<p> Anthropogenic contaminants have been well documented in Southern California coastal marine waters and are largely associated with point source pollution entities like waste water treatment plants (WWTPs). This study measured known and suspected contaminants capable of disrupting physiological and endocrine functions in marine organisms. Thyroid endocrine and hepatic contaminant concentrations were measured in English Sole (<i>Parophrys vetulus</i>) and Hornyhead Turbot (<i>Pleuronichthys verticalis</i>) residing at a WWTP outfall location and two other locations, up- and down-current from the outfall. Fish from the outfall and down current locations had higher levels of contaminant compounds and altered thyroid endocrine physiology compared to the up-current reference location. Selected contaminants were significantly correlated with thyroid endocrine parameters, consistent with observed differences in contaminant levels among sites.</p><p>

Endocrine disrupting chemicals (EDCs) such as pesticides and pharmaceuticals can upset amphibian development and contribute to worldwide amphibian population declines. The first objective of this doctoral research was to investigate if the widely used herbicide atrazine (ATZ; used on corn and soy crops) alters Lithobates (Rana) pipiens (Northern leopard frog) development using concentrations of ATZ reported in Canadian ecosystems. Chronic exposures to 0.1 and 1.8 mug/L ATZ on L. pipiens tadpoles were performed in semi-controlled mesocosms. Atrazine reduced metamorphosic success, induced female-biased sex ratio, altered the hepatic activity of steroid 5beta-reductase (srd5beta; an enzyme involves in the conversion of testosterone into 5beta-dihydrotestosterone) and affected the expression of estrogen receptor alpha in brain and deiodinase type 3 in tail. The second objective was to characterize the functions of the steroid 5alpha-reductase (srd5alpha; type 1, 2 and 3) and srd5beta in frogs. These enzymes represent a convergence in evolution: they share similar biological functions (e.g., testosterone reduction, bile acid biosynthesis and erythropoesis), but srd5alpha and srd5beta do not have a common ancestor. Using real-time RT-PCR analysis, these enzymes were detected throughout Silurana (Xenopus) tropicalis (Western clawed frog) early development. The prostate drug finasteride (a 5alpha-reductase type 2 and srd5beta inhibitor in humans) was used in short-term (25, 50 and 100 muM) and chronic (25 muM) exposures of S. tropicalis under laboratory conditions. Finasteride inhibited srd5beta and aromatase (cyp19) activities in whole embryos after short-term exposures. However, chronically exposed S. tropicalis until metamorphosis, revealed no effects of finasteride on cyp19 activity and an increase in male hepatic srd5beta activity. Furthermore, chronic treatment with finasteride induced testicular oocytes in developing males (also referred to as the intersex condition). In addition, real-time RT-PCR analysis showed that finasteride treatments altered sex steroid- and thyroid hormone-related gene expression. Alterations of thyroid hormone gene expression following the inhibition of srd5alpha and srd5beta suggest a complex relationship between the thyroid hormone-responsive genes and the androgen status in early frog development and at metamorphosis. In conclusion, real-time RT-PCR, enzymatic activity and histology analyses demonstrated that srd5alpha and srd5beta are important enzymes during frog development and are 'new' targets to EDCs.

