Thesis (Ph. D.)--University of Hawaii at Manoa, 2004. / Includes bibliographical references (leaves 92-105). / Also available by subscription via World Wide Web / xv, 105 leaves, bound ill. 29 cm

"August 2002" / Bibliography: leaves 141-176. / ix, 179 leaves : ill. (some col.) ; 30 cm / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Changes in maternal-foetal zinc homeostasis resulting in a foetal deficiency may be an important contributing factor in ethanol-realted teratogenicity. Ethanol induces expression of hepatic metallothionein, causing zinc transfer from the plasma to the liver. Rodent studies show that changes in plasma zinc correlate with a high incidence of abnormal fetuses in MT+/+ mice. Demonstrates a clear link between maternal hepatic MT induction, decreased foetal zinc supply, and teratogenicity, which has major implications for binge alcohol consumption in early pregnancy. The demonstration that zinc treatment is effective in preventing teratogenicity indicates potential treatment strategies. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 2003

Indiana University-Purdue University Indianapolis (IUPUI) / Down syndrome (DS) and Fetal Alcohol Syndrome (FAS) are two leading causes of birth defects with phenotypes ranging from cognitive impairment to craniofacial abnormalities. While DS originates from the trisomy of human chromosome 21 and FAS from prenatal alcohol consumption, many of the defining characteristics for these two disorders are stunningly similar. A survey of the literature revealed over 20 similar craniofacial and structural deficits in both human and mouse models of DS and FAS. We hypothesized that the similar phenotypes observed are caused by disruptions in common molecular or cellular pathways during development. To test our hypothesis, we examined morphometric, genetic, and cellular phenotypes during development of our DS and FAS mouse models at embryonic days 9.5-10.5. Our preliminary evidence indicates that during early development, dysregulation of Dyrk1a and Rcan1, cardinal genes affecting craniofacial and neurological precursors of DS, are also dysregulated in embryonic FAS models. Furthermore, Caspase 3 was also found to have similar expression in DS and FAS craniofacial neural crest derived tissues such as the first branchial arch (BA1) and regions of the brain. This may explain a developmental deficit by means of apoptosis. We have also investigated the expression of pAkt, a protein shown to be affected in FAS models, in cells located within the craniofacial precursor of Ts65Dn. Recent research shows that Ttc3, a gene that is triplicated and shown to be overexpressed in the BA1 and neural tube of Ts65Dn, targets pAkt in the nucleus affecting important transcription factors regulating cell cycle and cell survival. While Akt has been shown to play a role in neuronal development, we hypothesize that it also affects similar cellular properties in craniofacial precursors during development. By comparing common genotypes and phenotypes of DS and FAS we may provide common mechanisms to target for potential treatments of both disorders. One of the least understood phenotypes of DS is their deficient immune system. Many individuals with DS have varying serious illnesses ranging from coeliac disease to respiratory infections that are a direct result of this immunodeficiency. Proteasomes are an integral part of a competent and efficient immune system. It has been observed that mice lacking immunoproteasomes present deficiencies in providing MHC class I peptides, proteins essential in identifying infections. A gene, Psmg1 (Dscr2), triplicated in both humans and in Ts65Dn mice, is known to act as a proteasome assembly chaperone for the 20S proteasome. We hypothesized that a dysregulation in this gene promotes a proteasome assembly aberration, impacting the efficiency of the DS immune system. To test this hypothesis we performed western blot analysis on specific precursor and processed β-subunits of the 20S proteasome in thymic tissue of adult Ts65Dn. While the β-subunits tested displayed no significant differences between trisomic and euploid mice we have provided further insight to the origins of immunodeficiency in DS.