No description available.

Endocrine and metabolic disease or dysfunctions are of growing concern in modern societies across the globe, underlining the need for continued focus on the development of pharmaceuticals. Subsequent scientific research has revealed a trend in the increase of such abnormalities and expansion of chemical industries, highlighting concerns that these disorders may, in part, be caused by exposure to environmental pollutants. This has led to changes in legislation concerning chemicals safety testing involving an increasing number of vertebrate animal tests as a part of environmental risk assessment process, at significant financial and ethical costs. A solution that is appropriate and aligned with the three R’s (reduction, refinement and replacement) in relation to animal research is to exploit the use of small invertebrate organisms as possible replacements for mammals. In line with the above approach/solution, this thesis is based on the null hypothesis that common genes, proteins and processes in gastropod molluscs and humans underlie the response of male reproductive organs to androgenic chemicals. Using a freshwater pulmonate snail, Biomphalaria glabrata, physiological effects of two steroid androgens on the development of mollusc secondary sexual organs were studied. Furthermore, an exhaustive investigation on the mollusc nuclear receptor repertoire and reproductive type neuropeptides was conducted. This also included the study of the evolutionary degree of conservation of these genes in non-model molluscs. The results obtained suggest that the snails did not respond to, and were not affected by exposure to the androgens. These results were supported by the absence of the members of subfamily 3C of nuclear receptors, which includes some of the “vertebrate” steroid hormone targets, suggesting that this mollusc may be an inappropriate model for steroid hormone mediated mammalian endocrine function. The nuclear receptor (NR) repertoire of B. glabrata comprised of 39 nuclear receptors representing all the known subfamilies of the NR superfamily. 21 reproductive type neuropeptide genes were identified encoding precursors that are predicted to release over 124 bioactive cleavage products. The consequence of these findings is significant in the context of the development of alternative model organisms for chemical testing as well as elucidating the taxonomic scope of nuclear receptor mediated endocrine disruption.

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

No description available.

Androgen endocrine physiology is responsible for many processes in the body, from bone metabolism to skeletal muscle maintenance. Testosterone is one of the most potent androgens produced, with decades of research highlighting its androgenic-anabolic effect on skeletal muscle growth. The research has been further driven through the emergence of pharmaceutical derivates (steroids) of testosterone and their use in interventions for muscle wasting associated with disease and advancing age (sarcopenia). However, the molecular regulation of testosterone and the influence it has on cellular processes in promoting muscle development, hypertrophy and satellite cell activation (proliferation, differentiation) remain poorly understood. In summary, this thesis has highlighted the impact of testosterone in rescuing an aged phenotype in myoblast cells (PD cells) displaying prior reductions in regeneration and hypertrophy vs. relevant ‘un-aged’ controls (Sharples et al., 2011, Sharples et al., 2012). Importantly, the results provide evidence towards the mechanisms for testosterone induced hypertrophy, where in the presence of testosterone and a functional androgen receptor (shown via AR antagonism/ flutamide administration) testosterone is fundamental in regulating appropriate myoD, myogenin and myostatin expression in the control of myotube differentiation and hypertrophy. Increases in androgen receptor protein levels in PD myoblasts under a testosterone stimulus highlight the intrinsic responsiveness of aged myoblasts to a hypertrophic stimulus which may somewhat explain the use of testosterone as an effective clinical treatment in muscle wasting disease. Finally, myotube hypertrophy occurred in both aged and un-aged myoblasts with testosterone administration even in the presence of an IGF-I receptor inhibitor (Picropodophyllin) suggesting a limited role of the IGF-IR and associated signaling in testosterones mediated increases in differentiation and hypertrophy. Testosterone did appear however to increase Akt phosphorylation in cells that show a prior impaired regenerative capacity (PD cells), even in the presence-IGF-IR inhibitor suggesting that testosterone can directly activate Akt independently of upstream IGF-IR a novel finding that is presented in chapter 5. This interaction maybe mediated by myostatin, where increases in myostatin has been linked with directly inhibiting Akt (Dubois et al., 2014, Léger et al., 2008, Morissette et al., 2009), and in the present study we see an increase in myostatin mRNA and corresponding decrease in phospho-Akt when AR’s (via flutamide) action is inhibited and the protein level of AR is low (chapter 5). Furthermore in chapter 6 we further showed that inhibition of PI3K/AKT using LY294002 was sufficient to remove the prior rescuing of differentiation and hypertrophy in aged cells after testosterone administration. This was coupled with reductions in myostatin and increases in mTOR with testosterone administration. Overall AR seems to be the most fundamental pathway in testosterones induction of myotube differentiation and hypertrophy with important roles for myogenin, Akt, mTOR and myostatin in mediating these processes.

