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.

In this thesis I used Caenorhabitis elegans as a model of Fetal Alcohol Spectrum Disorder (FASD) to study the physical and behavioral effects of ethanol exposure during embryonic development. Davis et al. (2008) found that ethanol exposure during larval development in C. elegans produced physical/developmental and behavioral effects; however, whether exposure during embryonic development might produce similar outcomes remained to be elucidated. Because the type and degree of effects caused by developmental ethanol exposure was dependent on the pattern of ethanol treatment, in the first part of the thesis I investigated the physical/developmental effects of embryonic exposure to various ethanol doses, exposure durations, onsets and frequencies. I found that exposure to >30% ethanol for an hour during embryonic development was necessary to lower hatch rate, delay reproductive onset, and reduce body size in C. elegans. Furthermore, exposure during early embryonic development caused a larger effect than exposure during later stages, and multiple exposures produced a worse outcome than a single exposure for a comparable duration. In the second part of the thesis, I investigated locomotory activities and habituation of adult C. elegans exposed to various patterns of embryonic ethanol treatment. I found that the rate of locomotion was altered differently by chronic and acute embryonic ethanol exposure, but I did not find any effect in short- or long-term habituation. In summary, I have characterized the pattern of embryonic ethanol exposure necessary to produce physical/developmental effects in C. elegans, and identified the types of exposure conditions that would cause worse outcomes than others; in addition, I have found that embryonic ethanol exposure affects the rate of locomotion in C. elegans. In this thesis, I have established a foundation for the future investigation into the physical and motor defects caused by embryonic ethanol exposure in C. elegans. / Medicine, Faculty of / Graduate

Prenatal alcohol exposure (PAE) is associated with a range of physical, growth, and neurobehavioral deficits characteristic of individuals with fetal alcohol spectrum disorders (FASD). Although declarative memory impairment is a key feature of the neurocognitive profile of FASD, the mechanisms underlying this deficit require further clarification. The aim of this cross-sectional research was to examine, both directly and indirectly (via bottom-up and top-down processes), a critical cognitive mechanism that supports successful declarative memory functioning (viz., memory encoding), in children with FASD. Data were collected from a sample (N = 88) of South African children with and without PAE. In Study I, I used a blocked design functional magnetic resonance imaging (fMRI) paradigm to investigate neural activation during visual perception, a lower-order cognitive process essential to memory encoding. The task elicited bilateral category-specific activation during the visual perception of objects and scenes in all participants. The absence of between-group differences suggests that functional recruitment of brain regions during basic visual perception is less susceptible to the effects of PAE than during higher-order processes supporting memory encoding. In Study II, I used an event-related fMRI paradigm to investigate neural activation during memory encoding itself. All participants demonstrated similar memory performance accuracy and recruited extensive bilateral networks during memory encoding. However, participants with a diagnosis of fetal alcohol syndrome (FAS) or partial FAS (PFAS) activated additional regions associated with attentional function. Within the FAS/PFAS group, higher exposure levels were associated with smaller activation increases in the parahippocampal gyri and greater activation increases in the right hippocampal formation during encoding. Data from this study therefore suggest that children with FAS/PFAS recruited more extensive neural resources to support successful memory encoding during this task. In Study III, I used a behavioral source memory paradigm to investigate higher-order executive processes essential for memory encoding. Despite similar recognition accuracy across all diagnostic groups, participants in the FAS/PFAS group showed impaired memory for source details. This pattern of impairment was only partially mediated by working memory performance. These three studies provide novel clarification of the neural and cognitive mechanisms underlying declarative memory impairments in children with FASD.

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.

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