Children with Fetal Alcohol Spectrum Disorder have significantly delayed motor skills, and deficiencies in reflex development. The reasons underlying these motor deficits are not fully understood. The purpose of this thesis was to investigate the effect of embryonic exposure to ethanol (EtOH) on motor neuron and muscle fiber morphology and physiology in zebrafish. We observed that EtOH-exposed fish took longer to hatch and exhibited fewer swimming bouts in response to touch. Immunolabelling of motor neurons indicated that EtOH-exposed fish had significantly higher rates of motor neuron axon defects. Examination of muscle fiber morphology revealed that EtOH exposure resulted in significantly smaller muscle fibers. Miniature endplate current (mEPC) recordings from muscle fibers revealed that event amplitudes, rise times, half widths, frequencies and decay times were affected by EtOH exposure. These findings indicate that motor neurons and muscle fibers of zebrafish are affected by embryonic EtOH exposure, which may be related to deficits in locomotion. / Physiology, Cell and Developmental biology

While all women hope to deliver a healthy baby, approximately 3-5% babies are affected by birth defects. Birth defects can occur naturally or be induced by teratogens. Alcohol is a known teratogen that causes fetal alcohol spectrum disorder (FASD), the most commonly known cause of neurobehavioural and neurodevelopmental deficits. Individuals affected with FASD are likely to be involved with or require additional assistance from healthcare, education, social services, and justice sectors. Due to this immense burden, effective prevention of FASD can have a major public impact. Prevention of FASD can occur at different levels: primary prevention (preventing alcohol-induced birth defects from occurring in the first place); secondary prevention (preventing alcohol-induced birth defects from developing or progressing); tertiary prevention (improving the outcome of individuals affected with FASD); and quaternary prevention (preventing another child from being affected with FASD). The objective of this thesis was to explore a multilevel birth defect and FASD prevention strategy. Primary prevention by was investigated by maternal multivitamin supplementation to optimize fetal growing conditions, as alcoholics are commonly deficient in nutrients. A meta-analysis of maternal multivitamin supplementation demonstrated a decreased risk for certain congenital anomalies and pediatric cancers. Secondary prevention was investigated by a randomized double-blinded placebo-controlled evaluating the ability of high doses of antioxidants (vitamin C and vitamin E) to mitigate the effects of prenatal alcohol exposure. The study was ceased due to safety concerns regarding high doses of vitamin C and vitamin E in preeclamptic studies. Tertiary prevention was investigated by anonymous meconium screening of babies of Grey-Bruce, Ontario residents delivering at or transferred to St. Joseph’s Health Care in London, Ontario. A 30% prevalence of fatty acid ethyl esters (FAEE) positive meconium was observed at this high-risk unit. Meconium screening is also a means of quaternary prevention since positive screens also identify mothers who were unable to stop consuming alcohol after 13 weeks of pregnancy, and therefore are at risk of delivering another child who is prenatally exposed to alcohol. The identification and engagement of these mothers into treatment programs constitutes primary prevention of FASD in subsequent pregnancies.

Children with fetal alcohol spectrum disorders (FASD) have deficits across many cognitive, behaviour and social domains. However, despite social difficulty being proposed as a main deficit following prenatal alcohol exposure, the nature of their deficient social behaviour is largely unknown. One process that may underlie difficulties in social functioning is poor social cognition, which refers to one’s understanding of the self, others and social world. The primary goal of this dissertation was to determine whether social cognitive deficits represent a core disability underlying the socio-behavioural problems of FASD using a bottom-up approach. The first level of this approach is represented by face processing. Global and independent face feature processing was compared between FASD and normal controls (NC) using experimental and clinical measures. Eye gaze processing was investigated next using experimental and clinical tasks. At the highest level of the bottom-up approach, social perspective taking, including theory of mind and empathy were examined, along with how these abilities related to parent-rated behaviour. Finally, the lowest level consisted of specific aspects of the social neural network. White matter in three limbic pathways was investigated using diffusion tensor imaging (DTI). Results generally supported the bottom-up approach of social cognition in FASD. These children showed impaired processing of face features, when matching mouth shapes and partially occluded identity, compared with NC. The FASD group was slower to process gaze and arrow cues, suggesting impaired attention shifting. Children with FASD also showed impairments in social perspective taking, including understanding false beliefs and empathy, and these impairments were related to parent-rated attention and social problems, and autistic-like traits. Deficits in theory of mind got worse with age in FASD and empathy showed distinct sex-related differences. Although no group differences were observed on DTI indices, groups did show different age-related changes in white matter. In conclusion, deficits at each level of the current bottom-up approach may underlie the social impairments in FASD and may contribute to their broader social behavioural phenotype. The results from this dissertation have potential to inform clinical practice and lead to more effective diagnostic and treatment approaches in FASD.

