Maternal ethanol consumption during pregnancy can produce teratogenic outcomes in offspring, which are collectively termed Fetal Alcohol Spectrum Disorder (FASD). Central nervous system (CNS) dysfunction is a debilitating and permanent manifestation of FASD. Recent studies indicate that chronic prenatal ethanol exposure (CPEE), via maternal ethanol administration, also impairs metabolic function in offspring. The mechanism of ethanol teratogenicity is multi-faceted and could involve alterations in insulin and insulin-like growth factor (IGF) signaling pathways. These pathways are not only important for metabolism, but are also involved in CNS neuronal survival and plasticity, which are impaired by CPEE. The overall goal of this thesis research was to study, in the guinea pig, neurobehavioural and metabolic effects of CPEE and to investigate whether these effects were associated with altered CNS and peripheral insulin/IGF signaling pathways. In postnatal offspring, CPEE decreased brain weight and altered performance of the modified Biel-maze task, which was a sensitive measure of apparent cognitive dysfunction and executive function deficits. Furthermore, CPEE produced various manifestations of metabolic teratogenicity in offspring, including decreased birth weight, postnatal catch-up body growth, increased whole-body adiposity, disrupted pancreatic morphology, dysregulation of blood glucose concentration and increased liver weight in adulthood. The CPEE-induced neurobehavioural and metabolic effects were associated with alterations of the insulin/IGF signaling pathways in the CNS and periphery. In the liver, CPEE decreased mRNA expression of IGF-1, IGF-1 receptor, and IGF-2 in male and female offspring, and increased mRNA expression of insulin receptor substrate (IRS)-2 in male offspring only compared with nutritional control. Female CPEE offspring had decreased hepatic mRNA expression of insulin receptor compared with male CPEE offspring. In the prefrontal cortex, IRS-2 mRNA expression was increased in male and female CPEE offspring compared with nutritional control. The studies of this thesis have contributed to the understanding of the neurobehavioural and metabolic consequences of CPEE in offspring, which are associated with impairment of the insulin/IGF signaling pathways. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2014-04-25 10:52:50.048
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OKQ.1974/12077 |
| Date | 25 April 2014 |
| Creators | Dobson, CHRISTINE |
| Contributors | Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Rights | This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner. |
| Relation | Canadian theses |
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