechanisms relating prenatal exposure to complex mixtures of endocrine disrupting compounds (EDCs) to adverse neurodevelopment sequelae in children. Several classes of EDCs are known to interfere with thyroid function. Adequate thyroid function during pregnancy is a known determinant of successful fetal brain development and maternal thyroid hormone insufficiency is associated with adverse developmental outcomes in experimental animals and humans. Although several studies have evaluated risks associated with exposure to single classes of EDCs, these studies are limited in their evaluation of the complex mixtures within the human exposome and have not explored structural deficits in brain development leading to adverse outcomes. The proposed study attempts to address these limitations by developing a composite index of body burden to EDCs and by applying brain imaging methods to elucidate changes in brain structure and function following exposure. Specifically, the investigators propose to evaluate whether prenatal exposure to a complex mixture of EDCs is associated with a) disrupted maternal thyroid function, b) changes in brain structure and function in children at 5 years of age, and c) adverse neurobehavioral and psychological function in children at 5 years of age. The training and research will take place within the ongoing Metropolitan Study of Chemicals and Pregnancy Health (The Parent Study) (R21ES016610-01, principal investigators-Wapner). This is a prospective study of 316 mothers enrolled during pregnancy. The parent study provides information key to the current proposal including prenatal exposure levels to polybrominated diphenyl ethers (PBDEs) and perchlorate, an assessment of maternal thyroid function during the second trimester of pregnancy, and consent to contact mothers for prospective follow-up of their offspring. Additionally, stored biological samples are available for additional EDC analysis. During the initial K99 phase, Dr. Horton proposes to measure BPA and phthalates in stored maternal urine samples. In combination with the PBDE and perchlorate data, she will develop and apply sophisticated statistical methodologies to examine the impact of a complex mixture of EDCs on maternal thyroid function. Also during the K99 phase, Dr. Horton will receive intensive training in the use of brain imaging in epidemiological studies at the New York State Psychiatric Institute. During the transition to independence in the R00 phase of the award, she proposes to apply these trainings within the context of the parent study. Specifically she will follow 75 children, selected on exposure status, with brain imaging (anatomical and functional magnetic resonance imaging) and neurodevelopmental testing. Finally, Dr. Horton will apply these data to examine the complex relationships between prenatal EDC exposure, maternal thyroid function, children's brain structure and function and developmental outcomes using a meditational model. This K99/R00 proposal is a direct extension of the candidate's previous work in children's environmental health and a logical progression into a career as a life-course epidemiologist focused on environmental exposures. At the conclusion of this award, the candidate will have gained expertise in the emerging fields of chemical mixture analysis and brain imaging. The acquisition of these skills sets the candidate above other researchers by combining competence across several disciplines. Public Health Relevance: This proposal aims to understand the relationship between prenatal exposure to thyroid disrupting compounds, maternal thyroid function, and neurologic function in offspring. Information generated through this research effort is essential to fill research gaps and inform human risk assessment.

Public Health Relevance

I recently earned my doctoral degree in Environmental Health Sciences at Mailman School of Public Health. During my doctoral training, I developed expertise in the development and use of biological markers to measure prenatal and early life exposures to environmental toxicants. I am currently a postdoctoral fellow in the Sergievsky Center neuroepidemiology training program at Columbia University. As a postdoctoral fellow, I am studying the impact of prenatal exposure to pesticides and secondhand smoke on the trajectory of neuropsychological and behavioral function throughout childhood. My long term career goal is to be an independent NIH researcher with an interdisciplinary approach to children's environmental health focusing on the influence of the exposome on human neurodevelopment and psychological function over the life course. The purpose of this K99/R00 application is to propose a research and training program that will facilitate attainment of this goal. Through this training, I will attain competence in two important and evolving research areas to complement my prior training, thus defining my unique specialization as a life course epidemiologist with expertise in the following four domains;1) exposure science, 2) life course epidemiology, 3) complex mixture analysis and 4) brain imaging. This training and research proposal is an extension of my previous work in children's environmental health and a logical progression into a career as a life-course epidemiologist focused on environmental exposures. At the conclusion of this award, I will have gained expertise in the application of structural brain imaging as a tool for studying the neurodevelopmental effects of exposure to complex mixtures-a novel skill set that will enable me to design and conduct integrated yet seamless research in children's environmental health.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Career Transition Award (K99)
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Special Emphasis Panel (ZES1-LKB-J (K9))
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Shreffler, Carol K
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Columbia University (N.Y.)
Public Health & Prev Medicine
Schools of Public Health
New York
United States
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Horton, Megan K; Blount, Benjamin C; Valentin-Blasini, Liza et al. (2015) CO-occurring exposure to perchlorate, nitrate and thiocyanate alters thyroid function in healthy pregnant women. Environ Res 143:1-9
Horton, Megan K; Margolis, Amy E; Tang, Cheuk et al. (2014) Neuroimaging is a novel tool to understand the impact of environmental chemicals on neurodevelopment. Curr Opin Pediatr 26:230-6
Horton, Megan K; Kahn, Linda G; Perera, Frederica et al. (2012) Does the home environment and the sex of the child modify the adverse effects of prenatal exposure to chlorpyrifos on child working memory? Neurotoxicol Teratol 34:534-41
Rauh, Virginia A; Perera, Frederica P; Horton, Megan K et al. (2012) Brain anomalies in children exposed prenatally to a common organophosphate pesticide. Proc Natl Acad Sci U S A 109:7871-6
Rauh, Virginia; Arunajadai, Srikesh; Horton, Megan et al. (2011) Seven-year neurodevelopmental scores and prenatal exposure to chlorpyrifos, a common agricultural pesticide. Environ Health Perspect 119:1196-201