Alcohol abuse during pregnancy has been associated with Fetal Alcohol Spectrum Disorder (FASD). Research to date has focused on the role played by ethanol in the development of this disorder. In addition to ethanol, alcoholic drinks also contain methanol. Hence, consumption of alcohol can also lead to methanol accumulation. Methanol is metabolized to formaldehyde, which is then rapidly metabolized to formate, a toxic metabolite. Folate, a B-vitamin and antoxidant, is a cofactor in the metabolism of formate. This study assessed the relationship between formate and folate, formate kinetics in folate deficiency and, changes in antioxidant capacity during formate insult in folate deficiency. The findings of this study would lead to a better understanding of the role of formate in the development of the etiology of FASD and form the basis of future research. The relationship between formate and folate was investigated in intoxicated human female subjects, sober drug rehabilitating females and, pregnant women. A negative (inverse) relationship was observed between plasma formate and folate in pregnant sober women (correlation coefficient = -0.4989). Such a relationship, however, was not observed in whole blood in alcohol intoxicated (correlation coefficient = 0.0899) and detox women (correlation coefficient = 0.2382). Because of the health promoting ingredients in grain and fruit based alcoholic drinks, antioxidant B-vitamins were higher during intoxication while homocysteine levels were lower.<p>Formate kinetics during folate deficiency and changes in the body antioxidant capacity was investigated in folate deficient young swine. Folate deficiency altered formate kinetics leading to decreased systemic clearance (by approximately 2.3 fold), increased half-life (by 2.5 fold) and, consequently increased exposure (by 2.7 fold). Folate deficiency alone compromised antioxidant capacity. However, the combination of folate deficiency and formate insult further compromised antioxidant capacity.<p>In conclusion, methanol accumulates after alcohol intoxication, which can lead to formate build up in the body. During folate deficiency formate kinetics is altered leading to reduced formate clearance and increased exposure. Exposure to formate coupled to folate deficiency compromises antioxidant capacity, which can have deleterious effects on the fetus.

The purpose of this study was to come to a greater understanding of the experiences of birth mothers of children with FASD since the birth of their child. The principles of feminist research practice were utilized throughout in order to give a voice to the women who participated in the study. The research followed the general guidelines to conducting hermeneutic phenomenology outlined by van Manen (1990). Purposeful sampling was used to recruit four birth mothers of children with FASD who have been involved in the mothering of that child. Data was generated through three semi-structured interviews with each participant, including a hermeneutic interview in which the women participated in the process of interpretation. Data was analysed using selective, detailed and wholistic methods and through the process of writing and re-writing (van Manen, 1990).<p> The results focus on the social and emotional experiences of the women who participated in the study. The experience of being a birth mother of a child with FASD is represented in a discussion of four main themes: Living with the Past: Self-Forgiven, yet Always Present; Living with Others: Judgement and Understanding; Living with the Self: Unworthy and Unfit; and Living with Ambivalence: Mothering as a Birth Mother. The implications of this research in relation to the understanding of the experiences of birth mothers of children with FASD and potential supports are discussed.

