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Environmental Endocrine Disrupting Chemicals and Cardiac Arrhythmogenesis

Gao, Xiaoqian
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427799826

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Molecular, Cellular and Biochemical Pharmacology.
Environmental endocrine disrupting chemicals (EDCs) are a group of exogenous compounds that may interfere with the functioning of endogenous systems and affect human health. Bisphenol A (BPA) is one of most ubiquitous EDCs in the manufacturing industry as a plasticizing agent used in polycarbonate plastics and epoxy resins. It is well-documented that human exposure to BPA is extremely wide spread. It was demonstrated that BPA, at human-exposure relevant doses, rapidly promoted cardiac arrhythmias in female rat hearts. However, the molecular mechanisms underlying BPA’s pro-arrhythmic effects remain unclear. As a result of banning BPA’s use in various consumer products, bisphenol S (BPS) is increasingly used as a substitute agent for BPA. Human populations are reported to be widely exposed to BPS, but the biological activities and potential toxic effects of BPS are not well understood. The objective of this dissertation is to investigate the cardiac impact of EDCs including BPA and BPS, with a focus on their cardiac arrhythmogenesis and underlying cellular and molecular mechanisms. Of particular interest, was to elucidate the signaling cascades and protein targets underlying BPA’s rapid alteration of myocyte Ca2+ handling and promotion of arrhythmogenic-triggered activities in female rodent hearts; and to evaluate how BPS affects cardiac arrhythmogenesis in comparison to BPA. It was demonstrated that protein kinase A (PKA) and Ca2+/Calmodulin-dependent protein kinase II (CAMKII) signaling pathways are the two major signaling pathways activated by BPA. In isolated female rat ventricular myocytes, BPA exposure rapidly increased phosphorylation of the ryanodine receptors by PKA but not by CAMKII. BPA exposure also rapidly increased the phosphorylation of phospholamban by CAMKII but not PKA. These two pathways are mediated by estrogen receptor ß but not estrogen receptor α and are shown to be localized. Functional analysis also showed that both PKA and CAMKII were necessary contributors to the arrhythmogenesis of BPA on cardiomyocytes. This study identified the unique signaling cascades of BPA in the heart, and elucidated its novel effects on key Ca2+ handling proteins. Also of interest is the cardiac impact of BPS, especially on the electrical aspect of the heart. It was shown that in female rat hearts, BPS rapidly increased heart rate and promoted ventricular arrhythmias under stress conditions. BPS increased arrhythmogenic-triggered activities in isolated female myocytes via alteration of Ca2+ handling, in particular by increasing spontaneous sarco/endoplasmic reticulum Ca2+ release. BPS exposure increased phosphorylation of two key Ca2+ handling proteins, the ryanodine receptor and phospholamban. Additionally, the pro-arrhythmic effects of BPS were demonstrated to be female-specific, characterized by an inverted-U dose response curve. These results provide important mechanistic insights into the rapid cardiac arrhythmogenesis of BPS in female hearts, and contribute to the evaluation of the potential cardiac toxicity of BPS. Furthermore, the cardiac effects of probenecid were investigated. Collaboratively, it was shown that probenecid increased myocardial contractility using in vivo echocardiography, ex vivo Langendorff perfused heart and isolated myocyte system. The inotropic effect is likely mediated by transient receptor potential vanilloid 2 channels via enhanced sarco/endoplasmic reticulum Ca2+ release.
Hongsheng Wang, Ph.D. (Committee Chair)
Terence Kirley, Ph.D. (Committee Member)
Steven Kleene, Ph.D. (Committee Member)
Jo El Schultz, Ph.D. (Committee Member)
165 p.
Environmental Health
endocrine disruptors; bisphenol a; bisphenol s; heart; rapid action; molecular mechanism

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Citations

  • Gao, X. (2015). Environmental Endocrine Disrupting Chemicals and Cardiac Arrhythmogenesis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427799826

    APA Style (7th edition)

  • Gao, Xiaoqian. Environmental Endocrine Disrupting Chemicals and Cardiac Arrhythmogenesis. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427799826.

    MLA Style (8th edition)

  • Gao, Xiaoqian. "Environmental Endocrine Disrupting Chemicals and Cardiac Arrhythmogenesis." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427799826

    Chicago Manual of Style (17th edition)

ucin1427799826
996
© 2015, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.