It is well established that females are more immunocompetent than males as evidenced by higher humoral antibody titers, lowered susceptibility to infection, and more efficient graft rejection. Furthermore, females also exhibit a much higher incidence of autoimmune disease. These observations have led investigators to believe that the male hormonal environment may play a key role in the regulation of immune response. For this reason, this study is concerned with the expression of autoimmunity and of immune function in the mouse. This study included the New Zealand Black (NZB) mouse strain, as an animal model for human SLE, as well as normal DBA/2 and Balb/c strains. Animals were administered testosterone via subcutaneous implants in silastic tubing or by injection. Mice used were intact females, intact males and castrated males. Animals were otherwise untreated or had been exposed to a sublethal dose (400-550 rads) of irradiation. Target organ weight changes, immune capacity and peripheral blood picture changes were measured.

The gonadal steroids, testosterone and estradiol, are known to be important modulators of neuronal functions and behaviors in most vertebrate species. These steroid hormones also elicit changes in neuropeptide synthesis and secretion, alter specific neurohormone receptor levels, and alter neuronal morphology and electrophysiology. Many of the actions of androgens and estrogen are mediated by specific intracellular receptors found in certain regions of the brain. But where are these neuronal targets for androgens and estrogen found? The research in this thesis investigates the neuroanatomical distribution of androgen and estrogen receptors in the brain of a urodele amphibian, the roughskin newt, Taricha granulosa. Using immunocytochemistry with antibodies against these receptors, the distribution of both androgen and estrogen receptor-immunoreactive cells is described in the brain of this species. This study found brain regions that contain immunoreactive androgen receptors that have not previously been reported in poikilothermic vertebrates using other techniques. In addition, the distribution of estrogen receptor-immunoreactive cells in most brain areas, and the distribution of androgen receptor-immunoreactive cells in several brain areas, were found to be similar in this amphibian to those described in studies that employed in vivo autoradiographic techniques in other vertebrate species. This study suggests that the neuroanatomical distribution of gonadal steroid receptors is a relatively conserved trait in vertebrates. The widespread distribution of these receptors in the brain probably reflects the multiple functions that androgens and estrogen are known to have in the brain. / Graduation date: 1995

Thesis (Ph. D.)--Ohio State University, 2006. / Full text release at OhioLINK's ETD Center delayed at author's request

Thesis (M. Phil.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 73-126).

Boys with Attention-Deficit/Hyperactivity Disorder (ADHD) were recruited from a local neuropsychology office with controls recruited from the community to assess the relationship between prenatal androgen exposure and ADHD, as well as the possible cognitive correlates of this exposure. Putative physiological markers of prenatal androgen exposure that were measured for each child included several types of otoacoustic emissions (OAEs) as well as finger-length ratios (FLRs). Neurocognitive measures included tasks which assessed components of attention, general intelligence, reading ability, and visuospatial skills. Several other variables which may also be related to androgen exposure were included (e.g., sleep disturbance, handedness, number of older brothers) in the analyses. Children ranged in age from 7 to 12 years old with 13 controls, 19 children with ADHD/Combined Type (ADHD/C), 10 with ADHD/Inattentive Type (ADHD/IA), and an additional 11 children with ADHD/IA who were rated by their parents as having relatively high levels of an experimental construct (sluggish cognitive tempo; SCT). Because more boys than girls are diagnosed with ADHD, it was hypothesized that ADHD may be associated with prenatal masculinizing hormones (i.e., androgens), and that children with ADHD would appear more masculine on markers of androgen exposure (OAEs and FLRs) than controls. However, in our current study children with ADHD did not differ from controls on these measures. There was some evidence that children with SCT may represent a more homogenous group of children within the ADHD/IA diagnostic group, and that they may share a deficit in alerting attention. Consistent with theories suggesting subtype differences in attention, children with ADHD/C did not appear to have a deficit in alerting attention, but rather appeared more cognitively impulsive and to have a deficit in auditory attention. Children with SCT were more likely to be rated by their parents as having disrupted sleep.