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Description
Ethinyl estradiol, (EE) a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives (Shively, C., 1998), and is found in at least 30 different contraceptive formulations currently prescribed to women (Curtis et al., 2005). EE is also used in hormone therapies prescribed to menopausal women, such as FemhrtTM (Simon et al., 2003). Thus, EE is prescribed clinically to women at ages ranging from puberty through reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young, female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection. For these studies, the low and medium doses correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to the range of doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. For each study, cognition was evaluated with a battery of maze tasks tapping several domains of spatial learning and memory. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory; this was seen for both cyclic and tonic regimens. Cyclic and tonic delivery of low EE, a dose that corresponds to doses used in the clinic today, resulted in transient and null impairments, respectively, on cognition.
ContributorsMennenga, Sarah E (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Baxter, Leslie C. (Committee member) / Olive, Michael F. (Committee member) / Arizona State University (Publisher)
Created2012
Description
The shape of glucose response and one hour (1-hr) glucose during an oral glucose tolerance test (OGTT) are emerging biomarkers for type 2 diabetes. The purpose of this study was two-fold: (1) to investigate the utility of these novel biomakers to differentiate type 2 diabetes risk in Latino youth, and (2) to examine the genetic determinants in a Latino population.
Data from the ASU Arizona Insulin Registry (AIR) registry and the USC Study of Latino Adolescents at Risk for diabetes project were used to test the cross-sectional and prospective utility of novel biomarkers to identify youth at risk for type 2 diabetes. Pediatric and adult data from the ASU AIR registry were assessed to examine the association of single nucleotide polymorphisms (SNPs) with type 2 diabetes risk. Three KCNQ1 SNPs (rs151290; rs2237892; rs2237895) were examined as novel genetic variants for type 2 diabetes in Latinos.
Latino youth with a biphasic response in the AIR registry exhibited significantly better β-cell function (P < 0.05) compared to youth with a monophasic response. Additionally, Latino youth with a 1-hr glucose ≥155 mg/dL exhibited a significantly greater decline in β-cell function over 8 years compared with the <155 mg/dL group (β=-327.8±126.2, P = 0.01). Moreover, a 1-hr glucose ≥155 mg/dL was associated with a 2.5 times greater risk for developing prediabetes over time (P = 0.0001). 1-hr glucose was the most powerful predictor of prediabetes (area under the receiver operating characteristic curve=0.73) when compared to the traditional biomarkers including HbA1c (0.58), fasting (0.67), and 2-hr glucose (0.64). Two KCNQ1 SNPs (rs151290 and rs2237892) exhibited significant associations with type 2 diabetes risk factors. For the novel glycemic markers, 15 SNPs were associated with the glucose response curve, while 18 SNPs were associated with 1-hr glucose.
These data suggest that glucose response curve and 1-hr glucose during an OGTT independently differentiate type 2 diabetes risk among Latino youth. Furthermore, it was successful to replicate the association of type 2 diabetes risk with 2 KCNQ1 SNPs in a Latino population. Data suggest that novel glycemic biomarkers are influenced by genetic background in this high-risk population.
Data from the ASU Arizona Insulin Registry (AIR) registry and the USC Study of Latino Adolescents at Risk for diabetes project were used to test the cross-sectional and prospective utility of novel biomarkers to identify youth at risk for type 2 diabetes. Pediatric and adult data from the ASU AIR registry were assessed to examine the association of single nucleotide polymorphisms (SNPs) with type 2 diabetes risk. Three KCNQ1 SNPs (rs151290; rs2237892; rs2237895) were examined as novel genetic variants for type 2 diabetes in Latinos.
