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Effect of alcohol on global and locus specific DNA methylation in spermatozoa: implications for fetal alcohol spectrum disorders (FASD)Patel, Sanam 24 April 2013 (has links)
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.
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Fetal alcohol syndrome changes in transcriptional activation in the cerebellum caused by ethanol exposure during neurodevelopment /Acquaah-Mensah, George Kwamina, January 2001 (has links)
Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references. Available also from UMI/Dissertation Abstracts International.
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Fetal alcohol syndrome : changes in transcriptional activation in the cerebellum caused by ethanol exposure during neurodevelopment /Acquaah-Mensah, George Kwamina, January 2001 (has links)
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.
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A statewide survey of fetal alcohol syndrome /Bach, Kathryn S. January 1992 (has links) (PDF)
Thesis (M.A.)--Eastern Illinois University, 1992. / Includes bibliographical references (leaves 52-57).
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Fetal Alcohol Spectrum Disorder persons in Canadian criminal proceedings /Sorge, Geoff B. January 2006 (has links)
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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The role of alcohol dehydrogenase genes in the development of fetal alcohol syndrome in two South African Coloured communitiesNaidoo, Dhamari 21 February 2008 (has links)
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.
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N-methyl-D-aspartate receptor subunit expression following perinatal exposure to ethanol /Nixon, Kimberly, January 2000 (has links)
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.
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The effects of voluntary exercise on adult hippocampal neurogenesis and BDNF levels in a rodent model of fetal alcohol spectrum disordersBoehme, Fanny 30 May 2011 (has links)
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
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Temporal effects of prenatal ethanol exposure on the hypothalamo-neurohypophyseal system in the rat (Rattus norvegicus)Lim, Jenny M. January 2004 (has links)
Thesis (Ph. D.)--University of Hawaii at Manoa, 2004. / Includes bibliographical references (leaves 92-105).
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The impact of fetal alcohol syndrome on a child's classroom performance : a case study of a rural South African schoolLubbe, Melissa January 2016 (has links)
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.
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