Fetal alcohol spectrum disorders (FASD) is an umbrella term that describes a range of symptoms associated with prenatal alcohol exposure. Fetal Alcohol Syndrome (FAS) is the most severe disorder in the spectrum and is a major health problem in South Africa, with a prevalence rate of 68.0-89.2 per 1000 children of school-going age. The primary cause of FAS is in utero alcohol exposure. However, secondary factors that contribute to the syndrome include various genetic, epigenetic and additional environmental factors. The proposal that paternal preconception alcohol exposure has adverse effects on offspring development is supported by children born with FASD-like characteristics whose mothers did not drink but whose fathers were alcoholics. Mouse models further support these findings. One of the main epigenetic factors that have been shown to be affected by alcohol is DNA methylation. This chemical modification of DNA is associated with developmentally important genes known as imprinted genes. Imprinted genes are expressed in a parent of origin specific manner. Methylation occurs at specific regions in these genes known as differentially methylated regions (DMRs) or imprinting control regions (ICRs). Alcohol’s ability to alter DNA methylation at imprinted genes raises the possibility that epigenetic disruption could contribute to the clinical features seen in FASD. The main aim of this research was to examine global DNA methylation and locus specific H19 ICR DNA methylation in spermatozoa, related to alcohol exposure. This was done using the luminometric methylation assay (LUMA) and bisulfite based quantitative pyrosequencing, respectively. In this study there was no significant correlation between alcohol exposure and global DNA methylation (p = 0.17), nor was there a significant correlation with drinking frequency (p = 0.31). Although not significant, a slight trend towards decreased global DNA methylation in alcohol-exposed spermatozoa was observed. This suggests that either alcohol does not affect global sperm DNA methylation or that the technique used in this study was not sensitive enough to detect minor changes in global DNA methylation percentage. There was also no significant correlation between alcohol exposure and average H19 ICR DNA methylation (p = 0.051), nor was there a significant correlation with drinking frequency (p = 0.47). There was no significant correlation between alcohol exposure and DNA methylation at individual CpG sites except for CpG 3, where there was a significant increase in DNA methylation in the drinking group (p = 0.03). The findings of this study together with the findings of significant selective demethylation at individual CpG sites within the IG-DMR from another study on the same sperm samples, suggest that alcohol may have the ability to affect DNA methylation levels in spermatozoa at certain loci within the sperm genome. However, these loci-specific effects are not reflected in global DNA methylation levels. These findings do not disprove the hypothesis that there is an epigenetic mechanism responsible for the paternal effects seen in FASD. Instead they suggest that the techniques used in this study were not sensitive enough to detect these changes in DNA methylation or alternatively, alcohol may be exerting its effects through other epigenetic mechanisms.

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references. Available also from UMI/Dissertation Abstracts International.

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references (leaves 102-114). Available also in a digital version from Dissertation Abstracts.

Thesis (M.A.)--Eastern Illinois University, 1992. / Includes bibliographical references (leaves 52-57).

Thesis (M.A.)--York University, 2006. Graduate Programme in Psychology. / Typescript. Includes bibliographical references (leaves41-48). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR29619

Abstract Fetal alcohol syndrome (FAS) is a common cause of mental retardation and is attributable to the teratogenic effects of alcohol exposure in utero in individuals with genetic susceptibility. The Coloured communities from the Western and Northern Cape regions have some of the highest recorded incidence rates (~70 affected children per 1000 live births) in the world. The candidate genes selected for this study belong to the family of alcohol dehydrogenase genes that code for enzymes which metabolise alcohol. The ADH1B and ADH1C genes have previously been examined in the Western Cape Coloured community and the enzyme encoded by the allele ADH1B*2 was significantly associated with protection against the development of FAS. ADH4, a new candidate gene, was selected due to its role in both the alcohol and retinol metabolic pathways. A case-control genetic association study was performed to examine the potential roles of the ADH1B, ADH1C and ADH4 genes in the etiology of FAS in two Coloured populations from the Northern and Western Cape. Single nucleotide polymorphisms found within the candidate genes were typed by PCR-based methods in samples from the FAS children, their mothers and controls. Significant associations were observed in the Western Cape cohort but were not replicated in the Northern Cape. Allelic association tests revealed that ADH1B*2 may be a protective marker as it occurred more commonly in the controls than the mothers (p= 0.038). The alleles of the polymorphic variant, ADH4.8, have been shown to influence the promoter activity of ADH4 (the ‘A’ allele has been shown to increase the activity of the promoter when compared to the ‘C’ allele as the same position). The alleles of this polymorphic marker were significantly associated with the risk for FAS. The ‘A’ allele was shown to occur more commonly in the mothers and FAS-affected children (p= 0.002 and 0.035 respectively) when compared to the controls, suggesting a role in disease susceptibility while the ‘C’ allele was shown to occur more commonly in the controls. Itwas also observed that ADH1B and ADH4.8 when examined together in a haplotype demonstrated an association with susceptibility to the disease. While the 2-C haplotype (ADH1B-ADH4.8) was shown to be associated with protection against the development of FAS, the 1-A haplotype was associated with increased susceptibility. The results suggest that mothers with the common ADH1B*1 allele and presumably a normal ADH1B function but an increased level of ADH4 (allele ‘A’) as a result of the promoter mutation, will, when the blood alcohol concentration is high, have an increased risk of having a child with FAS. Conversely when the mothers have a faster alcohol metabolising rate due to the allele ADH1B*2 and normal levels of ADH4 protein (allele ‘C’), the circulating alcohol in the blood is removed efficiently resulting in maternal protection against developing the disease. This study has also highlighted the genetic diversity within individuals of the South African Coloured population. Haplotype analysis and logistic regression revealed that the Western and Northern Cape Coloured communities are genetically different and as a result, the samples could not be pooled for analysis. Although the two groups of controls were genetically diverse, haplotype analysis revealed that the sample of mothers and FAS-affected children were not statistically different between the provinces thus possibly suggesting a similar genetic etiology for the disease. The results from this study suggest that the ADH genes do play a role in the pathogenesis of FAS.