Latino youth with a biphasic response in the AIR registry exhibited significantly better β-cell function (P < 0.05) compared to youth with a monophasic response. Additionally, Latino youth with a 1-hr glucose ≥155 mg/dL exhibited a significantly greater decline in β-cell function over 8 years compared with the <155 mg/dL group (β=-327.8±126.2, P = 0.01). Moreover, a 1-hr glucose ≥155 mg/dL was associated with a 2.5 times greater risk for developing prediabetes over time (P = 0.0001). 1-hr glucose was the most powerful predictor of prediabetes (area under the receiver operating characteristic curve=0.73) when compared to the traditional biomarkers including HbA1c (0.58), fasting (0.67), and 2-hr glucose (0.64). Two KCNQ1 SNPs (rs151290 and rs2237892) exhibited significant associations with type 2 diabetes risk factors. For the novel glycemic markers, 15 SNPs were associated with the glucose response curve, while 18 SNPs were associated with 1-hr glucose.
These data suggest that glucose response curve and 1-hr glucose during an OGTT independently differentiate type 2 diabetes risk among Latino youth. Furthermore, it was successful to replicate the association of type 2 diabetes risk with 2 KCNQ1 SNPs in a Latino population. Data suggest that novel glycemic biomarkers are influenced by genetic background in this high-risk population.
ContributorsKim, Joon Young (Author) / Shaibi, Gabriel Q (Thesis advisor) / Mandarino, Lawrence J (Committee member) / Coletta, Dawn K (Committee member) / De Filippis, Elena A (Committee member) / Arizona State University (Publisher)
Created2015
Description
For animals that experience annual cycles of gonad development, the seasonal timing (phenology) of gonad growth is a major adaptation to local environmental conditions. To optimally time seasonal gonad growth, animals use environmental cues that forecast future conditions. The availability of food is one such environmental cue. Although the importance of food availability has been appreciated for decades, the physiological mechanisms underlying the modulation of seasonal gonad growth by this environmental factor remain poorly understood.
Urbanization is characterized by profound environmental changes, and urban animals must adjust to an environment vastly different from that of their non-urban conspecifics. Evidence suggests that birds adjust to urban areas by advancing the timing of seasonal breeding and gonad development, compared to their non-urban conspecifics. A leading hypothesis to account for this phenomenon is that food availability is elevated in urban areas, which improves the energetic status of urban birds and enables them to initiate gonad development earlier than their non-urban conspecifics. However, this hypothesis remains largely untested.
My dissertation dovetailed comparative studies and experimental approaches conducted in field and captive settings to examine the physiological mechanisms by which food availability modulates gonad growth and to investigate whether elevated food availability in urban areas advances the phenology of gonad growth in urban birds. My captive study demonstrated that energetic status modulates reproductive hormone secretion, but not gonad growth. By contrast, free-ranging urban and non-urban birds did not differ in energetic status or plasma levels of reproductive hormones either in years in which urban birds had advanced phenology of gonad growth or in a year that had no habitat-related disparity in seasonal gonad growth. Therefore, my dissertation provides no support for the hypothesis that urban birds begin seasonal gonad growth because they are in better energetic status and increase the secretion of reproductive hormones earlier than non-urban birds. My studies do suggest, however, that the phenology of key food items and the endocrine responsiveness of the reproductive system may contribute to habitat-related disparities in the phenology of gonad growth.
Urbanization is characterized by profound environmental changes, and urban animals must adjust to an environment vastly different from that of their non-urban conspecifics. Evidence suggests that birds adjust to urban areas by advancing the timing of seasonal breeding and gonad development, compared to their non-urban conspecifics. A leading hypothesis to account for this phenomenon is that food availability is elevated in urban areas, which improves the energetic status of urban birds and enables them to initiate gonad development earlier than their non-urban conspecifics. However, this hypothesis remains largely untested.
