This dissertation focuses on the effects of lead (Pb) on the expression of thyroid hormone distributor proteins and how that affects the developing brain in Xenopus laevis tadpoles. Previous work has shown that Pb has the ability to dysregulate thyroid hormone (TH)-signaling in vertebrates and that Pb can impair brain development. This dissertation reports results for a series of Pb-treatment experiments conducted in Xenopus laevis tadpoles. The first primary hypothesis of this dissertation is that Pb impairs TH-dependent mechanisms of brain development. The second primary hypothesis of this dissertation is that Pb-induced impairments of brain development happen via dysregulation of thyroid hormone distributor proteins (THDPs) transthyretin (TTR) and β-trace. Analyses of the effects of Pb on overall body growth showed dose-dependent decreases in body length with increasing concentrations. Evaluation of the effect of Pb on tectal size and cell death in the developing brain yielded bimodal changes that depended upon Pb concentration in both features. Furthermore, Pb impaired TH-induced changes in brain development, including neurogenesis and brain volume. Pb abolished the T4-mediated increase in proliferating cell nuclear antigen (PCNA) expression, while having only marginal effects on neuronal regeneration related protein (NREP) and Krueppel-like factor 9 (klf9). Analyses of the effects of Pb on TTR and β-trace expression yielded results demonstrating a significant decrease in expression of both proteins in response to Pb-treatment. Contrary to prior studies in the literature, I demonstrate here that TTR is present in the brains of Xenopus. While electroporation of TTR morpholino did result in fewer TTR puncta, electroporation with morpholinos for TTR and β-trace knock down did not mimic the effects of Pb on neurogenesis. However, overexpression of these proteins in the choroid plexus (CP) of these animals was sufficient to produce an increase in neurogenesis. Finally, overexpression of these proteins was sufficient to ameliorate the effects of Pb-treatment on neurogenesis. The results affirm both the primary and secondary hypotheses, illustrating that Pb does, indeed, impair TH-mediated mechanisms of brain development and that these impairments are mitigated by dysregulation of TTR and β-trace. / Doctor of Philosophy / This dissertation focuses on the effects of lead (Pb) poisoning on thyroid hormone (TH)-mediated mechanisms of brain development in Xenopus laevis tadpoles. The work detailed here seeks to shine a light on the effects of Pb on brain development and one mechanism by which those effects may be mediated. This dissertation details experiments done in Xenopus laevis tadpoles, which are a prime animal model for studying environmental toxicants, especially those that disrupt TH physiology. This dissertation focuses on two primary hypotheses within a two journal manuscript format. The first primary hypothesis of this dissertation is that Pb impairs TH-dependent mechanisms of brain development. The second primary hypothesis of this dissertation is that Pb-induced impairments of brain development happen via dysregulation of thyroid hormone distributor proteins (THDPs) TTR and β-trace. The results found in this dissertation are consistent with the conclusions that Pb impairs TH-mediated mechanisms of brain development and that those impairments are mitigated by dysregulation of THDPs in the brain and body.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/115784 |
| Date | 17 July 2023 |
| Creators | Dahora, Lara Iza |
| Contributors | Biological Sciences, Thompson, Christopher, Fox, Michael A., Sewall, Kendra, Pan, Yuchin Albert |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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