Ethanol teratogenicity involving the developing brain is the leading preventable cause of mental deficiency in the Western world. Chronic prenatal ethanol exposure (CPEE) may be a risk factor for ethanol abuse and altered responsiveness to nicotine in postnatal life. Previous studies in our laboratory have utilized maternal oral administration of a high-dose (4 g ethanol/kg maternal body weight/day) ethanol regimen that induces structural and functional deficits in the fetus and postnatal offspring. The objective of this thesis was to test the hypotheses that moderate CPEE produces in postnatal offspring: (i) structural and functional teratogenic effects; (ii) increased ethanol preference; (iii) altered responsiveness to acute nicotine; and (iv) increased nicotinic acetylcholine receptors (nAChR) in forebrain structures, namely the hippocampus and frontal cortex. Pregnant Dunkin-Hartley-strain guinea pigs were given 24-h access to aqueous ethanol solution (5%, v/v) sweetened with sucralose (1g/L) or aqueous sucralose solution (1g/L) throughout gestation. Spontaneous locomotor activity in an open field was measured in offspring on postnatal day (PD) 10. Beginning around PD 40, ethanol preference in the offspring was determined using a two-bottle-choice paradigm. Each animal was given 2-h daily access to aqueous ethanol solution (0 - 3%, v/v) and water over 33 days of testing. Subsequently, hippocampal and frontal cortical tissues were obtained for the measurement of nAChR population by radioligand binding. Moderate maternal consumption of the aqueous ethanol produced growth restriction in postnatal offspring of both sexes, and increased spontaneous locomotor activity in male offspring only. These postnatal outcomes are similar to the teratogenic effects produced by a high-dose, binge-type ethanol regimen. Compared with control, offspring from mothers that consumed ethanol throughout gestation exhibited greater preference for aqueous ethanol, and a decrease in the concentration of nAChRs in the frontal cortex, but not the hippocampus. These data demonstrate that, in the guinea pig, moderate maternal consumption of ethanol is a useful model for studying ethanol neurobehavioural teratogenicity; and chronic prenatal exposure to ethanol enhances ethanol preference in young adult offspring and altered expression of nAChRs in the frontal cortex. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2009-06-19 10:26:40.229

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