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).

Alcohol consumption during pregnancy can result in fetal alcohol spectrum disorders (FASD), which encompass a range of physical, behavioral, learning, emotional and social disturbances. Many mechanisms for this array of alcohol-derived fetal injuries have been proposed, but none fully accounts for the deficiencies observed. Alcohol is a ubiquitous drug that may affect the brain at any or all stages of development and at multiple sites; regional differences in vulnerability of different brain structures during different periods of exposure have been demonstrated. This study investigates possible mechanisms for the alcohol induced neurodevelopment damage seen as a result of prenatal alcohol exposure, and also includes evaluation of a potential intervention strategy (glutamine). These experiments all utilized the sheep model, which has distinct advantages over the rodent model for third trimester-equivalent studies (a time of increased vulnerability to the effects of alcohol). The fetal hippocampal formation (pyramidal cells in the CA1 and CA2/3 fields and granule cells of the dentate gyrus) and olfactory bulb (mitral cells) have been altered in response to alcohol exposure in rodent model studies. This study examined the effects on the fetal hippocampal formation and olfactory bulb in response to all three trimester-equivalent alcohol exposure in the sheep model, a species in which the third trimester-equivalent occurs in utero (as opposed to post-natal as occurs in the rodent). It is known that both maternal and fetal cortisol levels increase in response to alcohol. The role of cortisol in mediating fetal cerebellar Purkinje cell loss (known to occur with alcohol exposure) was analyzed. Lastly, the availability of circulating amino acids, both maternal and fetal, in response to alcohol are reported. The results of administration of a single acute dose of glutamine to the ewe, concurrent with alcohol, was evaluated for its ability to prevent the amino acid and pH perturbations known to occur in response to alcohol.

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

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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.

The chronic and severe executive functioning (EF) and self regulation deficits experienced by children with fetal alcohol spectrum disorders (FASD) are well documented and EF and self regulation have been identified as core targets for intervention. The goals of this dissertation were to: (i) examine the effects of a self regulation treatment for children with FASD on a range of EF measures (ii) examine neural markers of treatment outcome and determine if functional magnetic resonance imaging (fMRI) can differentiate treatment responders from nonresponders; (iii) determine if treatment effects generalize to child compliance and qualitatively examine the treatment process. Twenty-five children with FASD participated. Using a wait-list control design children were assigned to an immediate treatment (TXT; n = 12) or delayed treatment control (DTC; n = 13) condition. All children received an evaluation of EF and fMRI at baseline and 12-week follow-up. Parents also completed questionnaires assessing EF and behavior as well as a feedback questionnaire upon completion of treatment. A subset of parents tracked compliance over the course of their child’s therapy. For the TXT group only, parent questionnaires were readministered at 6 month follow-up. At 12-week follow-up, children in the TXT group displayed significant improvements in inhibitory control and social cognition. Additionally, parents reported improved behavioral and emotional regulation. This improvement, along with a further improvement in parent-rated inhibitory control, was maintained at the 6-month follow-up. Neuroplastic changes were also observed as the TXT group showed increased BOLD response in the right prefrontal cortex (PFC) and left caudate on a task of inhibitory control. When treatment responders were compared to nonresponders a pattern of increased BOLD response was found bilaterally in the PFC and left caudate. Compliance tracking revealed that self regulation therapy generalized to improved child compliance at home. Qualitative analysis indicated that perceived clinician competence, caregiver insight about child’s problems and caregiver perceptions of child’s insight about their problems, were the most commonly endorsed themes by caregivers. Results from this research signify that children with FASD are responsive to psychotherapy and following a brief intervention, showed improvements in self regulatory abilities that generalize to other EF areas and parent-reported behaviors.

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.