Fibrate pharmaceuticals are peroxisome proliferator-activated receptor alpha (PPARalpha) ligands that are detected in sewage treatment plant effluents, surface water and groundwater. In a previous study, male goldfish ( Carassius auratus) exposed to the fibrate gemfibrozil (GEM) in the water exhibited decreased plasma testosterone concentrations. The following studies investigate the effects of GEM and other PPAR ligands on components of the hypothalamic-pituitary-gonadal axis of the male goldfish; the pituitary and testes. In vitro cultures of dispersed goldfish pituitary cells and testis fragments were employed to study these two tissues in isolation. The secretion of neither luteinizing hormone nor growth hormone from pituitary cells was affected in a manner that could explain decreases in circulating testosterone. Testosterone synthesis in testis fragments stimulated with human chorionic gonadotropin (hCG) was suppressed following treatment with GEM. This inhibition appeared to be the result of impaired mitochondrial cholesterol transport. However, changes in the expression of two proteins important for mitochondrial cholesterol transport, steroidogenic acute regulatory protein and peripheral benzodiazepine receptor, were not affected by GEM treatment. Investigations on the involvement of extracellular-regulated signal kinase 1/2 (ERK 1/2) in the steroidogenic pathway revealed that phosphorylated ERK 1/2 (P-ERK 1/2) is required for hCG-stimulated testosterone synthesis and that GEM treatment decreased levels of P-ERK 1/2 in the mitochondria of this tissue. The main conclusions from these studies include the following: (1) The effect of waterborne GEM on the HPG axis of the goldfish is a direct effect on the testis, (2) GEM impairs mitochondrial cholesterol transport in the goldfish testis, (3) Phospho-ERK 1/2 is required for hCG-stimulated steroidogenesis in the goldfish testis, and (4) the proposed mechanism by which GEM impairs mitochondrial cholesterol transport is through a reduction in mitochondrial phospho-ERK 1/2.

Includes bibliographical references (leaves 45-52). / The aim of this study is to test the hypothesis that, for similar durations of diagnosed diatetes (DM); black South Africans have less atherosclerosis as measured by Carotid Intima Media Thickness (CIMT) than non-black South Africans.

Prolactin is a fertility hormone produced and released by the anterior pituitary gland. Normal changes in prolactin levels influence fertility and these changes are carefully regulated by neuroendocrine cells in the hypothalamus. Specifically, prolactin surges along with luteinizing hormone to stimulate ovulation and mating behaviors in rodents. Prolactin also follows a twice-daily surge pattern during rodent pregnancy, helping to maintain the pregnancy and prepare the maternal brain for offspring care. Dopamine is the primary regulatory of prolactin and acts through tonic inhibition during non-surge times. High levels of prolactin feedback to stimulate dopamine and thereby reduce prolactin back down to normal, low levels. However, dopamine is not alone in regulating prolactin release. Early mathematical models from the lab helped to identify some shortcomings in the understanding of prolactin regulation. Based on the existing literature, a model was designed to replicate experimental results. When I came to lab and began reviewing this literature and the model's assumptions, I began to ask some important questions: Do dopamine levels change dramatically with the prolactin surges? Does the timing signal in the model really act as an inhibitory signal? Does the stimulatory signal act alone to drive surges of prolactin release? What else is out that that feeds into this circuit? These perfectly timed surges of prolactin must somehow be controlled by the brain's central clock. One clock signal, VIP, has been implicated in indirect prolactin regulation. This neurotransmitter could stimulate prolactin either by inhibiting dopamine or by activating a prolactin simulator. In this dissertation, I show that it may in fact be doing both. Oxytocin is one potential, and particularly potent, prolactin stimulator that is itself implicated in reproduction and the associated social behaviors. Released at the posterior pituitary, I hypothesized that plasma oxytocin levels might be predictive of the large prolactin surges observed during times of fertility and pregnancy. However, the data fail to support such a clear direct correlation. Other hypothalamic factors that have also been proposed to be involved in prolactin regulation include the endogenous opioid dynorphin. One major hypothalamic source of dynorphin are the KNDy neurons that co-secrete kisspeptin, neurokinin B, and dynorphin. All these neurotransmitters have been studied for their roles in luteinizing hormone regulation. Research presented here shows that the KNDy neuron dynorphin, while directly involved in luteinizing hormone surge release, is not involved in prolactin surge release. In fact, another KNDy product is likely involved in the single, estrogen-induced fertility surge, while another, still unknown, source of dynorphin is involved during the twice-daily prolactin surge pattern. Overall, this dissertation explores many aspects beyond just dopamine as possible regulatory inputs to the prolactin control circuit. Our simplified rodent models and the mathematical modeling help to show us the limits of our understanding so we can ask the right questions for the next experiments. This multi-angled approach, employing different physiological states in the animals and discussing possible network scenarios with modelers, gives depth to the research program described in this dissertation. Further work will better elucidate important aspects of fertility regulation that have undoubted implications for human and animal health. / A Dissertation submitted to the Department of Biological Science in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Summer Semester 2015. / June 23, 2015. / cervical stimulation, dopamine, dynorphin, estradiol, oxytocin, prolactin / Includes bibliographical references. / Richard Bertram, Professor Co-Directing Dissertation; Paul Trombley, Professor Co-Directing Dissertation; Tim Logan, University Representative; Kim Hughes, Committee Member; Arturo Gonazalez-Iglesias, Committee Member.