My dissertation dovetailed comparative studies and experimental approaches conducted in field and captive settings to examine the physiological mechanisms by which food availability modulates gonad growth and to investigate whether elevated food availability in urban areas advances the phenology of gonad growth in urban birds. My captive study demonstrated that energetic status modulates reproductive hormone secretion, but not gonad growth. By contrast, free-ranging urban and non-urban birds did not differ in energetic status or plasma levels of reproductive hormones either in years in which urban birds had advanced phenology of gonad growth or in a year that had no habitat-related disparity in seasonal gonad growth. Therefore, my dissertation provides no support for the hypothesis that urban birds begin seasonal gonad growth because they are in better energetic status and increase the secretion of reproductive hormones earlier than non-urban birds. My studies do suggest, however, that the phenology of key food items and the endocrine responsiveness of the reproductive system may contribute to habitat-related disparities in the phenology of gonad growth.
ContributorsDavies, Scott (Author) / Deviche, Pierre (Thesis advisor) / Sweazea, Karen (Committee member) / McGraw, Kevin (Committee member) / Orchinik, Miles (Committee member) / Warren, Paige (Committee member) / Arizona State University (Publisher)
Created2014
Description
In an effort to begin validating the large number of discovered candidate biomarkers, proteomics is beginning to shift from shotgun proteomic experiments towards targeted proteomic approaches that provide solutions to automation and economic concerns. Such approaches to validate biomarkers necessitate the mass spectrometric analysis of hundreds to thousands of human samples. As this takes place, a serendipitous opportunity has become evident. By the virtue that as one narrows the focus towards "single" protein targets (instead of entire proteomes) using pan-antibody-based enrichment techniques, a discovery science has emerged, so to speak. This is due to the largely unknown context in which "single" proteins exist in blood (i.e. polymorphisms, transcript variants, and posttranslational modifications) and hence, targeted proteomics has applications for established biomarkers. Furthermore, besides protein heterogeneity accounting for interferences with conventional immunometric platforms, it is becoming evident that this formerly hidden dimension of structural information also contains rich-pathobiological information. Consequently, targeted proteomics studies that aim to ascertain a protein's genuine presentation within disease- stratified populations and serve as a stepping-stone within a biomarker translational pipeline are of clinical interest. Roughly 128 million Americans are pre-diabetic, diabetic, and/or have kidney disease and public and private spending for treating these diseases is in the hundreds of billions of dollars. In an effort to create new solutions for the early detection and management of these conditions, described herein is the design, development, and translation of mass spectrometric immunoassays targeted towards diabetes and kidney disease. Population proteomics experiments were performed for the following clinically relevant proteins: insulin, C-peptide, RANTES, and parathyroid hormone. At least thirty-eight protein isoforms were detected. Besides the numerous disease correlations confronted within the disease-stratified cohorts, certain isoforms also appeared to be causally related to the underlying pathophysiology and/or have therapeutic implications. Technical advancements include multiplexed isoform quantification as well a "dual- extraction" methodology for eliminating non-specific proteins while simultaneously validating isoforms. Industrial efforts towards widespread clinical adoption are also described. Consequently, this work lays a foundation for the translation of mass spectrometric immunoassays into the clinical arena and simultaneously presents the most recent advancements concerning the mass spectrometric immunoassay approach.
