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M.S. / Physiology / There has been a controversy among both clinicians and physiologists for a long time concerning the effects of various toxins on the thyroid gland. / The first sentence serves as the abstract for this thesis. The poor quality of the text is due to the onion skin paper the thesis was scanned from.

M.S. / Physiology / There is no abstract to this thesis. The thesis does not list department or major so it is only a guess that the thesis was awarded in physiology. The poor text quality is due to the onion skin paper the thesis was scanned from.

The normal function of the thyroid hormone (TH) system is essential for growth, development and metabolism in humans as well as in other species. The action of TH is dependent on its binding to thyroid hormone receptors (THR) found in the cell nucleus. In some situations, chemicals with structural similarities to TH can bind to these receptors and disrupt their normal function. It has been previously demonstrated that environmental contaminants including, carbamazapine, nonlyphenol (NP), bisphenol A (BPA), and several others are able to bind to the THR as either agonists or antagonists and modulate downstream biochemical responses. Municipal wastewater effluent (MWWE) is a major source of these contaminants entering aquatic environments. Recently extracts of MWWE have been shown to contain chemicals that are capable of binding to THRs. However, MWWE is a complex mixture of chemicals and the specific chemicals have not been identified. In this thesis, a proof of concept was developed for using an Effects Directed Assessment (EDA) approach to isolate thyroid receptor active compounds in MWWE. An EDA is a technique created to extract and identify chemicals from complex mixtures, using various fractionation methods. Once these chemicals have been identified, they are further reviewed for biological relevance. A competitive binding assay for THR was developed and applied to determine the relative binding affinity of known environmental contaminants to THR. Nuclear thyroid hormone receptors were isolated from rainbow trout liver by differential centrifugation. This method involved liver tissue homogenization and subsequent centrifugations to separate the nuclear fraction containing the receptors. The binding characteristics of the isolated THR were evaluated using the thyroid hormones triiodothyronine (T3) and thyroxine (T4) in a competitive binding assay. Minimal binding affinity was present in this assay and future studies should validate the assay further and assure that it is comparable to literature values. Environmental contaminants, including BPA, NP were also tested to determine their relative binding affinity to the THRs compared to the endogenous hormones. High concentrations of both BPA and NP bound to the thyroid hormone receptor, displacing radiolabeled T3 from its binding site. The rainbow trout competitive binding assay was also used to test the binding affinities of extracts from two municipal wastewater effluents collected in the Grand River watershed in southern Ontario. Effluents were extracted using a solid phase adsorbent (HLB Oasis cartridge), eluted with methanol, taken to dryness then reconstituted in ethanol for use in the assay. Both effluent extracts displaced the binding of radiolabeled T3 to the thyroid receptors. The studies demonstrate that a competitive THR assay can be used to detect chemicals in complex mixtures with the potential to interact with THRs. The next step should be to apply the assay using an EDA approach to isolate and identify specific chemicals in effluents that are not yet known to bind to the THR. Interference with the normal function of the TH system has the potential to disrupt normal growth, development and metabolism in aquatic organisms in the receiving environments.

Dissertation : Sciences : Chicago : 1913. / "Reprinted from the Journal of Experimental Medicine, Vol. XVIII, No. 6, 1913"--P. 636. Notes bibliographiques (p. 651-652).

Thesis (M.S.)--Rutgers University, 2009. / "Graduate Program in Biology." Includes bibliographical references (p. 51-56).

Thesis--M.D., University of Hong Kong, 1980.

Evidence suggests that thyroid hormone acts by binding to nuclear receptors which regulate expression of a discrete number of proteins, including cardiac ventricular myosin isoenzymes. Administration of thyroid hormone is known to stimulate synthesis of ventricular α-myosin heavy chain and inhibit production of a (beta)-myosin heavy chain. The first part of this study examines the effects of naturally occurring and synthetic thyroid analogs, catecholamines and high carbohydrate diets on ventricular myosin isoenzyme expression in thyroidectomized and hypophysectomized rats. Also, the effects on myosin isoenzyme expression of adrenalectomy and hydrocortisone replacement have been studied in euthyroid animals. Myocardial CO₂ production and hepatic α-glycerol phosphate dehydrogenase activity were measured to monitor the effects of these interventions on tissue respiration. The results indicate that thyroid hormone analogs do not selectively stimulate myosin isoenzyme expression as compared with their effects on energy production. No significant separation between the actions of these analogs on metabolic parameters and myosin isoenzyme patterns was found. However, high carbohydrate feeding in thyroidectomized and hypophysectomized rats increased the content of the α-myosin heavy chain. β-Adrenergic stimulation with isoproterenol and blockade with propranalol did not affect myosin isoenzyme expression. Adrenalectomy in euthyroid rats decreased the α-myosin heavy chain with a corresponding increase in the β-myosin heavy chain. This could be reversed by treatment with hydrocortisone. The results suggest that the mechanism for regulation of cardiac myosin isoenzymes may involve a primary signal related to dietary carbohydrate, which is modulated by thyroid hormone, and possibly glucocorticoids. The method for purification of the T₃-receptor-DNA complex is described. This complex is thought to mediate the action of T₃ on gene expression. The results indicate that a relatively pure form of an intact receptor-DNA complex (M.W. 111,000) can be isolated from a T₃-affinity gel. Only a single protein component (M.W. 58,000) was identified by electrophoresis and coomasie blue staining of the purified complex. The associated double stranded DNA fragment (M.W. 52,000) was estimated to contain about 88 basepairs. This complex could be dissociated by treatment with 0.4 M KCl or DNase I, but did not undergo spontaneous exchange with exogenous labeled DNA fragments. Equilibrium binding studies demonstrated a single class of high affinity T₃-binding site with a dissociation constant (50 pM) which was significantly lower than that of the micrococcal digest (1.1 nM).

published_or_final_version / Medicine / Master / Doctor of Medicine

No description available.