Master of Science, The Ohio State University, 2020, Comparative and Veterinary Medicine

Sepsis and neonatal maladjustment syndrome (NMS) are major causes of morbidity and mortality in neonatal foals. The hypothalamic-pituitary-adrenal axis (HPAA) is essential for a multitude of biological functions, and HPAA dysfunction is frequent in critically ill newborn foals. Most information on adrenocortical function in healthy and sick foals has been through the investigation of adrenocorticotropic hormone (ACTH) and glucocorticoids, and more recently on mineralocorticoids and progestogens, but little is known about androgens and estrogens. In response to physiological needs or stress conditions, HPAA activation results in ACTH secretion, which stimulates the adrenal gland to produce cortisol, and to lesser extend other steroids (aldosterone, steroid precursors). Most sick foals have elevated concentrations of steroids, which is likely an appropriate response. However, a number of critically ill foals have a poor steroid response to ACTH (high ACTH:steroid ratio), indicating adrenocortical dysfunction, a phenomenon termed relative adrenocortical insufficiency (RAI)/critical illness-related corticosteroid insufficiency (CIRCI). The equine fetal adrenal and gonads produce steroid precursors that are metabolized by the placenta into progestogens, androgens, estrogens, and other steroids. High progestogens have been associated with sepsis and NMS in hospitalized foals.1,2 Administration of exogenous progestogens (altrenogest, progesterone) is common practice in the equine industry. Exogenous steroids cross the placental barrier and can be found in the plasma of newborn foals.3 Changes in gestational length and clinical pathology have been documented in foals born to altrenogest-treated mares.4,5 However, little is known about the effects of exogenous progestogens on the endocrine profile of newborn foals, and whether there is an association with neonatal disorders. For the first study, we hypothesized that androgens and estrogens would be elevated in sick compared (open full item for complete abstract)

Committee: Ramiro Toribio (Advisor); Teresa Burns (Committee Member); Laura Hostnik (Committee Member) Subjects: Veterinary Services

PHD, Kent State University, 2016, College of Arts and Sciences / Department of Psychological Sciences

Anxiety disorders are the most common mental disorder with nearly 30% of individuals meeting criteria for an anxiety disorder over the course of their lifetime, generating significant personal, financial and emotional burden. Additionally, women are 60% more likely than men to be diagnosed with an anxiety disorder, such as PTSD. Inappropriate fear that occurs in normally safe environments, or fear generalization, is a key symptom of many anxiety disorders. The current set experiments explores sex differences in the generalization of fear and identifies mechanisms by which estradiol affects fear generalization. Results demonstrate that females generalize fear at a faster rate than males, and this process is driven, in part, by estradiol. However, in males, estradiol acts to attenuate generalization rather than to induce generalization. In fact, testosterone also attenuates generalization in gonadectomized males and does so through conversion into estradiol via aromatase. Estradiol impacts generalization through effects on memory retrieval rather than memory acquisition/consolidation. In females, estradiol acts through activation of cytosolic ERß within the dorsal CA1 region of the hippocampus and the anterior cingulate cortex (ACC), but not the ventral CA1 region of the hippocampus. Finally, estradiol-induced generalization in females appears to be a result of augmented glutamatergic signaling within the dorsal CA1 and ACC; blocking glutamate receptor activation attenuates estradiol-induced generalization. These mechanisms can help explain the discrepancies in prevalence rates for anxiety disorders between males and females, and are also crucial for development of more effective, and potentially sex-specific, treatments for anxiety disorders such as PTSD.

Committee: Aaron Jasnow Ph.D (Advisor); David Riccio Ph.D (Advisor); Stephen Fountain Ph.D (Committee Member); Karin Coifman Ph.D (Committee Member); John Johnson Ph.D (Committee Member); Heather Caldwell Ph.D (Committee Chair) Subjects: Animals; Behavioral Psychology; Biology; Endocrinology; Experimental Psychology; Neurobiology; Pharmacology

PHD, Kent State University, 2013, College of Arts and Sciences / Department of Biological Sciences