ContributorsOran, Paul (Author) / Nelson, Randall (Thesis advisor) / Hayes, Mark (Thesis advisor) / Ros, Alexandra (Committee member) / Williams, Peter (Committee member) / Arizona State University (Publisher)
Created2011
Description
Though for most of the twentieth century, dogma held that the adult brain was post-mitotic, it is now known that adult neurogenesis is widespread among vertebrates, from fish, amphibians, reptiles and birds to mammals including humans. Seasonal changes in adult neurogenesis are well characterized in the song control system of song birds, and have been found in seasonally breeding mammals as well. In contrast to more derived vertebrates, such as mammals, where adult neurogenesis is restricted primarily to the olfactory bulb and the dentate gyrus of the hippocampus, neurogenesis is widespread along the ventricles of adult amphibians. I hypothesized that seasonal changes in adult amphibian brain cell proliferation and survival are a potential regulator of reproductive neuroendocrine function. Adult, male American bullfrogs (Rana catesbeiana; aka Lithobates catesbeianus), were maintained in captivity for up to a year under season-appropriate photoperiod. Analysis of hormone levels indicated seasonal changes in plasma testosterone concentration consistent with field studies. Using the thymidine analogue 5-bromo-2-deoxyuridine (BrdU) as a marker for newly generated cells, two differentially regulated aspects of brain cell neogenesis were tracked; that is, proliferation and survival. Seasonal differences were found in BrdU labeling in several brain areas, including the olfactory bulb, medial pallium, nucleus accumbens and the infundibular hypothalamus. Clear seasonal differences were also found in the pars distalis region of the pituitary gland, an important component of neuroendocrine pathways. BrdU labeling was also examined in relation to two neuropeptides important for amphibian reproduction: arginine vasotocin and gonadotropin releasing hormone. No cells co-localized with BrdU and either neuropeptide, but new born cells were found in close proximity to neuropeptide-containing neurons. These data suggest that seasonal differences in brain and pituitary gland cell neogenesis are a potential neuroendocrine regulatory mechanism.
ContributorsMumaw, Luke (Author) / Orchinik, Miles (Thesis advisor) / Deviche, Pierre (Committee member) / Chandler, Douglas (Committee member) / Arizona State University (Publisher)
Created2012
Description
Reproduction is energetically costly and seasonal breeding has evolved to capitalize on predictable increases in food availability. The synchronization of breeding with periods of peak food availability is especially important for small birds, most of which do not store an extensive amount of energy. The annual change in photoperiod is the primary environmental cue regulating reproductive development, but must be integrated with supplementary cues relating to local energetic conditions. Photoperiodic regulation of the reproductive neuroendocrine system is well described in seasonally breeding birds, but the mechanisms that these animals use to integrate supplementary cues remain unclear. I hypothesized that (a) environmental cues that negatively affect energy balance inhibit reproductive development by acting at multiple levels along the reproductive endocrine axis including the hypothalamus (b) that the availability of metabolic fuels conveys alterations in energy balance to the reproductive system. I investigated these hypotheses in male house finches, Haemorhous mexicanus, caught in the wild and brought into captivity. I first experimentally reduced body condition through food restriction and found that gonadal development and function are inhibited and these changes are associated with changes in hypothalamic gonadotropin-releasing hormone (GnRH). I then investigated this neuroendocrine integration and found that finches maintain reproductive flexibility through modifying the release of accumulated GnRH stores in response to energetic conditions. Lastly, I investigated the role of metabolic fuels in coordinating reproductive responses under two different models of negative energy balance, decreased energy intake (food restriction) and increased energy expenditure (high temperatures). Exposure to high temperatures lowered body condition and reduced food intake. Reproductive development was inhibited under both energy challenges, and occurred with decreased gonadal gene expression of enzymes involved in steroid synthesis. Minor changes in fuel utilization occurred under food restriction but not high temperatures. My results support the hypothesis that negative energy balance inhibits reproductive development through multilevel effects on the hypothalamus and gonads. These studies are among the first to demonstrate a negative effect of high temperatures on reproductive development in a wild bird. Overall, the above findings provide important foundations for investigations into adaptive responses of breeding in energetically variable environments.