Behavioral deficits caused by fetal-alcohol are well expressed in juvenile subjects but usually ameliorate with maturation. It suggests some kind of postnatal regeneration. The aim of the present study was to examine the potential correlation between behavioral recovery and the postnatal hippocampal development in the fetal-alcohol rats. This study included behavioral tests applied to juvenile and adult subjects, unbiased stereology to investigate changes in neuron numbers and hippocampal volumes, the postnatal tracing and analysis of the hippocampal principal neuron&rsquo / s morphology, investigation of age-dependent changes in the distribution of doublecortin-expressing neurons, and evaluation of synaptic development by assessing age-dependent changes in the regional immunoreactivity/expression of synaptophysin and PSD95. Rats have been exposed to ethanol throughout 7-21 gestation days with daily ethanol dose of 6g/kg delivered by intragastric intubation to the pregnant dams. The morphological characteristics were examined on postnatal days P1, P10, P30, P60, in hippocampal CA1, CA3, and DG subregions, in fetal-alcohol and control rats. Both, stereological and doublecortin-immunoreactivity data pointed towards a possibility of limited neurogenesis taking place during a protracted postnatal period not only in the germinal zones (SGZ and SVZ) but also in the hippocampal CA regions. Ethanol effect on postnatal hippocampal development was limited to marginally lower number of granular cells in DG on P30. It correlated with poorer cognitive performance in the fetal-alcohol group. The treatment effect on the morphology of hippocampal neurons was observed mainly in CA region at P1 and seemed to be attributed more to the intubation stress than the ethanol itself.

Children with fetal alcohol spectrum disorders (FASD) have deficits across many cognitive, behaviour and social domains. However, despite social difficulty being proposed as a main deficit following prenatal alcohol exposure, the nature of their deficient social behaviour is largely unknown. One process that may underlie difficulties in social functioning is poor social cognition, which refers to one’s understanding of the self, others and social world. The primary goal of this dissertation was to determine whether social cognitive deficits represent a core disability underlying the socio-behavioural problems of FASD using a bottom-up approach. The first level of this approach is represented by face processing. Global and independent face feature processing was compared between FASD and normal controls (NC) using experimental and clinical measures. Eye gaze processing was investigated next using experimental and clinical tasks. At the highest level of the bottom-up approach, social perspective taking, including theory of mind and empathy were examined, along with how these abilities related to parent-rated behaviour. Finally, the lowest level consisted of specific aspects of the social neural network. White matter in three limbic pathways was investigated using diffusion tensor imaging (DTI). Results generally supported the bottom-up approach of social cognition in FASD. These children showed impaired processing of face features, when matching mouth shapes and partially occluded identity, compared with NC. The FASD group was slower to process gaze and arrow cues, suggesting impaired attention shifting. Children with FASD also showed impairments in social perspective taking, including understanding false beliefs and empathy, and these impairments were related to parent-rated attention and social problems, and autistic-like traits. Deficits in theory of mind got worse with age in FASD and empathy showed distinct sex-related differences. Although no group differences were observed on DTI indices, groups did show different age-related changes in white matter. In conclusion, deficits at each level of the current bottom-up approach may underlie the social impairments in FASD and may contribute to their broader social behavioural phenotype. The results from this dissertation have potential to inform clinical practice and lead to more effective diagnostic and treatment approaches in FASD.

While all women hope to deliver a healthy baby, approximately 3-5% babies are affected by birth defects. Birth defects can occur naturally or be induced by teratogens. Alcohol is a known teratogen that causes fetal alcohol spectrum disorder (FASD), the most commonly known cause of neurobehavioural and neurodevelopmental deficits. Individuals affected with FASD are likely to be involved with or require additional assistance from healthcare, education, social services, and justice sectors. Due to this immense burden, effective prevention of FASD can have a major public impact. Prevention of FASD can occur at different levels: primary prevention (preventing alcohol-induced birth defects from occurring in the first place); secondary prevention (preventing alcohol-induced birth defects from developing or progressing); tertiary prevention (improving the outcome of individuals affected with FASD); and quaternary prevention (preventing another child from being affected with FASD). The objective of this thesis was to explore a multilevel birth defect and FASD prevention strategy. Primary prevention by was investigated by maternal multivitamin supplementation to optimize fetal growing conditions, as alcoholics are commonly deficient in nutrients. A meta-analysis of maternal multivitamin supplementation demonstrated a decreased risk for certain congenital anomalies and pediatric cancers. Secondary prevention was investigated by a randomized double-blinded placebo-controlled evaluating the ability of high doses of antioxidants (vitamin C and vitamin E) to mitigate the effects of prenatal alcohol exposure. The study was ceased due to safety concerns regarding high doses of vitamin C and vitamin E in preeclamptic studies. Tertiary prevention was investigated by anonymous meconium screening of babies of Grey-Bruce, Ontario residents delivering at or transferred to St. Joseph’s Health Care in London, Ontario. A 30% prevalence of fatty acid ethyl esters (FAEE) positive meconium was observed at this high-risk unit. Meconium screening is also a means of quaternary prevention since positive screens also identify mothers who were unable to stop consuming alcohol after 13 weeks of pregnancy, and therefore are at risk of delivering another child who is prenatally exposed to alcohol. The identification and engagement of these mothers into treatment programs constitutes primary prevention of FASD in subsequent pregnancies.