MUSIAL, ANDREA T., Ph.D., December 2013 BIOLOGICAL SCIENCES REANALYZING THE ROLE OF ESTRADIOL IN THE DEVELOPING ZEBRA FINCH BRAIN (125 PP.) Director of Dissertation: Sean L. Veney, Ph.D. The neural dimorphisms in the zebra finch present one of the most unique examples of sexual differentiation observed in vertebrates. Although knowledge of these differences has been established for over 45 years, the exact mechanism by which they arise is not known. This dissertation provides additional support for estrogens' involvement in brain development. Specifically, blocking of estrogen receptors with ICI 182,780 decreased neuron soma size of song control regions in both sexes during development. These results are distinctive since previous attempts to block estrogen receptors failed to see the large degree of difference my work displayed. I further supported the role of estrogens in neural brain dimorphisms by decreasing the synthesis of aromatase, an enzyme needed for estradiol production, with the administration of Fadrozole. This successfully decreased neuron soma sizes, neuron number, and nuclear volume in song control regions in males and females, which had not been seen in prior attempts from other laboratories. I have concluded that the route of delivery used in these experiments is likely the largest contributing factor to generating these unique results. I also provide evidence of a potential role for ER alpha by displaying its presence at an early post-hatching age in two auditory processing regions. Taken together, my work provides further support for the role of estrogens in the dimorphic development of the brain, and establishes that it is unlikely that ER alpha contributes to neural dimorphisms in the zebra finch.

Committee: Sean Veney Ph.D (Advisor); Eric Mintz Ph.D (Committee Member); David Glass Ph.D (Committee Member); Stephen Fountain Ph.D (Committee Member); Mary Ann Raghanti Ph.D (Committee Member) Subjects: Biology

PhD, University of Cincinnati, 2001, Medicine : Cell and Molecular Biology

The goal of this dissertation was to determine at the molecular level how compounds that are structurally dissimilar from estradiol are able to exert estrogen-like biological activity through the estrogen receptor (ER). This was investigated using yeast genetic systems expressing the human ER to determine the ability of these compounds to bind to the receptor and induce a transcriptionally active ER dimer. I have monstrated that the environmental estrogens octylphenol, bisphenol-A, and o,p'-DDT could induce transcriptionally active ER dimers, although at concentrations 3000-times higher than estradiol. The presence of the coactivator RIP140 dramatically amplified estradiol, octylphenol, bisphenol-A, and o,p'-DDT induction of ER-dependent gene transcription by 100-fold. A yeast whole-cell [3H]estradiol binding assay demonstrated that octylphenol and bisphenol-A bound to the ER ligand binding domain (LBD). The antiestrogens tamoxifen and ICI182,780 have been portrayed as competitive antagonists of the estrogen binding site of the ER. In contrast, the data presented here shows that tamoxifen and ICI182,780 were able to induce ER dimerization and ER-dependent transcription. In the presence of RIP140, transcription was increased up to 30-fold. Whole yeast cell [3H]estradiol binding studies demonstrated that tamoxifen bound to the ER LBD, whereas, ICI182,780 treatment resulted in a 4-fold increase in [3H]estradiol binding to the receptor, indicating a possible allosteric binding site. No antagonism of estradiol was observed with tamoxifen or ICI182,780 in any of the yeast models employed.Data from this dissertation indicates that ER expressed in yeast does become phosphorylated in the presence of estradiol, possibly through the MAPK pathway. Preliminary data also shows that serines at amino acid residues 104, 106, and 118 may play a role in ligand-dependent dimerization. This dissertation shows that several compounds commonly found in the environment activate the ER throu (open full item for complete abstract)

Committee: Dr. Sohaib Khan (Advisor) Subjects: Biology, Molecular

PhD, University of Cincinnati, 2010, Engineering and Applied Science: Environmental Science