ContributorsValle, Shelley (Author) / Deviche, Pierre (Thesis advisor) / McGraw, Kevin (Committee member) / Orchinik, Miles (Committee member) / Propper, Catherine (Committee member) / Sweazea, Karen (Committee member) / Arizona State University (Publisher)
Created2018
Description
In wild birds, the stress response can inhibit the activity of the innate immune system, which serves as the first line of defense against pathogens. By elucidating the mechanisms which regulate the interaction between stress and innate immunity, researchers may be able to predict when birds experience increased susceptibility to infections and can target specific mediators to mitigate stress-induced suppression of innate immune activity. Such elucidation is especially important for urban birds, such as the House Sparrow (Passer domesticus), because these birds experience higher pathogen prevalence and transmission when compared to birds in rural regions. I investigated the role of corticosterone (CORT) in stress-induced suppression of two measures of innate immune activity (complement- and natural antibody-mediated activity) in male House Sparrows. Corticosterone, the primary avian glucocorticoid, is elevated during the stress response and high levels of this hormone induce effects through the activation of cytosolic and membrane-bound glucocorticoid receptors (GR). My results demonstrate that CORT is necessary and sufficient for stress-induced suppression of complement-mediated activity, and that this relationship is consistent between years. Corticosterone, however, does not inhibit complement-mediated activity through cytosolic GR, and additional research is needed to confirm the involvement of membrane-bound GR. The role of CORT in stress-induced inhibition of natural antibody-mediated activity, however, remains puzzling. Stress-induced elevation of CORT can suppress natural antibody-mediated activity through the activation of cytosolic GR, but the necessity of this mechanism varies inter-annually. In other words, both CORT-dependent and CORT-independent mechanisms may inhibit natural antibody-mediated activity during stress in certain years, but the causes of this inter-annual variation are not known. Previous studies have indicated that changes in the pathogen environment or food availability can alter regulation of innate immunity, but further research is needed to test these hypotheses. Overall, my dissertation demonstrates that stress inhibits innate immunity through several mechanisms, but environmental pressures may influence this inhibitory relationship.
ContributorsGao, Sisi (Author) / Deviche, Pierre (Thesis advisor) / DeNardo, Dale (Committee member) / McGraw, Kevin (Committee member) / Orchinik, Miles (Committee member) / Moore, Michael C. (Committee member) / Arizona State University (Publisher)
Created2017
Description
Type 1 diabetes (T1D) is a chronic disease that affects 1.25 million people in the United States. There is no known cure and patients must self-manage the disease to avoid complications resulting from blood glucose (BG) excursions. Patients are more likely to adhere to treatments when they incorporate lifestyle preferences. Current technologies that assist patients fail to consider two factors that are known to affect BG: exercise and alcohol. The hypothesis is postprandial blood glucose levels of adult patients with T1D can be improved by providing insulin bolus or carbohydrate recommendations that account for meal and alcohol carbohydrates, glycemic excursion, and planned exercise. I propose an evidence-based decision support tool, iDECIDE, to make recommendations to improve glucose control by taking into account meal and alcohol carbohydrates, glycemic excursion and planned exercise. iDECIDE is deployed as a low-cost and easy to disseminate smartphone application.
A literature review was conducted on T1D and the state-of-the-art in diabetes technology. To better understand self-management behaviors and guide the development of iDECIDE, several data sources were collected and analyzed: surveys, insulin pump paired with glucose monitoring, and self-tracking of exercise and alcohol. The analysis showed variability in compensation techniques for exercise and alcohol and that patients made unaided decisions, suggesting a need for better decision support.
The iDECIDE algorithm can make insulin and carbohydrate recommendations. Since there were no existing in-silico methods for assessing bolus calculators, like iDECIDE, I proposed a novel methodology to retrospectively compare insulin pump bolus calculators. Application of the methodology shows that iDECIDE outperformed the Medtronic insulin pump bolus calculator and could have improved glucose control.
This work makes contributions to diabetes technology researchers, clinicians and patients. The iDECIDE app provides patients easy access to a decision support tool that can improve glucose control. The study of behaviors from diabetes technology and self-report patient data can inform clinicians and the design of future technologies and bedside tools that integrate patient’s behaviors and perceptions. The comparison methodology provides a means for clinical informatics researchers to identify and retrospectively test promising insulin blousing algorithms using real-life data.
