Ethanol consumption during pregnancy can result in wide range of negative outcomes, including pre-and post-natal mortality, growth retardation, physical abnormalities and brain deficits, manifested as behavioural impairments. These outcomes can result from “binge-drinking” (generally defined as >5 standard drinks on a single occasion) or chronic ethanol consumption. Ethanol-induced zinc (Zn) deficiency is one of the mechanisms proposed as a cause of ethanol teratogenicity. We have previously demonstrated in mice that ethanol exposure on gestational day (GD)8 (during organogenesis) can alter Zn homeostasis by inducing the Zn-binding protein metallothionein (MT) in the maternal liver. This causes plasma Zn concentrations to decrease as Zn redistributes into the liver, and consequently decreases the fetal Zn supply and increases the risk of teratogenicity. Subcutaneous Zn treatment with ethanol on GD8 can prevent the deleterious effects of ethanol on the fetus (i.e. physical abnormalities and spatial memory impairments). The main objective of this thesis was to investigate whether a less invasive approach of giving dietary Zn supplementation throughout pregnancy could provide similar protective benefits against a range of adverse outcomes caused by prenatal binge or chronic ethanol exposure. Binge ethanol exposure in early pregnancy (i.e. where mice are injected with 25% ethanol (0.015 ml/g) intraperitoneally at 0 and 4 hours on GD8) significantly increased the incidence of birth abnormalities measured on GD18. These included craniofacial abnormalities (microphthalmia, anophthalmia) and limb defects. Ethanol also increased postnatal mortality between birth and postnatal day (PD)60. In a separate study, offspring from dams given ethanol on GD8 were subjected to a physical and behavioural screening protocol (including tests for vision, olfactory, exploratory, anxiety and motor impairments) and subsequently a cohort of phenotypically-normal offspring were randomly selected for testing in a cross-maze escape task (for spatial learning and memory) and an object recognition test (for short-term non-spatial memory). While ethanol did not affect behaviour measured during screening, it resulted in spatial memory and object recognition memory impairments in adult offspring. The most important finding was that dietary Zn supplementation throughout pregnancy significantly increased plasma Zn concentrations at the time of ethanol exposure (avoiding the “typical” ethanol-induced decrease in plasma Zn) and prevented all negative outcomes resulting from early ethanol exposure (birth abnormalities, mortality, spatial and object recognition memory impairments). In the chronic ethanol mouse model (i.e. where mice were fed a liquid diet containing 27 % v/v ethanol-derived calories from GD6-18), ethanol did not affect offspring growth between birth and PD21 or spatial memory in adult offspring, thus, the influence of Zn supplementation could not be examined for these parameters. While ethanol decreased offspring weight at PD50 and increased mortality between birth and PD40, they were not prevented by Zn supplementation throughout pregnancy. The findings from this thesis emphasise that organogenesis is a particularly vulnerable period to ethanol exposure and even a binge of ethanol during this time can result in dysmorphology, mortality and spatial and object memory impairments in adulthood. In addition, dietary Zn supplementation is protective against the deleterious effects of binge ethanol exposure in early pregnancy. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1368113 / Thesis (Ph.D.) - University of Adelaide, School of Molecular and Biomedical Sciences, 2009

Fetal alcohol spectrum disorders (FASD), caused by maternal alcohol consumption during pregnancy, has been extensively studied in the human. Animal studies show that alcohol exposure during very early development may result in severe brain damage, often incompatible with a postnatal life. However, for surviving offspring it is unknown whether they suffer long term brain damage. The final assembly of the mature brain results from a controlled balance between proliferation of glial and neuronal precursors and programmed cell death. The overall aim of the current study was to use a physiologically relevant mouse model to assess the acute and long-term effects of binge alcohol exposure on the early embryo, to simulate human pregnancy at the third week of gestation when pregnancy may be undetected. A number of paradigms were used to assess the acute dose-response effect, the blood alcohol concentration (BAC) profile and the extent of cell death following alcohol exposure on gestational day (G) 7.5. The exposure paradigms were single binge IG6.5, IG4.5, IP4.5, or an extended binge IG4.5+, IG3.0+. Two control groups were Con6.5 and Con4.5+. Acute cell death was determined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), activated caspase-3 staining, and transmission electron microscopy. Cell proliferation was investigated using S-phase immuno-labeling, bromodeoxyuridine (BrdU) birthdating and immuno-detection (BrdU/anti-BrdU). The long-term effects were investigated at G18.5 and postnatal day (PN) 60. Unbiased stereological methods were used to assess the effect of ethanol exposure at G7.5 on neocortical volume, cell number and density of neurons, glial cells, and capillary cells at PN60. The first principal finding of the present study was that binge ethanol exposure during gastrulation resulted in acute apoptotic cell death in the ectoderm of the mouse embryo. Cell death was dependent on both peak BAC and the duration of elevated BAC. Significant increased cell death (TUNEL labeling) was observed in groups IG6.5 (9.43 � 2.08%) and IG4.5+ (8.97 � 2.12%) compared with control groups Con6.5 (2.14 � 0.09%) and Con4.5+ (2.81 � 0.36%). There was no significant increased cell death in ethanol exposed groups IG4.5 (3.43 � 0.45%), IP4.5 (3.68 � 0.67%), or IG3.0+ (1.72 � 0.24%). TEM analysis revealed that cell death exhibited characteristics of the apoptotic pathway. The second principal finding of the present study was that binge ethanol exposure during gastrulation resulted in acute arrested proliferation in the ectoderm of the mouse embryo. The S-phase proliferation was significantly decreased within the whole ectoderm in the ethanol exposed group IG6.5 (45.58 � 2.34%) compared with control group Con6.5 (62.08 � 3.11%). The third principal finding of the present study was that binge ethanol exposure during gastrulation induced the long term effect of laminate disorganization in the neocortex. The incidence of abnormal lamination was 87.5% in IG6.5 compared with 16.7% in IG3.0+ and 14.3% in Con6.5. Although ethanol exposure increased embryonic reabsorption, decreased litter size, and increased abnormal offspring, neocortical volume, and the total number of neurons, glial cells, and capillary cells was not affected. The total number (10⁶) of neurons, glial cells, and endothelial cells respectively was 12.221 � 0.436, 4.865 � 0.167, and 2.874 � 0.234 in IG6.5; 11.987 � 0.416, 4.942 � 0.133, and 2.922 � 0.130 in IG3.0+; and 11.806 � 0.368, 5.166 � 0.267, and 3.284 � 0.217 in controls, at PN60. These results provide important information pertinent to fetal outcome for those women who drink heavily in early pregnancy. The results also demonstrate the importance of the pattern of ethanol exposure and blood alcohol concentration in determining the magnitude of ethanol�s teratogenic impact. Ethanol exposure on G7.5 that resulted in a high transient BAC, induced disorganized neocortical lamination, indicative of a permanent structural change. This disruption may result in altered neocortical function and requires further investigation.

