Effect of prenatal exposure to glucocorticoids and ionizing radiation on programming of adaptive behaviour and neural genetic dysregulation in adult offspring

Abstract

Early life exposure to stress can lead to physiological and behavioural adaptations in offspring. Adaptive changes do not always benefit the organism, as it may result in adult diseases such as hypertension and diabetes in response to prenatal nutritional deficiencies. This thesis investigates the behavioural and genetic profiles of offspring exposed to two pathways of oxidative stress and DNA methylation: synthetic glucocorticoids and ionizing radiation. Synthetic glucocorticoids are able to bypass the placental enzymatic barrier and directly interfere with fetal gene expression by binding to glucocorticoid binding elements to either promote or inhibit expression as well as inducing changes in methylation of CpG islands. Ionizing radiation induces reactive oxygen species that will initiate DNA damage and oxidative stress leading to epigenetic modifications of gene regulation. The exposure to synthetic glucocorticoids induced adaptive phenotypical changes in Wistar-Kyoto offspring, inducing a stress-coping strategy and increased exploratory activity in combination with gene dysregulation in the prefrontal cortices. Exposure to ionizing radiation in C57Bl/6J mice did not induce significant behavioural changes; however, did elicit a few changes in gene expression in the prefrontal cortices, cerebral cortices, hippocampi, and cerebella that were sexually dimorphic. In contrast, the same radiation exposure study replicated in BALB/c mice induced extra-activity in offspring when faced with stress, arguably an adaptive response that may pose a risk to the animal. Significant gene dysregulation of oxidative stress and neuronal proliferation pathways was discovered in the prefrontal cortices, cerebral cortices, and cerebella of the BALB/c offspring. In consideration of the literature and the results of these studies, fetal programming of adult behavioural profiles may be accomplished through stress-induced genetic modifications.