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 140-164). Available also in a digital version from Dissertation Abstracts.

Alcohol consumption during pregnancy is detrimental to the developing nervous system of the unborn offspring. The hippocampus, one of the two brain regions where neurogenesis persists into adulthood, is particularly sensitive to the teratogenic effects of alcohol. The present study examined the effects of alcohol exposure throughout all three trimester equivalents on the stages of adult neurogenesis. Prenatal and early postnatal alcohol exposure (PPAE) altered cell proliferation in adult but not adolescent animals and increased early neuronal differentiation without affecting cell survival in both age groups. The levels of brain-derived neurotrophic factor (BDNF) were not affected by PPAE in the dentate gyrus but were significantly decreased in the Cornu ammonis region of the hippocampus. These results might explain the functional deficits seen in this hippocampal sub-region. This study identified that voluntary wheel running increased cell proliferation, differentiation and survival as well as BDNF expression in both PPAE and control animals. / Graduate

Thesis (Ph. D.)--University of Hawaii at Manoa, 2004. / Includes bibliographical references (leaves 92-105).

Fetal Alcohol Syndrome (FAS) is the most severe of a spectrum of birth defects caused by a mother drinking alcohol whilst pregnant. Its manifestation in the Central Nervous System causes intellectual and behavioural abnormalities, which pose considerable challenges in the classroom. This case study explores the classroom environment and educational outcomes of learners with FAS in a rural South African school. The study was conducted at Elizabethfontein Primary School (EFPS), a farm school near Clanwilliam in the Western Cape. The sample comprises of all 170 learners in Grade 1 to Grade 4. A prevalence rate of FAS of 124 per 1000 (12.4%) was found. EFPS is a Quintile 1 school that relies heavily on fundraising (especially in the form of Riel Dancing) and sponsorship to afford extra staff (such as Koshuis Tannies and teaching assistants), maintenance and transportation of learners. The lack of Grade R school preparation and the environment learners grow up in results in discipline problems, many learners repeating, being progressed before they are ready and a high dropout rate. Child abuse and neglect is common today, prompting the EFPS boarding house to act as "safe haven" during the week for two thirds of its learners. The school provides security, routine and constant meals (as part of the School Nutrition Program and supplemented by the school garden). Data on educational outcomes was collected through participant observation (classroom behaviour), collection of information from existing sauces (Home Language Marks and Mathematics Marks) and collection of new data (Reading Score). A physician diagnosed those children with FAS using a three-stage process. Having FAS is associated with lower home language marks ( 2.8 to 8.55 percentage points) and behavioural scores (1.73 to 4.21 percentage points). The mitigating effect of the school on FAS learners might have reduced the impact of FAS. Children with FAS struggle academically and in following rules and principles as they have lower intellectual capabilities and cannot generalise from one situation to the next. Memory deficits, especially verbally and visuospatially, present challenges in following instructions and copying from the board. Children with FAS are also hyperactive, distractible and inattentive, which causes classroom disruptions and pose a negative externality to other learners. They find it difficult to follow social cues, but want to be helpful and well liked, making children with FAS vulnerable to manipulation. Strategies for intervention have been explored by specialised schools and studies, but must be translated into viable options for the mainstream under-resourced classroom. In order to develop appropriate strategies for classroom intervention a comprehensive understanding of FAS in this context must first be established. Many learners are isolated by a lack of tarred roads and cell phone reception within the large catchment area of EFPS. As descendants of local tribes and slaves the history of this farming area still influences them today. The legacy of the Dop system can still be seen, as alcohol forms a cornerstone of social interactions, especially in binge drinking over weekends, which exposes children to the cycle of alcohol addiction from a young age. Racial segregation and the impact of Apartheid have influenced the educational trajectory of coloured children. The value of this study lies in the in-depth insight into the context learners find themselves in, and the specific challenges associated with FAS learners. Future studies can build on the methodology and explore ways to improve the lives of children with FAS. Research must be interdisciplinary and in collaboration with the community. In response to this research EFPS has declared 2016 as "The Year of Alcohol Awareness" . Intervention strategies must be aimed towards these isolated, under resourced communities.