The fate of seven steroids: estrone (E1), estradiol (E2), estriol (E3), ethinylestradiol (EE2), testosterone (TEST), androstenedione (AND), and progesterone (PROG), in the presence of synthetic wastewater was studied in order to establish the role abiotic processes play in the elimination of these chemicals from the environment. Comprehension of these mechanisms will foster the optimization of the existing wastewater treatment technologies and the development of sustainable alternatives. Distinctive behavior was encountered for the target compounds in accordance with their chemical structure, hence, different physico-chemical properties and reactivity. Estrogenic compounds, comprising E1, E2, E3 and EE2, were found to undergo a catalytic transformation when contacted with a model vegetable material present in the synthetic wastewater. This transformation occurred in the absence of biological and enzymatic activity. On the other hand, the concentration of TEST, AND, and PROG stayed constant and in agreement with the spiked amount. The fastest transformation rate corresponded to E3, the least hydrophobic compound in the study. This may indicate that the catalytic reaction occurred in the aqueous phase. The contribution of steric and electronic factors, such as critical oxidation potential, in the reaction rate cannot be discarded; consequently, the hypothesis of a surface catalyzed reaction cannot be rejected. The use of 14C4-estradiol (14C-E2) as model estrogenic compound corroborated the occurrence of a catalytic reaction, most likely through an oxidative coupling mechanism. Under oxic conditions, the mass balance for radioactivity was closed after extended experimental periods (72 h), while the concentration of 14C-E2 measured by Liquid Chromatography coupled with a Triple Quadrupole Mass Spectrometer (LC/MS/MS) did not match the spiked one when analyzed independently in liquid and solid phases. Furthermore, radioactivity was found to distribute in the aqueous ph (open full item for complete abstract)

Committee: Makram Suidan PhD (Committee Chair); George Sorial PhD (Committee Member); Margaret Kupferle PhD, PE (Committee Member); Marc Mills PhD (Committee Member) Subjects: Environmental Engineering

Doctor of Philosophy, The Ohio State University, 2003, Pharmacy

Natural isoflavones are well known as phytoestrogens due to their biological activities that mimic endogenous estrogens. For this reason, we recognized the isoflavone nucleus as a promising privileged structure for the development of new therapeutics for hormone-dependent breast cancer, in which estrogens play a key role in growth and development of tumor. We envisioned that a specific activity could be achieved by introducing proper functional groups into the isoflavone nucleus, and we designed a library of novel 2-substituted isoflavones. For the library synthesis, we developed efficient synthetic routes, in which alpha-oxoketene dithioacetals are employed as key intermediates. Various 2-(alkylthio)isoflavones were obtained directly from readily available deoxybenzoins and electrophiles using a phase transfer catalysis procedure. Alternatively, 2-substituted isoflavones were prepared through a 1,4-conjugate addition-elimination reaction of 2-(methylsulfonyl)isoflavones using a variety of commercially available nucleophiles. With efficient synthetic routes developed, we examined the potential utility of this approach for the discovery of new leads towards specific molecular targets in the breast cancer. Initially, we have focused on two major classes of therapeutic agents, aromatase inhibitors and selective estrogen receptor modulators (SERMs). As potential aromatase inhibitors, we prepared various isoflavones possessing a nitrogen-containing heterocycle, which may interfere with aromatase activity by coordinating with its heme iron. Several compounds were identified with potent aromatase inhibitory activities. As potential SERMs, we prepared a series of isoflavones containing an amine-bearing side chain, which is known to be essential for the tissue selectivity of many known SERMs. Several compounds in this series were highly potent in inhibiting proliferation of human breast cancer cells. However, their low binding affinities for estrogen receptors suggest that t (open full item for complete abstract)

Committee: Robert Brueggemeier (Advisor) Subjects:

MA, Kent State University, 2013, College of Arts and Sciences / Department of Psychological Sciences

Anxiety disorders are the most prominent mental disorder in the United States, and women are 60% more likely than men to have an anxiety disorder. One hypothesis for this sex difference is faster fear generalization rates in females. In previous studies using male subjects, context change disrupted a fear response at a short, but not long retention interval. An incidental observation suggested that females would show a different temporal pattern of fear generalization. In Experiment 1, male and intact female rats displayed disrupted fear responses in a novel context at 1 day. Males displayed context discrimination at all intervals, whereas females exhibited generalization by 5 days. In Experiment 2, ovariectomized females were given an empty capsule or a capsule containing 17ß-estradiol to determine the role of estrogens in fear generalization. Female rats with no hormone replacement displayed context discrimination at 5 days, whereas those receiving estradiol generalized their fear response to a novel context. These results demonstrate that fear generalization for contextual cues occurs faster in female rats and that this effect is mediated, in part, by estrogens. Understanding the sex differences in fear generalization is likely to be critical to developing effective treatments for anxiety disorders.

Committee: David Riccio (Advisor); Aaron Jasnow (Committee Member); Stephen Fountain (Committee Member); Beth Wildman (Committee Member) Subjects: Psychology