Thesis (M.A.)--University of Delaware, 2007. / Principal faculty advisor: Anna Klintsova, Dept. of Psychology. Includes bibliographical references.

Thesis (Ph.D.)--University of Delaware, 2008. / Principal faculty advisor: Mark E. Stanton, Dept. of Psychology. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 69-73).

Thesis (Ph. D.)--West Virginia University, 2005. / Title from document title page. Document formatted into pages; contains vi, 124 p. : ill. Vita. Includes abstract. Includes bibliographical references.

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) offer unique, noninvasive methods of measuring, respectively, in vivo quantitative neuroanatomy and neurochemistry. The main purpose of the present study was to identify and compare the neuroanatomical and neurochemical abnormalities that are associated with prenatal exposure to alcohol in both fetal alcohol syndrome (FAS)-diagnosed children and those diagnosed with fetal alcohol effects (FAE). MR data of three age-, gender- and race-balanced groups of children, FAS-diagnosed, FAE-diagnosed and non-exposed controls, were compared. Effects of prenatal alcohol exposure, regardless of diagnosis, were found in the caudate nucleus. Specifically, a significantly smaller caudate nucleus was found for the FAS and FAE participants compared to the controls. In addition, the metabolite ratio of N-acetyl-aspartate to creatine (NAA/Cr), an indicator of neuronal function, in left caudate nucleus of both the FAS and FAE participants was elevated compared to the control group. Analysis of absolute concentrations revealed that the increase in the ratio of NAA/Cr was due to an increase in NAA alone. Although its exact function in the CNS is unknown, NAA is believed to be a neuronal marker due to its exclusive localization to neurons. Some also speculate a role for NAA in myelination. Elevated NAA in the prenatal alcohol-exposed participants could indicate a lack of normal program cell death, dendritic pruning and/or myelination during development. The present study demonstrates that prenatal alcohol-exposed children, with or without facial dysmorphology, have abnormal brain anatomy and chemistry.

No description available.

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.

