Master of Science
Anatomy and Cell Biology
Willmore, Katherine. E.
Hardy, Daniel. B.
Prenatal alcohol exposure (PAE) is the leading preventable cause of adverse fetal outcomes. Individuals with PAE are susceptible to developing secondary deficits such as depression and metabolic disorders. These secondary deficits are variable, creating challenges for clinical research and identifying at-risk individuals. Juvenile stress has been proposed to contribute to this variation. We established pre-clinical mouse models of early, acute PAE and late-juvenile sub-chronic unpredictable mild stress (SUMS) to investigate the resulting depressive-like phenotypes and metabolic dysfunction in offspring. Behavioural testing revealed that PAE offspring were susceptible to multiple depressive-like phenotypes, whereas juvenile SUMS offspring displayed only a subset. Metabolic analyses revealed that both PAE and juvenile SUMS offspring were susceptible to metabolic dysfunction, with the greatest dysmetabolism observed in females. Overall, this study provides novel findings into variation of outcomes of PAE and juvenile SUMS, and robust models to further investigate the combination of PAE and juvenile SUMS.
Summary for Lay Audience
Prenatal alcohol exposure (PAE) is the leading preventable cause of birth defects. Despite the well-known risks, PAE is common, especially during early pregnancy. Most pregnancies are unplanned; although many women stop drinking alcohol when they find out they are pregnant, they may have unknowingly consumed alcohol during the first few weeks of pregnancy, a window of development that is vulnerable to the toxic effects of alcohol. Children with PAE are at-risk of developing depression and metabolic disorders later in life. However, not all individuals with PAE will develop these disorders. Likewise, the symptoms can differ greatly among individuals that do develop these disorders. Because of this variation, it is difficult to determine individuals at-risk of developing depression and metabolic disorders, hampering efforts to provide timely support for these individuals. Exposure to childhood stress is one factor that may contribute to these differential outcomes. In this study, I used mouse models to investigate depressive and metabolic outcomes in offspring following PAE or juvenile stress. I used behaviour tests to measure depression and observed that both PAE and juvenile stress offspring were susceptible to depressive symptoms, although juvenile stress offspring to a lesser extent. To measure metabolic function, I tested offspring for glucose metabolism and insulin levels, and observed that both PAE and juvenile stress offspring were susceptible to abnormal glucose metabolism and insulin levels, and in both groups, the effects were greatest in females. Finally, I investigated the co-occurrence of multiple depression and metabolic symptoms and observed that PAE offspring were more susceptible to having multiple symptoms simultaneously, whereas juvenile stress offspring typically only displayed one symptom. In the future, we plan to investigate the combined effects of PAE and juvenile stress on offspring susceptibility to developing depression and metabolic symptoms. Overall, these findings contribute to our understanding of the depressive and metabolic outcomes that can develop in offspring following PAE, and importantly, the variation in these outcomes. Ultimately, the goal of this work is to provide insight that can help guide clinical research and eventually clinical approaches to helping individuals who suffer from depression and metabolic disorders following PAE.
Pietrantonio, Amy, "Offspring Susceptibility of Developing Depressive-like Phenotypes and Metabolic Dysfunction Following Prenatal Alcohol Exposure and Juvenile Stress in a Mouse Model" (2023). Electronic Thesis and Dissertation Repository. 9457.
Available for download on Thursday, July 17, 2025