A literature review was conducted on T1D and the state-of-the-art in diabetes technology. To better understand self-management behaviors and guide the development of iDECIDE, several data sources were collected and analyzed: surveys, insulin pump paired with glucose monitoring, and self-tracking of exercise and alcohol. The analysis showed variability in compensation techniques for exercise and alcohol and that patients made unaided decisions, suggesting a need for better decision support.
The iDECIDE algorithm can make insulin and carbohydrate recommendations. Since there were no existing in-silico methods for assessing bolus calculators, like iDECIDE, I proposed a novel methodology to retrospectively compare insulin pump bolus calculators. Application of the methodology shows that iDECIDE outperformed the Medtronic insulin pump bolus calculator and could have improved glucose control.
This work makes contributions to diabetes technology researchers, clinicians and patients. The iDECIDE app provides patients easy access to a decision support tool that can improve glucose control. The study of behaviors from diabetes technology and self-report patient data can inform clinicians and the design of future technologies and bedside tools that integrate patient’s behaviors and perceptions. The comparison methodology provides a means for clinical informatics researchers to identify and retrospectively test promising insulin blousing algorithms using real-life data.
ContributorsGroat, Danielle (Author) / Grando, Maria Adela (Thesis advisor) / Kaufman, David (Committee member) / Thompson, Bithika (Committee member) / Arizona State University (Publisher)
Created2017
Description
Obesity and its underlying insulin resistance are caused by environmental and genetic factors. DNA methylation provides a mechanism by which environmental factors can regulate transcriptional activity. The overall goal of the work herein was to (1) identify alterations in DNA methylation in human skeletal muscle with obesity and its underlying insulin resistance, (2) to determine if these changes in methylation can be altered through weight-loss induced by bariatric surgery, and (3) to identify DNA methylation biomarkers in whole blood that can be used as a surrogate for skeletal muscle.
Assessment of DNA methylation was performed on human skeletal muscle and blood using reduced representation bisulfite sequencing (RRBS) for high-throughput identification and pyrosequencing for site-specific confirmation. Sorbin and SH3 homology domain 3 (SORBS3) was identified in skeletal muscle to be increased in methylation (+5.0 to +24.4 %) in the promoter and 5’untranslated region (UTR) in the obese participants (n= 10) compared to lean (n=12), and this finding corresponded with a decrease in gene expression (fold change: -1.9, P=0.0001). Furthermore, SORBS3 was demonstrated in a separate cohort of morbidly obese participants (n=7) undergoing weight-loss induced by surgery, to decrease in methylation (-5.6 to -24.2%) and increase in gene expression (fold change: +1.7; P=0.05) post-surgery. Moreover, SORBS3 promoter methylation was demonstrated in vitro to inhibit transcriptional activity (P=0.000003). The methylation and transcriptional changes for SORBS3 were significantly (P≤0.05) correlated with obesity measures and fasting insulin levels. SORBS3 was not identified in the blood methylation analysis of lean (n=10) and obese (n=10) participants suggesting that it is a muscle specific marker. However, solute carrier family 19 member 1 (SLC19A1) was identified in blood and skeletal muscle to have decreased 5’UTR methylation in obese participants, and this was significantly (P≤0.05) predicted by insulin sensitivity.
These findings suggest SLC19A1 as a potential blood-based biomarker for obese, insulin resistant states. The collective findings of SORBS3 DNA methylation and gene expression present an exciting novel target in skeletal muscle for further understanding obesity and its underlying insulin resistance. Moreover, the dynamic changes to SORBS3 in response to metabolic improvements and weight-loss induced by surgery.