Thesis (M Speech Path)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: This study was done in collaboration with the Foundation for Alcohol Related Research (FARR), a non-governmental organization whose primary objective is to develop and maintain Fetal Alcohol Spectrum Disorder (FASD) prevention programmes across South Africa. Research has shown the occurrence of FASD in South Africa to be much higher than in other parts of the world. As part of their prevention programmes, FARR uses a three part diagnostic process, including a maternal interview, a dysmorphological examination, as well as a general developmental assessment. The maternal interview questionnaire that FARR currently uses takes an average of two hours per interviewee to complete. Even though a recent study indicates that FASD prevention programmes administered by FARR can potentially reduce FASD prevalence, shorter maternal interviews could improve the use of FARR resources and the ability of FASD research studies to gather meaningful information and inform future prevention efforts. The main purpose of this study was to adjust the maternal interview questionnaire used by FARR in order to make interviews with mothers shorter while delivering the information needed for successful FASD prevention programmes. Data related to the adequacy of the adjusted maternal interview questionnaire was collected and analysed according to an action research approach in four consecutive phases. The research procedures consisted of two separate focus group interviews with five key role players from FARR. During the first focus group interview the main problems with the questionnaire was identified as being (i) the length of the questionnaire, (ii) the unsuitability of the questionnaire to interview someone other than the biological mother, and (iii) inconsistency between interviewers when using the questionnaire. During the second phase of the study the questionnaire was adjusted and revised as part of a second focus group interview. The interviewers, data capturer and data analyst who used the adjusted questionnaire as part of a larger FASD prevention programme made several suggestions on how the questionnaire could be further adjusted to suit the needs of FARR. These suggestions were addressed during the final phase of the study, after which the adjusted questionnaire was finalized. Findings from the study suggest that identified problems with FARR’s original maternal interview questionnaire were successfully addressed by the adjusted questionnaire, while simultaneously satisfying the objectives of a maternal interview as identified by participants during the first focus group interview. Results confirmed that more maternal interviews could be conducted in the same time period using the adjusted interview questionnaire compared to when the original questionnaire was used, due to the fact that the questionnaire was shorter and took less time to administer. As part of this study an additional questionnaire was developed specifically for caregiver interviews. According to FARR role players, inconsistency between interviewers was for the most past successfully addressed by the development of this additional questionnaire and the development of an interviewer guideline. Recommendations for future research include the further development and evaluation of the caregiver questionnaire and interviewer guideline. / AFRIKAANSE OPSOMMING: Hierdie studie is uitgevoer in samewerking met die “Foundation for Alcohol Related Research” (FARR), ‘n nie-regeringsorganisasie met die primêre objektief om Fetale Alkohol Spektrum Afwyking (FASA) voorkomingsprogramme in Suid-Afrika te ontwikkel en te handhaaf. Volgens navorsing is die voorkoms van FASA in Suid-Afrika beduidend hoër as in ander dele van die wêreld. ‘n Drie-delige diagnostiese proses word as deel van FARR se voorkomingsprogramme gebruik, insluitend ‘n onderhoud gefokus op moeders, ‘n dismorfologiese ondersoek, asook ‘n evaluasie van die kind se algehele ontwikkeling. Die moeder-onderhoudsvraelys wat tans deur FARR gebruik word neem gemiddeld twee ure om te voltooi. Alhoewel ‘n onlangse studie aandui dat die voorkomingsprogramme deur FARR oor die potensiaal beskik om die prevalensie van FASA te verlaag, kan korter moeder-onderhoude potensieël daartoe lei dat bronne beter benut word, asook dat FASA voorkomingstudies betekenisvolle inligting versamel vir die ontwikkeling van toekomstige voorkomingsprogramme. Die hoofdoel van die huidge studie was om die moeder-onderhoudsvraelys wat tans deur FARR gebruik word aan te pas, om sodoende die onderhoude met moeders korter te maak terwyl die nodige inligting vir suksesvolle FASA voorkomingsprogramme steeds verkry word. Gedurende hierdie studie is data rakende die toereikendheid van die aangepaste moederonderhousdvraelys versamel en geanaliseer volgens ‘n aksie-navorsingsbenadering in vier opeenvolgende fases. Die navorsingsprosedures het bestaan uit twee afsonderlike fokusgroeponderhoude met vyf van die sleutelrolspelers van FARR. Gedurende die eerste fokusgroeponderhoud is die hoofprobleme met die vraelys geïdentifiseer as (i) die lengte van die vraelys, (ii) die ongeskiktheid van die vraelys om ‘n onderhoud met iemand anders as die biologiese moeder te voer, en (iii) die inkonsekwentheid tussen onderhoudvoerders met die gebruik van die vraelys. Gedurende die tweede fase van die studie is die vraelys aangepas en hersien as deel van ‘n tweede fokusgroeponderhoud. Die onderhoudvoerders, data verwerker en data analis wat die aangepaste vraelys gebruik het as deel van ‘n groter FASA voorkomingsprogram het verskeie aanbevelings gemaak rakende hoe die vraelys verder aangepas kan word om te voldoen aan FARR se behoeftes. Laasgenoemde aanbevelings is aangespreek gedurende die laaste fase van die studie, waarna die aangepaste vraelys gefinaliseer is. Die bevindinge van die studie dui aan dat die geïdentifiseerde probleme met FARR se oorspronklike moeder-onderhoudsvraelys suksesvol deur die aangepaste vraelys aangespreek is, terwyl die objektiewe van ‘n moeder-onderhoud (soos geïdentifiseer deur die deelnemers aan die eerste fokusgroeponderhoud) steeds vervul is. Resultate het bevestig dat meer moeder-onderhoude in dieselfde tydsperiode met behulp van die aangepaste vraelys gevoer kon word as met die oorspronklike vraelys, as gevolg van die feit dat dit korter was en minder tyd geneem het om te voltooi. As deel van die studie is ‘n bykomstige vraelys spesifiek vir sorggewer-onderhoude ontwikkel. Volgens die FARR rolspelers is inkonsekwentheid tussen die onderhoudvoerders grootliks suksesvol aangespreek deur middel van die ontwikkeling van hierdie bykomstige vraelys asook die ontwikkeling van ‘n riglyn vir onderhoudvoerders. Aanbevelings vir verdere navorsing sluit die verdere ontwikkeling en evaluasie van die sorggewer-vraelys en onderhoudvoerder riglyn in.