Background Hyperthyroidism occurs in about 1 per 5000 children and adolescents. Graves disease (GD) is the most common cause of hyperthyroidism in children and adolescents. The treatments that are currently available for children with GD include Carbimazole (CMZ), radioactive iodine (RAI) therapy and surgery. The paucity of GD data in children from the sub-Saharan African region, challenge the physician in identifying the best suited diagnostic and treatment strategies for the patient population in their setting. Objective The aim was to describe the population group attending the Paediatric and Adolescent Endocrinology Services (PAES) at Red Cross War Memorial Children's Hospital (RCCH) and Groote Schuur Hospital (GSH) in Cape Town, Western Cape. This study hoped to contribute information to the body of evidence concerning GD in the paediatric population of South Africa. Methods This was a retrospective folder review of all children and adolescents diagnosed with GD, attending the PAES in the previous two decades. Their demographic profile, clinical and laboratory findings and the treatment modalities utilised were described. All patients diagnosed with GD between the ages of 1 and 20 years old were included. Data were described as proportions and percentages. The measures of central tendency were described by median, and inter-quartile range (IQR). Results Thirty-one patients were included in the study. Twenty-six patients were female. The median age at presentation was 10.1 years (IQR: 8.9; 11.7). All patients were initially treated medically with Carbimazole (CMZ). Two patients experienced mild adverse reactions attributed to CMZ. Twelve (39%) patients went into remission after a single course of CMZ, after a median of 16.3 months(IQR: 8.6; 35.1). At the study's conclusion, nine (29%) patients were in remission, nine (29%) remained on CMZ therapy, ten (32%) underwent RAI and three (10%) relapsed before GD remission was achieved. One-quarter of the patients (n=8) were known with Down syndrome (DS). These patients presented at a significantly younger age than those without DS. Conclusion The children and adolescents diagnosed with GD managed in the PAES were similar in sex distribution, slightly younger in age and tolerated CMZ better than reported in literature. This study demonstrated the importance of considering prolonging CMZ therapy in patients not yet in remission and as a viable retreatment option in patients that relapse.

Includes bibliographical references (leaves 67-80). / Although the treatment of gestational impaired glucose tolerance (GIGT) has been shown to be beneficial, the cost implications in treating GIGT in resource constrained economies needs examination. Thus this study assessed: (i) pregnancy outcomes in pre-gesational types 1 and 2 diabetes (DM) with particular emphasis on the modality of therapy for pregnant women with type 2 DM, (ii) pregnancy outcomes in subjects with gestational diabetes (GDM) and the effect of stratification by fasting plasma glucose (FPG) and 2 hour oral glucose tolerance test (OGTT) plasma glucose values, and (iii) the effect of OGLAs on pregnancy outcomes in GDM.

Includes abstract. / Includes bibliographical references (leaves 56-60). / To audit the crod blood thryoid screening programme in the Peninsula Maternal and Neonatal Services (PMNS) in the 5 year period from 01/01/2000 to 31/12/2004, focusing on coverage, recall rate and success, number of cases detected, incidence of congenital hypothryoidism in this population; and cost efficiency of the programme. All babies born in the PMNS from 01/01/2000 to 31/12/2004 were included in the audit. The medical records of all babies recalled following an abnormal screen were examined. 140 507 babies were born in the PMNS during the audit period, while 130 389 primary Thyroid Stimulating Hormone (TSH) screens were done (92.8% coverage). 2 207 of the screened babies had abnormal results requiring review.

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