Assessment of DNA methylation was performed on human skeletal muscle and blood using reduced representation bisulfite sequencing (RRBS) for high-throughput identification and pyrosequencing for site-specific confirmation. Sorbin and SH3 homology domain 3 (SORBS3) was identified in skeletal muscle to be increased in methylation (+5.0 to +24.4 %) in the promoter and 5’untranslated region (UTR) in the obese participants (n= 10) compared to lean (n=12), and this finding corresponded with a decrease in gene expression (fold change: -1.9, P=0.0001). Furthermore, SORBS3 was demonstrated in a separate cohort of morbidly obese participants (n=7) undergoing weight-loss induced by surgery, to decrease in methylation (-5.6 to -24.2%) and increase in gene expression (fold change: +1.7; P=0.05) post-surgery. Moreover, SORBS3 promoter methylation was demonstrated in vitro to inhibit transcriptional activity (P=0.000003). The methylation and transcriptional changes for SORBS3 were significantly (P≤0.05) correlated with obesity measures and fasting insulin levels. SORBS3 was not identified in the blood methylation analysis of lean (n=10) and obese (n=10) participants suggesting that it is a muscle specific marker. However, solute carrier family 19 member 1 (SLC19A1) was identified in blood and skeletal muscle to have decreased 5’UTR methylation in obese participants, and this was significantly (P≤0.05) predicted by insulin sensitivity.
These findings suggest SLC19A1 as a potential blood-based biomarker for obese, insulin resistant states. The collective findings of SORBS3 DNA methylation and gene expression present an exciting novel target in skeletal muscle for further understanding obesity and its underlying insulin resistance. Moreover, the dynamic changes to SORBS3 in response to metabolic improvements and weight-loss induced by surgery.
ContributorsDay, Samantha Elaine (Author) / Coletta, Dawn K. (Thesis advisor) / Katsanos, Christos (Committee member) / Mandarino, Lawrence J. (Committee member) / Shaibi, Gabriel Q. (Committee member) / Dinu, Valentin (Committee member) / Arizona State University (Publisher)
Created2017
Description
Applications of non-traditional stable isotope variations are moving beyond geosciences to biomedicine, made possible by advances in multiple collector inductively coupled plasma mass spectrometry (MC-ICP-MS) technology. Mass-dependent isotope variation can provide information about the sources of elements and the chemical reactions that they undergo. Iron and calcium isotope systematics in biomedicine are relatively unexplored but have great potential scientific interest due to their essential nature in metabolism. Iron, a crucial element in biology, fractionates during biochemically relevant reactions. To test the extent of this fractionation in an important reaction process, equilibrium iron isotope fractionation during organic ligand exchange was determined. The results show that iron fractionates during organic ligand exchange, and that isotope enrichment increases as a function of the difference in binding constants between ligands. Additionally, to create a mass balance model for iron in a whole organism, iron isotope compositions in a whole mouse and in individual mouse organs were measured. The results indicate that fractionation occurs during transfer between individual organs, and that the whole organism was isotopically light compared with food. These two experiments advance our ability to interpret stable iron isotopes in biomedicine. Previous research demonstrated that calcium isotope variations in urine can be used as an indicator of changes in net bone mineral balance. In order to measure calcium isotopes by MC-ICP-MS, a chemical purification method was developed to quantitatively separate calcium from other elements in a biological matrix. Subsequently, this method was used to evaluate if calcium isotopes respond when organisms are subjected to conditions known to induce bone loss: 1) Rhesus monkeys were given an estrogen-suppressing drug; 2) Human patients underwent extended bed rest. In both studies, there were rapid, detectable changes in calcium isotope compositions from baseline - verifying that calcium isotopes can be used to rapidly detect changes in bone mineral balance. By characterizing iron isotope fractionation in biologically relevant processes and by demonstrating that calcium isotopes vary rapidly in response to bone loss, this thesis represents an important step in utilizing these isotope systems as a diagnostic and mechanistic tool to study the metabolism of these elements in vivo.
ContributorsMorgan, Jennifer Lynn Louden (Author) / Anbar, Ariel D. (Thesis advisor) / Wasylenki, Laura E. (Committee member) / Jones, Anne K. (Committee member) / Shock, Everett (Committee member) / Arizona State University (Publisher)
Created2011