Alcohol abuse during pregnancy has been associated with Fetal Alcohol Spectrum Disorder (FASD). Research to date has focused on the role played by ethanol in the development of this disorder. In addition to ethanol, alcoholic drinks also contain methanol. Hence, consumption of alcohol can also lead to methanol accumulation. Methanol is metabolized to formaldehyde, which is then rapidly metabolized to formate, a toxic metabolite. Folate, a B-vitamin and antoxidant, is a cofactor in the metabolism of formate. This study assessed the relationship between formate and folate, formate kinetics in folate deficiency and, changes in antioxidant capacity during formate insult in folate deficiency. The findings of this study would lead to a better understanding of the role of formate in the development of the etiology of FASD and form the basis of future research. The relationship between formate and folate was investigated in intoxicated human female subjects, sober drug rehabilitating females and, pregnant women. A negative (inverse) relationship was observed between plasma formate and folate in pregnant sober women (correlation coefficient = -0.4989). Such a relationship, however, was not observed in whole blood in alcohol intoxicated (correlation coefficient = 0.0899) and detox women (correlation coefficient = 0.2382). Because of the health promoting ingredients in grain and fruit based alcoholic drinks, antioxidant B-vitamins were higher during intoxication while homocysteine levels were lower.<p>Formate kinetics during folate deficiency and changes in the body antioxidant capacity was investigated in folate deficient young swine. Folate deficiency altered formate kinetics leading to decreased systemic clearance (by approximately 2.3 fold), increased half-life (by 2.5 fold) and, consequently increased exposure (by 2.7 fold). Folate deficiency alone compromised antioxidant capacity. However, the combination of folate deficiency and formate insult further compromised antioxidant capacity.<p>In conclusion, methanol accumulates after alcohol intoxication, which can lead to formate build up in the body. During folate deficiency formate kinetics is altered leading to reduced formate clearance and increased exposure. Exposure to formate coupled to folate deficiency compromises antioxidant capacity, which can have deleterious effects on the fetus.

The purpose of this study was to come to a greater understanding of the experiences of birth mothers of children with FASD since the birth of their child. The principles of feminist research practice were utilized throughout in order to give a voice to the women who participated in the study. The research followed the general guidelines to conducting hermeneutic phenomenology outlined by van Manen (1990). Purposeful sampling was used to recruit four birth mothers of children with FASD who have been involved in the mothering of that child. Data was generated through three semi-structured interviews with each participant, including a hermeneutic interview in which the women participated in the process of interpretation. Data was analysed using selective, detailed and wholistic methods and through the process of writing and re-writing (van Manen, 1990).<p> The results focus on the social and emotional experiences of the women who participated in the study. The experience of being a birth mother of a child with FASD is represented in a discussion of four main themes: Living with the Past: Self-Forgiven, yet Always Present; Living with Others: Judgement and Understanding; Living with the Self: Unworthy and Unfit; and Living with Ambivalence: Mothering as a Birth Mother. The implications of this research in relation to the understanding of the experiences of birth mothers of children with FASD and potential supports are discussed.