The Brain and Beyond: Maternal and Fetal Targets of Chronic Alcohol Exposure in Pregnancy

Abstract

Fetal alcohol spectrum disorders (FASD) persists as significant a public health threat partly due to enmeshment of drinking culture in modern society and partly because of the inherent complexity of alcohol-mediated pathogenesis. Discernment of FASD pathogenesis remains warranted because of the persistence of this threat coupled with extremely limited treatment options for affected patients. In the following studies (Chapters 2 & 3) we used classic approaches to describe a potential mechanism for alcohol-mediated pathogenesis in an atypical focal point of FASD investigation: the maternal uterine artery. The latter part of this work (Chapters 5 & 6) applied advanced technologies (HPLC, next-gen RNA sequencing) to identify new foci in a classic FASD target: the fetal brain. All studies were completed using a well characterized in vivo model of chronic binge prenatal alcohol exposure with clinical relevance. In the uterine artery, alcohol impaired the myogenic response and endothelial-mediated vasodilation, and dysregulation of the nitric oxide (NO) pathway and the enzyme responsible for NO synthesis (eNOS) were presented as susceptible candidates for this dysfunction. Brain studies described here bolster support for pursuing investigation of how excitatory amino acid imbalances influence neurotoxicity, expressly in the developing cerebellum and hippocampus. Transcriptome analysis also identified new hippocampal genes and canonical pathways of investigational interest based on their previous linkage to alcohol and FASD-adjacent pathology but were not tied to FASD contextually to FASD until now. Ultimately, we affirmed that alcohol use during pregnancy is unsafe and poses significant health risks not only to fetal development but to maternal physiology essential for sustaining this development.