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Dioxin Impact on Cardiac Development, Structure, Function, and Health, and Implications for Disease

de Gannes, Matthew K
http://orcid.org/0000-0001-8265-3539
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613748020897261

Abstract Details

2020, PhD, University of Cincinnati, Medicine: Toxicology (Environmental Health).
The focus of this dissertation is the characterization of the epigenetic, structural, and functional consequences of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin), a potent ligand of the aryl hydrocarbon receptor (AHR), in differentiated cardiomyocytes and the adult heart as a result of continuous exposure from fertilization through adulthood. Congenital heart disease (CHD) is the most common congenital abnormality and one of the leading causes of mortality worldwide. Ongoing scientific investigations show that a precise etiology remains elusive, but is likely to result from complex interactions between genetic and environmental factors during heart development, at a time when the heart adapts to diverse physiological and pathophysiological conditions. Crucial among these is the regulation of cardiomyocyte development and postnatal maturation, governed by dynamic changes in DNA methylation. Previous work from our laboratory showed that exposure to the environmental toxicant tetrachlorodibenzo-p-dioxin (TCDD) disrupts several molecular networks responsible for heart development and function. In addition, interference with endogenous developmental functions of the AHR, either by gene ablation or by in utero exposure to TCDD, was shown to cause structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. These studies demonstrated the potential role of AHR in the pathogenesis of CHD by its disruption during development. The biological half-life of TCDD is 7-10 years in humans. Therefore, it is of clinical importance to understand the consequences of continuous activation of AHR by TCDD from development through adulthood on cardiac structure and function. Chapter One summarizes the current body of knowledge surrounding TCDD, the AHR, heart development, CHD, the risk and mechanisms of heart failure, and the role of DNA methylation in cardiomyocyte maturation. Chapter Two describes the effects of TCDD on DNA methylation dynamics in genes that govern cardiomyocyte maturation using a selection-based model of differentiated cardiomyocytes in culture. Chapter Three extends on previous work exposing developing mouse embryos to TCDD in utero by continuing exposure throughout adulthood, and by examining phenotypes related to heart electrical function as well as pathologies related to the renin-angiotensin system and heart failure with preserved ejection fraction (HFpEF). Finally, Chapter Four summarizes the findings of the studies described in prior chapters and provides overall conclusions, implications, and potential future directions. Overall, the results presented in this dissertation further underscores previous evidence that AHR signaling in the developing mammalian heart is central to regulating cardiomyocyte maturation as well as cardiac structure and function. The work outlines potentially new biological avenues for further study at the level of epigenetics as well as interplay between the AHR, environmental factors, and the renin-angiotensin system that may be key contributors to CHD and adult cardiovascular disease.
Alvaro Puga, Ph.D. (Committee Chair)
Katherine Burns, Ph.D. (Committee Member)
Jack Rubinstein, M.D. (Committee Member)
Ying Xia, Ph.D. (Committee Member)
Xiang Zhang, Ph.D. (Committee Member)
117 p.
Toxicology
DNA methylation; TCDD; aryl hydrocarbon receptor; epigenetics; heart failure; heart development

Recommended Citations

Citations

  • de Gannes, M. K. (2020). Dioxin Impact on Cardiac Development, Structure, Function, and Health, and Implications for Disease [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613748020897261

    APA Style (7th edition)

  • de Gannes, Matthew. Dioxin Impact on Cardiac Development, Structure, Function, and Health, and Implications for Disease. 2020. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613748020897261.

    MLA Style (8th edition)

  • de Gannes, Matthew. "Dioxin Impact on Cardiac Development, Structure, Function, and Health, and Implications for Disease." Doctoral dissertation, University of Cincinnati, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613748020897261

    Chicago Manual of Style (17th edition)

ucin1613748020897261
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© 2020, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.